Clinical trial NCT01360866
Conditions: Depressive Disorder Depression Depressive Disorder, Major Mood Disorders Mental Disorders
Keywords: OPC-34712 brexpiprazole Major Depressive Disorder Adjunctive Treatment
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2011-10-01; Completion date: 2017-05-18
Enrollment: 2944 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
To assess the long-term safety and tolerability of oral OPC-34712 (brexpiprazole), given in addition to an FDA approved antidepressant (ADT) for the treatment of adults with Major Depressive Disorder (MDD)

Detailed description:

Arms: arm 1: OPC-34712: Oral tablet; 0.5 to 3 mg/day Escitalopram: Oral tablet; 10 or 20 mg/day arm 2: OPC-34712: Oral tablet; 0.5 to 3 mg/day Fluoxetine: Oral capsules; 20 or 40 mg/day arm 3: OPC-34712: Oral tablet; 0.5 to 3 mg/day Paroxetine CR: Oral controlled-release tablets; 37.5 or 50 mg/day arm 4: OPC-34712: Oral tablet; 0.5 to 3 mg/day Sertraline: Oral tablets; 100, 150, or 200 mg/day arm 5: OPC-34712: Oral tablet; 0.5 to 3 mg/day Duloxetine: Oral delayed-release capsules; 40 or 60 mg/day arm 6: OPC-34712: Oral tablet; 0.5 to 3 mg/day Venlafaxine XR: Oral extended-release capsules; 75, 150, or 225 mg/day
Interventions: intervention 1: OPC-34712 intervention 2: Escitalopram intervention 3: Fluoxetine intervention 4: Paroxetine CR intervention 5: Sertraline intervention 6: Duloxetine intervention 7: Venlafaxine XR
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Capsule intervention 4: Controlled-release tablets intervention 5: Tablets intervention 6: Delayed-release capsules intervention 7: Extended-release capsules

Protocol documents:
Prot_000.pdf: 
Protocol: 331-10-238 
Confidential - Proprietary Information 
 Protocol number: 331-10-238. 
 Document title: A Long-term, Phase 3, Multicenter, Open-label Trial to 
Evaluate the Safety and Tolerability of Oral OPC-34712 as Adjunctive 
Therapy in Adults with Major Depressive Disorder, the Orion Trial. 
 Version number: Amendment 4. 
 Date of the document: 13 Jun 2014. 
 NCT number: NCT01360866. 


Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
REVISED CLINICAL PROTOCOL
A Long-term, Phase 3, Multicenter, Open-label Trial to Evaluate the Safety and 
Tolerability of Oral OPC-34712 as Adjunctive Therapy in Adults with Major Depressive 
Disorder, the Orion Trial
Protocol No. 331-10-238
IND No. 103,958
EudraCT No. 2011-001351-37
CONFIDENTIAL – PROPRIETARY INFORMATION
Drug Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland  20850, United States
Sponsor Representatives:
Phone 
Fax 
E-mail 
Phone 
Fax 
E-mail 
Phone 
Fax 
E-mail 
Immediately Reportable Event 
INC Research (see Appendix 2)
Issue Date:
11 May 2011
Date of Amendment 1:
23 Nov 2011
Date of Amendment 2:
16 Nov 2012
Date of Amendment 3:
11 Apr 2014
Date of Amendment 4:                                   13 Jun 2014


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Protocol Synopsis
Name of Company:  Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Product:  Brexpiprazole (OPC-34712)
Protocol #331-10-238
IND #103,958
EudraCT #2011-001351-37
Protocol Title:
A Long-term, Phase 3, Multicenter, Open-label Trial to 
Evaluate the Safety and Tolerability of Oral OPC-34712 as 
Adjunctive Therapy in Adults with Major Depressive 
Disorder, the Orion Trial
Clinical Phase:
3
Treatment Indication: Major Depressive Disorder (MDD)
Objective(s):
Primary:  To assess the long-term safety and tolerability of oral 
OPC-34712 (hereafter referred to by the generic name 
“brexpiprazole”) as adjunctive therapy in the treatment of 
adults with MDD.
Secondary:  To assess the long-term efficacy of oral 
brexpiprazole as adjunctive therapy in the treatment of adults 
with MDD.
Trial Design:
This is a multicenter, 26-week, open-label trial designed to 
assess the long-term safety, tolerability, and efficacy of 
adjunctive brexpiprazole in depressed adults on concurrent 
antidepressant therapy (ADT).  The trial will be conducted on 
an outpatient basis.  Enrollment into the trial will be drawn 
from eligible subjects who have completed the last scheduled 
visit of a double-blind, phase 3 brexpiprazole MDD trial and 
who, in the investigator’s judgment, could potentially benefit 
from adjunctive treatment with oral brexpiprazole for MDD.
The original 52 week open-label trial design has been modified 
in this Amendment 3 to shorten the duration of the trial to 26 
weeks; ongoing subjects who have not reached their Week 26 
visit will be re-consented and will follow Amendment 3 
schedule of assessments.  Ongoing subjects who have already 
completed their Week 26 visit at the time of Amendment 3 
will follow Amendment 3 week 26/ET schedule of 
assessments at their next scheduled visit.
The trial will be organized as follows:
Screening/Baseline:  Subjects will be screened for eligibility at 
the last scheduled visit of the prior double-blind phase 3 trial.  
Subjects will sign a separate informed consent form for 
participation in Trial 331-10-238 before any procedures 


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specific to the open-label trial are performed.  The assessments 
from the last scheduled visit of the prior double-blind phase 3 
trial will serve as the baseline measures for Trial 331-10-238 
for any assessment that is not unique to the open-label trial.  
Medical history will be updated, if necessary.
Treatment Phase:  Eligible subjects will receive daily 
treatment with open-label brexpiprazole and ADT as described 
in the Investigational Medicinal Product, Dose, Formulation, 
Mode of Administration section.  Visits will occur at the end 
of Weeks 1, 2, 4, 8, 14, 20, and 26.  All subjects will receive 
up to 26 weeks of open-label treatment in Trial 331-10-238.
Follow-up:  Subjects will be followed for safety via telephone 
contact or clinic visit 30 (+ 2) days after the last dose of open-
label medication.
Subject Population:
The subject population will consist of eligible subjects who, in 
the investigator’s judgment, could potentially benefit from 
adjunctive treatment with brexpiprazole for MDD according to 
the following criteria:

Subjects who participated in Trial 331-10-227,
Trial 331-10-228 or 331-13-214 will be eligible for the 
331-10-238 trial if they meet one of the following 
conditions:

Subjects who completed participation in the 
double-blind randomization phase (ie, Week 14 visit of 
Phase B) in Trial 331-10-227,  Trial 331-10-228 or 
Trial 331-13-214 or

Subjects who continued into Phase A+ (were not 
randomized into Phase B) at the end of prospective 
treatment (ie, Week 8 visit of Phase A) in 
Trial 331-10-227, Trial 331-10-228 or
Trial 331-13-214, BUT DID NOT meet criteria for 
remission (defined as a Montgomery Asberg 
Depression Rating Scale Total Score of 10) at the 
Week 14 visit of Phase A+ in Trial 331-10-227, Trial 
331-10-228 or Trial 331-13-214.

Subjects who participated in another double-blind phase 3 
brexpiprazole MDD trial will be eligible for 331-10-238 
Trial if they have completed the last scheduled visit of the 
prior double-blind phase 3 trial.

Subjects must qualify for Trial 331-10-238 at the last 
scheduled visit of the prior double-blind phase 3 trial and 


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must be able to continue therapy without interruption 
between the double-blind and open label trials.  Based on 
the projected enrollment estimates for the prior 
double-blind phase 3 brexpiprazole MDD trials, up to
approximately 3,000 subjects may enroll into 
Trial 331-10-238.
Investigational 
Medicinal Product, 
Dose, Formulation,
Mode of 
Administration:
Trial medication (ie, investigational medicinal product [IMP]) 
will be provided to the investigator(s) by the sponsor (or 
designated agent) and will consist of open-label brexpiprazole
and open-label ADTs.
Brexpiprazole:  Open-label brexpiprazole will be supplied as 
0.5, 1, 2, and 3-mg tablets packaged in weekly blister cards, 
each containing sufficient tablets for 7 (+ 2 days).  Blister
cards will be dispensed at each scheduled visit and at 
unscheduled visits if the dose of brexpiprazole is changed.  All 
doses of brexpiprazole should be taken orally once daily and 
can be administered without regard to meals.  For 
convenience, brexpiprazole may be taken with the first daily 
dose of ADT.
All subjects will be dosed as follows:

The first dose of open-label brexpiprazole will be taken one 
day after the last dose is taken for the prior double-blind, 
phase 3 brexpiprazole MDD trial so that adjunctive 
treatment will continue without interruption.  It is 
anticipated that the last dose of the double-blind, phase 3 
brexpiprazole MDD trial will be taken the day of the last 
scheduled visit, ie, the day of the Screening/Baseline visit 
for the open-label trial.  Subjects will initiate open-label 
dosing with brexpiprazole 0.5 mg/day for 1 week.  Subjects 
unable to tolerate brexpiprazole 0.5 mg/day must be 
withdrawn from the trial.

The dose of brexpiprazole will be increased to 1 mg/day at 
the Week 1 visit.  Subjects unable to tolerate brexpiprazole 
1 mg/day may decrease to 0.5 mg/day at any time after the 
Week 1 visit.

Investigators may further increase the dose to brexpiprazole 
2 mg/day and then to brexpiprazole 3 mg/day, with an 
interval of at least 5 days between dose increases.  An 
interval of at least 5 days between dose adjustments is 
recommended for dose decreases; however, the dose of 
brexpiprazole can be decreased at the investigator’s 
discretion in a step-wise manner at any time after the 


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Week 1 visit as needed for tolerability to a minimum of 
0.5 mg/day.  Dose adjustments must ultimately be made 
based upon the clinical judgment of the investigator as it 
relates to tolerability and therapeutic response.

Subjects who tolerate a reduced dose of brexpiprazole 
0.5 mg/day should be rechallenged with brexpiprazole 
1 mg/day at least once during the trial.  In addition, the
dose of brexpiprazole can be re-escalated as necessary 
following any dose decrease if, in the investigator’s 
judgment, rechallenge with a higher dose is warranted in 
order to identify an optimum dose for the subject.  Subjects 
must return to the clinic for unscheduled visits if changes to 
the dose of brexpiprazole (increases or decreases) are 
required between scheduled visits.
ADT:  During the Treatment Phase of Trial 331-10-238,
subjects will remain on the same assigned open-label ADT 
from the prior double-blind, phase 3 brexpiprazole MDD trial.  
The initial dose of ADT will be the same as the ADT dose 
taken on the last scheduled visit of the prior double-blind 
phase 3 trial.  It is recommended that the dose of ADT not be 
changed while the dose of brexpiprazole is being optimized 
(ie, no change to ADT up to and including the Week 4 visit).  
After the Week 4 visit, the dose of ADT can be modified if 
necessary to achieve optimum efficacy and tolerability for the 
treatment regimen using the following rules:  1) at least 5 days
must elapse between dose increases (either brexpiprazole or 
ADT), 2) an interval of at least 5 days between dose 
adjustments (either brexpiprazole or ADT) is recommended 
for dose decreases; however, the ADT dose can be decreased 
at the investigator’s discretion at any time as needed for 
tolerability, and 3) subjects must return to the clinic for 
unscheduled visits if changes to the ADT dose are required 
between scheduled visits.
ADTs for open-label treatment will be provided in commercial 
packaging (eg, bottles), with additional labeling for use in this 
trial, as necessary to fulfill regulatory requirements.  
Numbered ADT bottles to be dispensed to the subject will be 
assigned by the IVRS or IWRS.  The ADTs to be used in this 
trial, including allowable doses within the therapeutic range, 
are as follows:
Selective Serotonin Reuptake Inhibitors:


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Escitalopram (Lexapro) tablets, 10 and 20 mg/day
Fluoxetine (Prozac) capsules, 20 and 40 mg/day
Paroxetine CR (Paxil CR) controlled-release (CR) tablets, 
37.5 and 50 mg/day
Sertraline (Zoloft) tablets, 100, 150, and 200 mg/day
Serotonin-norepinephrine Reuptake Inhibitors:
Duloxetine (Cymbalta) delayed-release capsules, 40 and 
60 mg/day
Venlafaxine XR (Effexor XR) extended-release (XR) 
capsules, 75, 150, and 225 mg/day
All doses of ADT will be administered orally once daily 
except for duloxetine 40 mg/day that can be administered once 
daily or as duloxetine 20 mg twice daily, duloxetine 60 mg/day 
that can be administered once daily or as duloxetine 30 mg 
twice daily, and fluoxetine 40 mg/day that can be administered 
once daily or in divided doses twice daily.  All ADTs can be 
given without regard to meals, except for venlafaxine XR 
which should be taken with food.  Subjects should be 
instructed to take the ADT at approximately the same time 
each day, if possible.
Criteria for 
Evaluation:
Primary Outcome Variable:
The primary outcome variable is the safety and tolerability of 
brexpiprazole which will be assessed by examining the 
frequency and severity of adverse events (AEs).
Secondary Outcome Variables:
Efficacy:  Efficacy variables will be as follows:

Change from baseline in Clinical Global Impression -
Severity of Illness scale score;

Mean Clinical Global Impression - Improvement scale 
score;

Change from baseline in Sheehan Disability Scale score.

Change from baseline in the Inventory of Depressive 
Symptomatology (Self-Report) Total Score
Safety:  In addition to AEs, safety variables to be examined in 
this trial will include physical examinations, vital signs, body 
weight, waist circumference, clinical laboratory tests 
(hematology, serum chemistry, urinalysis, and pregnancy 
tests), and electrocardiograms (ECGs).  In general, descriptive 


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statistics of changes from baseline will be provided for safety 
variables based on all available data.  Prospectively defined 
criteria will be used to identify potentially clinically relevant 
abnormal values for clinical laboratory tests, vital signs, ECGs, 
and body weight.  Change from baseline in body mass index 
(derived programmatically from body weight and height 
measurements) will be summarized.  In addition to the analysis 
of standard safety variables, other safety variables including 
the Simpson Angus Scale, the Abnormal Involuntary 
Movement Scale, the Barnes Akathisia Rating Scale, the 
Columbia-Suicide Severity Rating Scale, and the 
Massachusetts General Hospital Sexual Functioning 
Questionnaire will also be evaluated.
Other Outcomes:  Responses to the Resource Utilization Form 
(RUF) will be summarized appropriately to explore the impact 
of treatment on health care resources.
Trial Duration:
The duration of this trial from first subject enrolled to last 
subject completed is estimated to be approximately 57 months, 
of which approximately 51 months are allotted for rollover of 
subjects from the prior double-blind phase 3 brexpiprazole 
MDD trials.  Individual participation for subjects who 
complete the trial without early withdrawal will be 
approximately 30 weeks (26 weeks of treatment and 30-day 
follow-up).


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Table of Contents
Protocol Synopsis...........................................................................................2
Table of Contents...........................................................................................8
List of In-text Tables ...................................................................................13
List of In-text Figures..................................................................................14
List of Appendices........................................................................................15
List of Abbreviations and Definitions of Terms .......................................16
1
Introduction ........................................................................................19
1.1
Nonclinical Studies............................................................................................20
1.1.1
Efficacy Pharmacology...................................................................................20
1.1.2
Safety Pharmacology......................................................................................21
1.2
Clinical Studies..................................................................................................21
1.2.1
Pharmacokinetics/Pharmacodynamics ...........................................................21
1.2.2
Major Depressive Disorder.............................................................................23
1.2.3
Schizophrenia .................................................................................................23
1.2.4
Other Indications ............................................................................................24
1.3
Known and Potential Risks and Benefits ..........................................................24
2
Trial Rationale and Objectives..........................................................25
2.1
Trial Rationale...................................................................................................25
2.2
Dosing Rationale...............................................................................................26
2.3
Trial Objectives.................................................................................................26
3
Trial Design.........................................................................................27
3.1
Type/Design of Trial .........................................................................................27
3.2
Trial Treatments ................................................................................................29
3.2.1
Treatment Administration...............................................................................29
3.2.1.1
Brexpiprazole..............................................................................................29
3.2.1.2
ADT ............................................................................................................30
3.2.2
Dose Adjustments...........................................................................................31
3.2.2.1
Brexpiprazole..............................................................................................31


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3.2.2.2
ADT ............................................................................................................32
3.3
Trial Population.................................................................................................33
3.4
Eligibility Criteria..............................................................................................33
3.4.1
Informed Consent ...........................................................................................33
3.4.2
Inclusion Criteria ............................................................................................34
3.4.3
Exclusion Criteria...........................................................................................35
3.5
Primary and Secondary Outcome Variables .....................................................38
3.5.1
Primary Outcome Variable.............................................................................38
3.5.2
Secondary Outcome Variables .......................................................................38
3.5.2.1
Efficacy Variables.......................................................................................38
3.5.2.2
Safety Variables ..........................................................................................39
3.5.2.3
Other Outcome Variables............................................................................39
3.6
Trial Procedures ................................................................................................39
3.6.1
Schedule of Assessments................................................................................43
3.6.1.1
Screening/Baseline......................................................................................43
3.6.1.2
Week 1 ........................................................................................................44
3.6.1.3
Week 2 ........................................................................................................44
3.6.1.4
Week 4 ........................................................................................................45
3.6.1.5
Week 8 ........................................................................................................46
3.6.1.6
Week 14 ......................................................................................................47
3.6.1.7
Week 20 ......................................................................................................48
3.6.1.8
End of Treatment (Week 26/ET).................................................................48
3.6.1.9
Follow-up....................................................................................................49
3.6.2
Safety Assessments.........................................................................................49
3.6.2.1
Clinical Laboratory Tests............................................................................49
3.6.2.2
Physical Examination and Vital Sign Assessments ....................................52
3.6.2.2.1
Physical Examination..............................................................................52
3.6.2.2.2
Vital Signs ...............................................................................................53
3.6.2.3
ECG Assessments .......................................................................................54
3.6.2.4
Other Safety Assessments...........................................................................54
3.6.2.4.1
Simpson Angus Scale (SAS)...................................................................55
3.6.2.4.2
Abnormal Involuntary Movement Scale (AIMS)....................................55


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3.6.2.4.3
Barnes Akathisia Rating Scale (BARS) ..................................................55
3.6.2.4.4
Suicidality................................................................................................56
3.6.2.4.5
Sexual Function.......................................................................................56
3.6.3
Efficacy Assessments .....................................................................................56
3.6.3.1
Clinical Global Impression - Severity of Illness Scale (CGI-S) .................57
3.6.3.2
Clinical Global Impression - Improvement Scale (CGI-I)..........................57
3.6.3.3
Subject Assessment Recording ...................................................................57
3.6.3.3.1
Sheehan Disability Scale (SDS)..............................................................57
3.6.3.3.2
Inventory of Depressive Symptomatology (Self-Report)........................57
3.6.3.3.3
Resource Utilization Form (RUF)...........................................................58
3.6.4
End of Trial.....................................................................................................58
3.7
Stopping Rules, Withdrawal Criteria and Procedures.......................................58
3.7.1
Entire Trial or Treatment Arm(s) ...................................................................58
3.7.2
Individual Center ............................................................................................58
3.7.3
Individual Subject...........................................................................................58
3.8
Screen Failures ..................................................................................................59
3.9
Definition of Completed Subjects.....................................................................59
3.10
Definition of Lost to Follow-up ........................................................................60
3.11
Subject Compliance...........................................................................................60
3.12
Protocol Deviations...........................................................................................60
4
Restrictions..........................................................................................61
4.1
Prohibited Medications......................................................................................61
4.2
Other Restrictions..............................................................................................62
4.2.1
Restricted Therapies and Precautions.............................................................62
4.2.2
Non-therapy Precautions and Restrictions......................................................64
4.2.2.1
Precautions..................................................................................................64
4.2.2.2
Restrictions..................................................................................................64
5
Reporting of Adverse Events.............................................................65
5.1
Definitions.........................................................................................................65
5.2
Eliciting and Reporting Adverse Events ...........................................................67
5.3
Immediately Reportable Events (IRE) ..............................................................67


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5.4
Potential Hy’s Law Cases..................................................................................68
5.5
Pregnancy..........................................................................................................68
5.6
Follow-up of Adverse Events............................................................................69
5.6.1
Follow-up of Non-serious Adverse Events.....................................................69
5.6.2
Follow-up of Post Trial Serious Adverse Events ...........................................70
5.6.3
Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact ..................................................................................70
6
Pharmacokinetic Analysis..................................................................70
7
Statistical Analysis..............................................................................70
7.1
Primary and Secondary Outcome Variable Analysis........................................70
7.1.1
Data Sets for Analysis ....................................................................................70
7.1.2
Handling of Missing Data...............................................................................71
7.1.3
Primary Outcome Analysis.............................................................................71
7.1.4
Secondary Outcome Analysis.........................................................................71
7.2
Sample Size.......................................................................................................71
7.3
Analysis of Demographic and Baseline Characteristics....................................72
7.4
Safety Analyses .................................................................................................72
7.4.1
Adverse Events ...............................................................................................72
7.4.2
Clinical Laboratory Data ................................................................................72
7.4.3
Physical Examination and Vital Signs Data ...................................................73
7.4.4
ECG Data........................................................................................................73
7.4.5
Other Safety Data ...........................................................................................73
7.5
Other Outcomes.................................................................................................73
8
Trial Drug Management ....................................................................74
8.1
Packaging and Labeling ....................................................................................74
8.2
Storage...............................................................................................................75
8.3
Accountability ...................................................................................................75
8.4
Returns and Destruction....................................................................................75
8.5
Reporting of Product Quality Complaints.........................................................75
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................76
8.5.2
Information Required for Reporting Purposes ...............................................76


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8.5.3
Return Process ................................................................................................77
8.5.4
Assessment/Evaluation...................................................................................77
9
Records Management.........................................................................77
9.1
Source Documents.............................................................................................77
9.2
Data Collection..................................................................................................77
9.3
File Management at the Trial Site.....................................................................78
9.4
Records Retention at the Trial Site....................................................................78
10
Quality Control and Quality Assurance...........................................79
10.1
Monitoring.........................................................................................................79
10.2
Auditing.............................................................................................................79
11
Ethics and Responsibility...................................................................79
12
Confidentiality ....................................................................................80
13
Amendment Policy..............................................................................80
14
References............................................................................................81


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List of In-text Tables
Table 3.2.1.1-1
Dosing Schedule for Brexpiprazole...............................................30
Table 3.2.1.2-1
Open-label Antidepressant Therapy (ADT) Allowable Doses 
Within Therapeutic Dose Ranges for MDD ..................................31
Table 3.2.2.1-1
Dose Modifications for Brexpiprazole...........................................32
Table 3.4.2-1
Inclusion Criteria ...........................................................................34
Table 3.4.3-1
Exclusion Criteria ..........................................................................35
Table 3.6-1
Schedule of Assessments...............................................................40
Table 3.6.2.1-1
Safety Clinical Laboratory Tests ...................................................51
Table 4.1-1
List of Medications Prohibited During the Trial............................61


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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................28


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List of Appendices
Appendix 1
Names of Sponsor Personnel .........................................................84
Appendix 2
Institutions Concerned With the Trial............................................86
Appendix 3
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance 89
Appendix 4
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .........................................................................90
Appendix 5
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance .........................................................................91
Appendix 6
Clinical Global Impression - Severity of Illness Scale 
(CGI-S)
92
Appendix 7
Clinical Global Impression - Improvement Scale (CGI-I) ............93
Appendix 8
Sheehan Disability Scale (SDS).....................................................94
Appendix 9
Inventory of Depressive Symptomatology (Self-Report) 
(IDS-SR) 96
Appendix 10
Simpson Angus Scale (SAS) .........................................................99
Appendix 11
Abnormal Involuntary Movement Scale (AIMS)........................102
Appendix 12
Barnes Akathisia Rating Scale (BARS).......................................103
Appendix 13
Columbia-Suicide Severity Rating Scale (C-SSRS)....................105
Appendix 14
Massachusetts General Hospital Sexual Functioning 
Questionnaire (MSFQ).................................................................110
Appendix 15
Resource Utilization Form (RUF) ...............................................111
Appendix 16
Protocol Amendment(s)/Administrative Change(s) ....................113


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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ADHD
Attention-deficit/hyperactivity disorder
ADT
Antidepressant therapy
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALP
Alkaline phosphatase
ALT (SGPT)
Alanine transaminase
APO
Apomorphine
aPTT
Activated partial thromboplastin time
AST (SGOT)
Aspartate transaminase
AUCt
Area under the concentration-time curve calculated to the last 
observable concentration at time t
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CGI-I
Clinical Global Impression - Improvement scale
CGI-S
Clinical Global Impression - Severity of Illness scale
Cmax
Maximum (peak) plasma concentration of the drug
CNS
Central nervous system
CPK
Creatine phosphokinase
CR
Controlled-release
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
D2
Dopamine type 2 receptor
D3
Dopamine type 3 receptor
DBP
Diastolic blood pressure
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition, Text Revision
ECG
Electrocardiogram
eCRF
Electronic case report form
ECT
Electroconvulsive therapy
EPS
Extrapyramidal symptoms
ET
Early termination
EudraCT
European Clinical Trial Data Base
FDA
Food and Drug Administration
5-HT
Serotonin
5-HT1A
Serotonin type 1A receptor
5-HT2A
Serotonin type 2A receptor
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
HAM-D17
17-item Hamilton Depression Rating Scale


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HbA1c
Glycosylated hemoglobin
HDL
High density lipoprotein
HEENT
Head, eyes, ears, nose, and throat
hERG
Human ether-a-go-go
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonization
ID
Identification
IDDM
Insulin-dependent diabetes mellitus
IDS-SR
Inventory of Depressive Symptomatology (Self-Report)
IEC
Independent ethics committee
IMP
Investigational medicinal product
INR
International Normalized Ratio
IRB
Institutional review board
IRE
Immediately reportable event
IUD
Intrauterine device
IVRS
Interactive voice response system
IWRS
Interactive web response system
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LOCF
Last-observation-carried-forward
MADRS
Montgomery Asberg Depression Rating Scale
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MSFQ
Massachusetts General Hospital Sexual Functioning 
Questionnaire
NMS
Neuroleptic malignant syndrome
OC
Observed cases
OPC
Otsuka Pharmaceutical Co.
OPDC
Otsuka Pharmaceutical Development & Commercialization, 
Inc.
OTC
Over-the-counter
PET
Positron emission tomography
PK
Pharmacokinetic
PT
Prothrombin time
QTc
Corrected QT interval
QTcB
QT interval as corrected by Bazett’s formula
QTcF
QT interval as corrected by Fridericia’s formula
QTcN
QT interval as corrected by the FDA Neuropharm Division 
formula
RBC
Red blood cell
RUF
Resource Utilization Form
SAE
Serious adverse event
SAS
Simpson Angus Scale
SBP
Systolic blood pressure


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SDS
Sheehan Disability Scale
SNRI
Serotonin-norepinephrine reuptake inhibitor
SSRI
Selective serotonin reuptake inhibitor
STAR*D
Sequenced Treatment Alternatives to Relieve Depression
T4
Thyroxine
TEAE
Treatment-emergent adverse event
tmax
Time to maximum (peak) plasma concentration
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBC
White blood cell
WOCBP
Women of childbearing potential
XR
Extended-release
Term
Definition
Investigational 
medicinal product 
(IMP)
For the purposes of this protocol, IMP refers to all trial 
medication supplied to the sites by the sponsor (or designated 
agent) and includes bottles of protocol-specified ADTs and blister 
cards containing brexpiprazole.
Remission
Montgomery Asberg Depression Rating Scale Total Score 10.


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1
Introduction
Major depressive disorder (MDD) is a debilitating and chronic illness characterized by a 
broad spectrum of emotional and physical symptoms.  Despite the availability of 
numerous treatments (eg, pharmacotherapy, cognitive behavioral psychotherapy, 
electroconvulsive therapy [ECT], etc.), achievement of consistent and favorable 
long-term outcomes still represents an unmet medical need.  For patients who experience 
an initial major depressive episode, the probability of experiencing another episode at 
some point in the future can be as high as 85%.1  In addition, 15% of patients may endure 
chronic symptoms after the first episode, while 35% may experience recurrent episodes.2  
Remission rates are low for initial antidepressant monotherapy treatment (less than 30%) 
and partial response is common.3  Incomplete response to treatment for MDD is 
associated with an increased risk of relapse, 4,5 impaired social and occupational 
functioning,6 and consequently, an increased economic burden.7, 8  Practice guidelines 
emphasize the importance of adequate treatment for MDD, including continuation of 
pharmacotherapy after an initial response is achieved to prevent relapse and maintenance 
treatment in individuals at risk of recurrence.9  Augmentation of ADT with agents such 
as lithium, thyroid hormone, anticonvulsants, or psychostimulants has also been explored 
as a possible means of achieving a more robust response to treatment.
Antipsychotics have been used in combination with antidepressants for treatment of 
psychotic or delusional forms of depression.  However, the use of antipsychotics as 
adjunctive therapy for non-psychotic depression has been limited due to safety concerns, 
specifically, the potential for extrapyramidal symptoms (EPS), hyperprolactinemia, 
weight gain, and excessive sedation.  The introduction of atypical antipsychotics has
created a renewed interest in adjunctive therapy for MDD, particularly for 
treatment-resistant MDD.  Although initial studies produced mixed results, several 
atypical antipsychotics have been shown to enhance the response to ADT.10,11,12,13,14
OPC-34712 (hereafter referred to by the generic name “brexpiprazole”) is an organic 
compound synthesized by Otsuka Pharmaceutical Co, Ltd, that is a 
 at 
, 
, and 
, an 
, and has a 
y for 
 and 
.  Details of the receptor affinity profile of 
brexpiprazole are summarized in Section 1.1.1.  Activity at dopamine and serotonin 
receptors has been shown to be useful in the treatment of psychiatric disorders, eg, 


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schizophrenia and bipolar mania.  Hence, brexpiprazole is expected to be a promising 
antipsychotic agent.  As the relative activity at these and other receptors appears to be 
related to the side effect profiles of antipsychotic drugs,15,16,17,18 brexpiprazole may have 
the potential to exhibit improved safety compared to other agents.  The more potent 
antagonism at 5-HT2A receptors for brexpiprazole relative to aripiprazole may afford a 
more favorable profile with respect to sleep quality; whereas, the low binding affinities 
for histamine and muscarinic receptors suggest that brexpiprazole may have less potential 
to cause H1-receptor-related weight gain than olanzapine.  Preclinical data also suggest 
that brexpiprazole will have lower potential for hyperprolactinemia than risperidone.  
Results from initial phase 2 trials showed brexpiprazole to be well tolerated by subjects 
with MDD and schizophrenia (see Section 1.3).
1.1
Nonclinical Studies
Efficacy and safety pharmacology are summarized in Section 1.1.1 and Section 1.1.2.  A 
complete description of the available data from nonclinical studies, including 
pharmacokinetic and toxicology studies in different animal species can be found in the 
Investigator Brochure.19
1.1.1
Efficacy Pharmacology
Brexpiprazole functions as a partial agonist at the D2 receptor.  In in vitro assay systems 
based on forskolin-induced cyclic AMP accumulation and calcium (Ca2+) mobilization in 
human dopamine D2L receptor-expressing cells, its intrinsic activity at the D2 receptor 
was slightly lower than that of aripiprazole, another D2 receptor partial agonist.  
Brexpiprazole inhibited apomorphine (APO)-induced hyperlocomotion, APO-induced 
stereotyped behavior, and conditioned avoidance response in rats, which are predictive 
animal models for antipsychotic-like efficacy.  The inhibitory effects of brexpiprazole
were more potent than those of aripiprazole.  Moreover, in contrast to the D2 receptor 
antagonist risperidone, brexpiprazole did not increase plasma prolactin levels in 
reserpine-treated rats, thus demonstrating a D2 receptor partial agonistic profile in vivo.  
Despite its lower intrinsic activity at the D2 receptor, the in vivo catalepsy liability of 
brexpiprazole, an index of EPS, was similar to that of aripiprazole, but still lower than 
that of the typical antipsychotic haloperidol.  Furthermore, brexpiprazole showed high 
binding affinity for the 5-HT2A receptor and dose-dependently inhibited 
()-2,5-dimethoxy-4-iodoamphetamine-induced head twitch response in rats, indicating 
that the compound has 5-HT2A receptor antagonistic activity; the effect of brexpiprazole
was more potent than that of aripiprazole.  In addition, brexpiprazole exhibited high 


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binding affinities for the D3 and 5-HT1A receptors, acting as a partial agonist at these 
receptors.
1.1.2
Safety Pharmacology
In safety pharmacology studies in rats at an oral dose of 30 mg/kg or higher, 
brexpiprazole induced pharmacologically mediated clinical signs considered to be due to 
depression of the central nervous system (CNS) and dose-dependent decreases in body 
temperature.  When orally administered at up to 30 mg/kg in conscious male beagle dogs, 
brexpiprazole showed no effect on respiratory parameters or heart rate at any dose tested.  
Brexpiprazole decreased blood pressure at doses of 3 mg/kg or higher and prolonged both 
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 (hERG) current in Chinese 
hamster ovary cells (CHO-K1) 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 blood pressure 
decreasing effect of brexpiprazole was suggested to result from a blockade of the 
1-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 Studies
1.2.1
Pharmacokinetics/Pharmacodynamics
The pharmacokinetics 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 pharmacokinetics were linear 
following single oral doses of brexpiprazole 0.2 to 8 mg to healthy subjects.  The 


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terminal phase elimination half-life of brexpiprazole and DM-3411 was 48.3 to 
80.8 hours and 48.6 to 77.5 hours, respectively.  The median time to maximum (peak) 
plasma concentration (tmax) occurred at approximately 2 to 6 hours postdose for 
brexpiprazole and at approximately 10 to 24 hours postdose for DM-3411.  In healthy 
subjects, administration of single-dose brexpiprazole with a high-fat meal did not affect 
its rate and extent of absorption.
Steady state pharmacokinetics 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 (Cmax) and area under the 
concentration-time curve calculated to the last observable concentration at time t (AUCt) 
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 CYP3A4 and CYP2D6 isozymes and was not an inhibitor of CYP3A4, CYP2B6, 
CYP2D6, or P-glycoprotein.  Coadministration 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.  Of note, administration of
brexpiprazole with fluoxetine, paroxetine, or duloxetine (MDD medications 
coadministered in this trial) may potentially increase brexpiprazole plasma concentrations 
by up to 2-fold.
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 pharmacokinetic/pharmacodynamic modeling, it was predicted that the 


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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.
Additional information on the pharmacokinetics/pharmacodynamics of brexpiprazole and 
its metabolites in humans can be found in the Investigator Brochure.19
1.2.2
Major Depressive Disorder
The efficacy of brexpiprazole as adjunctive therapy for the treatment of MDD has been 
studied in one completed placebo-controlled trial (Trial 331-08-211).  An additional 
placebo-controlled efficacy trial (Trial 331-09-222) and one long-term open-label safety 
trial (Trial 331-08-212) are ongoing.  Trial 331-08-211 was a multicenter, randomized, 
double-blind, placebo-controlled trial designed to assess the safety and efficacy of 
brexpiprazole (0.15 to 2 mg daily) as adjunctive treatment to an assigned open-label ADT 
in subjects with MDD who have demonstrated an incomplete response to prospective 
treatment with the same ADT.  Subjects with an incomplete response after 8 weeks of 
treatment with single-blind placebo plus open-label ADT were randomized to 6 weeks of 
double-blind treatment with either brexpiprazole-plus-ADT or placebo-plus-ADT.  
Responders continued to receive placebo-plus-ADT for an additional 6 weeks.  
Randomized subjects received brexpiprazole 0.15 mg/day, 0.50 0.25 mg/day, 
1.5 0.50 mg/day, or matching placebo.  Subjects randomized to the brexpiprazole 
0.50 0.25 mg/day and brexpiprazole 1.5 0.50 mg/day arms were titrated to the target 
doses (0.50 and 1.5 mg, respectively) over a 2-week period.  Dose adjustments were 
permitted after the subjects received 1 week of treatment at the target dose.  Subjects who 
could not tolerate the lowest dose (brexpiprazole 0.15, 0.25, or 1.0 mg/day or matching 
placebo, respectively) were to be discontinued from the trial.  In this trial, adjunctive 
brexpiprazole dosed at 1.5 0.50 mg/day was superior to adjunctive placebo with respect 
to the primary endpoint (change from Week 8 to Week 14 in Montgomery Asberg 
Depression Rating Scale [MADRS] Total Score) and several secondary efficacy 
endpoints.20  Ongoing Trial 331-09-222 is of similar design to Trial 331-08-211, but is 
exploring an expanded dose range (brexpiprazole 1 to 3 mg/day).
1.2.3
Schizophrenia
A dose-ranging, placebo-controlled trial for the monotherapy treatment of adults with 
schizophrenia has been performed in subjects experiencing an acute exacerbation of 
schizophrenia (Trial 331-07-203).  The outcome of this trial suggests an active dose range 


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of brexpiprazole 1 to 6 mg/day for the treatment of schizophrenia.21  In addition to the 
double-blind, placebo-controlled trial, a long-term open-label safety trial 
(Trial 331-08-210) is ongoing.
1.2.4
Other Indications
Brexpiprazole is being investigated in a proof-of-concept trial in adult ADHD 
(Trial 331-08-213).  This is a multicenter, randomized, double-blind, placebo-controlled, 
flexible-dose trial in which adults with ADHD who have an incomplete/partial response 
to stimulant therapy in a prospective treatment phase are randomized to double-blind 
treatment with either brexpiprazole-plus-stimulant or placebo-plus-stimulant.  This trial is 
ongoing; therefore, results are not available.
1.3
Known and Potential Risks and Benefits
As of 31 Dec 2010, 14 clinical trials involving brexpiprazole have been completed 
worldwide, including 10 in the United States (US), 1 in multiple countries (including the 
US), 2 in Japan, and 1 in Korea.  An additional 4 trials are currently ongoing (3 in the US
and 1 in multiple countries [including the US]).  The collective trials can be classified as 
follows:  four phase 1 pharmacokinetic (PK) trials in healthy subjects, 2 drug interaction 
trials in healthy subjects, one phase 1 PET trial in healthy subjects, one phase 1b 
polysomnography trial in subjects with schizophrenia, five phase 1 PK trials in specific 
patient populations, and six phase 2 efficacy and/or safety trials.  Brexpiprazole has been 
well tolerated by healthy volunteers at single doses up to 6 mg and at multiple doses up to 
2 mg/day.  In patient trials, brexpiprazole has been well tolerated at multiple doses up to 
12 mg/day in subjects with schizophrenia or schizoaffective disorder, up to 4 mg/day in 
subjects with MDD who received concomitant ADT, and up to 4 mg/day in adults with 
ADHD who received concomitant stimulant therapy.
In the 11 completed phase 1 and 2 clinical trials performed under the US IND (two phase 
2 trials, one phase 1b trial, and eight phase 1 trials), 673/973 (69.2%) subjects who 
received brexpiprazole either alone or coadministered with another marketed medication
reported at least one treatment-emergent adverse event (TEAE) compared to 
158/253 (62.5%) subjects who received placebo either alone or coadministered with 
another marketed medication.  The most common TEAEs reported for brexpiprazole in 
the completed trials (5% in the total brexpiprazole group and more than the total 
placebo group) were headache (10.6%), dizziness (8.0%), anxiety (7.1%), akathisia 
(7.0%), and nausea (5.5%).  In the total placebo group, TEAEs that occurred in 5% of 
subjects were headache (9.9%), insomnia (9.1%), and constipation (5.5%).


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One death was reported in the completed phase 2 trial in adults with acute schizophrenia 
(Trial 331-07-203).  The subject was not on any investigational medicinal product (IMP) 
at the time of death, and the death was not considered by the investigator to be related to 
IMP.  The incidence of serious TEAEs (fatal and non-fatal) that were reported during 
treatment with brexpiprazole administered either alone or coadministered with another 
medication (19/973 subjects, 2.0%) was comparable to placebo administered either alone 
or coadministered with another medication (4/253 subjects, 1.6%).  Furthermore, 
treatment with brexpiprazole does not appear to promote suicidal behavior in subjects 
with MDD or schizophrenia.
Brexpiprazole did not result in any consistent, clinically relevant changes in laboratory 
values, vital signs (blood pressure or heart rate), or electrocardiogram (ECG) parameters 
in the completed phase 1 and 2 clinical trials in subjects with MDD or schizophrenia.  
Statistically significant increases in weight were observed with brexpiprazole relative to 
placebo in both sample populations.  Brexpiprazole exhibited a favorable profile with 
respect to movement disorders in subjects with MDD at doses up to 3 mg/day
(Trial 331-09-221) and in subjects with schizophrenia at doses up to 12 mg/day
(Trial 331-08-205).  In the dose-ranging trial that enrolled subjects who were 
experiencing an acute exacerbation of schizophrenia (Trial 331-07-203), an increase in 
the incidence of EPS was observed at the highest dose (ie, brexpiprazole 
5.0 1.0 mg/day).
Please refer to the current Investigator Brochure for a summary of available nonclinical 
and clinical safety data.19
Risks associated with use of the selective serotonin reuptake inhibitors (SSRIs) and 
serotonin-norepinephrine reuptake inhibitors (SNRIs) used in Trial 331-10-238 can be 
found in the prescribing information for the open-label ADTs.
2
Trial Rationale and Objectives
2.1
Trial Rationale
Investigations of the interactions between serotonin and norepinephrine following 
sustained treatment with SSRIs provide a pharmacological basis for use of atypical 
antipsychotics as an augmentation strategy in treatment-resistant MDD.  At the cellular 
level, increased serotonergic activity from prolonged reuptake inhibition appears to 
attenuate the firing of noradrenergic neurons indirectly through increased activation of 


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5-HT2A receptors.22  The resulting decrease in noradrenergic tone may contribute to the 
suboptimal therapeutic response observed clinically with long-term administration of 
SSRIs.23  As brexpiprazole demonstrated antagonism at 5-HT2A receptors, the attenuated 
response to SSRIs may be reversed with coadministration of brexpiprazole and SSRIs, 
thus enhancing clinical outcomes.
Because the management of MDD may require prolonged administration of ADT(s) with 
or without an augmenting agent, safety monitoring for longer than the period required to 
achieve initial response is warranted.  In the brexpiprazole clinical development program 
for MDD, phase 2 and phase 3 trials examined the 6-week safety and efficacy of 
brexpiprazole augmentation of ADTs.  For phase 2, subjects who completed either of the 
trials had the option to enroll into an open-label rollover trial in which they received 
brexpiprazole for up to 52 weeks (Trial 331-08-212).  The current trial (Trial 331-10-238) 
provides an open-label rollover option for double-blind phase 3 brexpiprazole MDD trials
and will expand on the knowledge gained in these trials by assessing the long-term 
safety, tolerability, and efficacy of brexpiprazole when administered concomitantly with 
antidepressant medications.
2.2
Dosing Rationale
A dose range of brexpiprazole 0.5 to 3 mg/day was selected for the current open-label 
trial to encompass the dose range of the double-blind efficacy trials (ie, brexpiprazole 
1 to 3 mg/day) and to include an option for a reduced dose for tolerability (ie, 
0.5 mg/day) in order to maximize subject retention in the long-term trial.  Therapeutic 
dose ranges of ADT are based on product labels and clinical practice.  Data from phase 1 
drug interaction trials (Trial 331-08-207 and Trial 331-08-208) indicated that 
coadministration of CYP2D6 inhibitors (eg, paroxetine, fluoxetine, and duloxetine) with 
brexpiprazole could cause potentially higher plasma concentrations of brexpiprazole (up 
to 2-fold).  In order to limit the potential higher exposure of brexpiprazole when 
coadministered with such inhibitors, the upper limit of the therapeutic ADT dose is
limited to 40 mg for fluoxetine, 50 mg for paroxetine CR, and 60 mg for duloxetine in the 
current trial.
2.3
Trial Objectives
Primary:
To assess the long-term safety and tolerability of oral brexpiprazole as 
adjunctive therapy in the treatment of adults with MDD.


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Secondary:
To assess the long-term efficacy of oral brexpiprazole as adjunctive 
therapy in the treatment of adults with MDD.
3
Trial Design
3.1
Type/Design of Trial
This is a multicenter, 26-week, open-label trial designed to assess the long-term safety, 
tolerability, and efficacy of adjunctive brexpiprazole in depressed adults on concurrent 
ADT.  The trial will be conducted on an outpatient basis.  Enrollment into the trial will be 
drawn from eligible subjects who have completed the last scheduled visit of a
double-blind phase 3 brexpiprazole MDD trial and who, in the investigator’s judgment, 
could potentially benefit from adjunctive treatment with oral brexpiprazole for MDD.  A 
schematic of the trial design is presented in Figure 3.1-1.
The trial will be organized as follows:
Screening/Baseline:  Subjects will be screened for eligibility at the last scheduled visit of 
the prior double-blind phase 3 trial.  Subjects will sign a separate informed consent form 
(ICF) for participation in Trial 331-10-238 before any procedures specific to the 
open-label trial are performed.  The assessments from the last scheduled visit of the prior 
double-blind phase 3 trial will serve as the baseline measures for Trial 331-10-238 for 
any assessment that is not unique to the open-label trial.  Medical history will be updated, 
if necessary.
Treatment Phase:  Eligible subjects will receive daily treatment with open-label 
brexpiprazole and ADT as described in Section 3.2.  Visits will occur at the end of 
Weeks 1, 2, 4, 8, 14, 20, and 26.  All subjects will receive up to 26 weeks of open-label 
treatment in Trial 331-10-238 and follow the schedule of assessments described in Table 
3.6-1.
Follow-up:  Subjects will be followed for safety via telephone contact or clinic visit 
30 (+ 2) days after the last dose of open-label medication.


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Figure 3.1-1
Trial Design Schematic
Follow-up
30 (+ 2) days 
after last dose
Eligible subjects who
completed the last 
scheduled visit of a double-
blind phase 3 brexpiprazole 
MDD trial and who could 
potentially benefit from 
adjunctive treatment with 
brexpiprazole for MDD per 
investigator
Telephone 
contact or clinic 
visit
Visits at Weeks 1, 2, 4, 8, 14, and 20
(Unscheduled visits as necessary for dose adjustments)
Week 26 visit of 
Trial 331-10-238
Last scheduled visit of 
a double-blind phase 3 
brexpiprazole MDD
trial
Screening/Baselinea
Open-label Brexpiprazole (0.5 to 3 mg/day) + ADT
Treatment Phase
a
Occurs simultaneously with the last scheduled visit of a double-
blind phase 3 brexpiprazole MDD trial.


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3.2
Trial Treatments
3.2.1
Treatment Administration
3.2.1.1
Brexpiprazole
The first dose of open-label brexpiprazole will be taken one day after the last dose is 
taken for the prior double-blind, phase 3 efficacy trial so that adjunctive treatment will 
continue without interruption.  It is anticipated that the last dose of the double-blind, 
phase 3 efficacy trial will be taken the day of the last scheduled visit ie, the day of the 
Screening/Baseline visit for the open-label trial.  Subjects will initiate open-label dosing 
with brexpiprazole 0.5 mg/day for 1 week.  Subjects unable to tolerate brexpiprazole 
0.5 mg/day must be withdrawn from the trial.  The dose of brexpiprazole will be 
increased to 1 mg/day at the Week 1 visit.  Subjects unable to tolerate brexpiprazole 
1 mg/day may decrease to 0.5 mg/day at any time after the Week 1 visit.
Investigators may further increase the dose to brexpiprazole 2 mg/day and then to 
brexpiprazole 3 mg/day, with an interval of at least 5 days between dose increases.  An 
interval of at least 5 days between dose adjustments is recommended for dose decreases; 
however, the dose of brexpiprazole can be decreased at the investigator’s discretion in a 
step-wise manner at any time after the Week 1 visit as needed for tolerability to a 
minimum of 0.5 mg/day.  Dose adjustments must ultimately be made based upon the 
clinical judgment of the investigator as it relates to tolerability and therapeutic response.  
Subjects must return to the clinic for unscheduled visits if changes to the dose of 
brexpiprazole (increases or decreases) are required between scheduled visits.  The dosing 
schedule is summarized in Table 3.2.1.1-1.  Additional information on dose adjustments 
is provided in Section 3.2.2.1.
All doses of brexpiprazole should be taken orally once daily and can be administered 
without regard to meals.  For convenience, brexpiprazole may be taken with the first 
daily dose of ADT.


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Table 3.2.1.1-1
Dosing Schedule for Brexpiprazole
IMP
Trial Visit
Screening/ 
Baseline
Week 1a
Week 2b
Week 4b
Visits at Weeks 8, 14, and 20 b
Brexpiprazole
(mg/day)c
0.5
1
0.5, 1 or 2
0.5, 1, 2 or 3
0.5, 1, 2, or 3
ADTd
Final dose 
from double-
blind trial
No changee
No changee
No changee
Change to ADT dose is permitted as 
described in Section 3.2.2.2.
aSubjects unable to tolerate brexpiprazole 1 mg/day may decrease to 0.5 mg/day at any time after the 
Week 1 visit.
bStep-wise increases in the dose of brexpiprazole must be separated by at least 5 days.  Although step-
wise decreases in the brexpiprazole dose are permitted at any time after the Week 1 visit to a 
minimum of 0.5 mg/day, an interval of at least 5 days between dose adjustments is recommended.  
See Section 3.2.2.1 for additional information on dose adjustments.  Subjects must return to the clinic 
for unscheduled visits if changes to the dose of brexpiprazole (increases or decreases) are required 
between scheduled visits.
cSubjects unable to tolerate the minimum dose of brexpiprazole (ie, 0.5 mg/day) must be withdrawn 
from the trial.
dThroughout Trial 331-10-238, the subject must remain on the same ADT that was assigned in the prior 
double-blind phase 3 trial.
eIt is recommended that the dose of ADT not be changed while the dose of brexpiprazole is being 
optimized.
3.2.1.2
ADT
During the Treatment Phase of Trial 331-10-238, subjects will remain on the same 
assigned open-label ADT from the prior double-blind, phase 3 efficacy trial.  Numbered 
ADT bottles to be dispensed to the subject will be assigned by the IVRS or IWRS.  The 
initial dose of ADT for the open-label trial will be the same as the ADT dose taken on the 
last scheduled visit of the prior double-blind phase 3 trial.  The ADTs to be used in 
Trial 331-10-238, including allowable doses within the therapeutic range, are listed in 
Table 3.2.1.2-1.  Adjustments to the ADT dose are permitted as described in 
Section 3.2.2.2.  If in the clinical judgment of the investigator a subject should 
permanently discontinue their assigned ADT or change to a different ADT, the subject 
must be withdrawn from the trial.  All doses of ADT will be administered orally once 
daily except for duloxetine 40 mg/day that can be administered once daily or as 
duloxetine 20 mg twice daily, duloxetine 60 mg/day that can be administered once daily 
or as duloxetine 30 mg twice daily, and fluoxetine 40 mg/day that can be administered 
once daily or in divided doses twice daily.  All ADTs can be given without regard to 
meals, except for venlafaxine XR, which should be taken with food.  Subjects should be 
instructed to take the ADT at approximately the same time each day, if possible.


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Table 3.2.1.2-1
Open-label Antidepressant Therapy (ADT) Allowable Doses 
Within Therapeutic Dose Ranges for MDD
Generic Name
Brand Name
Dosage Form
Allowable Doses 
Within Therapeutic 
Dose Range (mg/day)a
SSRIs
Escitalopram
Lexapro
Tablet
10 and 20
Fluoxetine
Prozac
Capsule
20 and 40
Paroxetine CR
Paxil CR
Controlled-release 
Tablet
37.5 and 50
Sertraline
Zoloft
Tablet
100, 150, and 200
SNRIs
Duloxetine
Cymbalta
Delayed-release capsule
40 and 60
Venlafaxine XR
Effexor XR
Extended-release 
capsule
75, 150, and 225
CR = controlled release; XR = extended release.
aAll doses are to be administered orally once daily except for duloxetine 40 mg/day that can be
administered once daily or as duloxetine 20 mg twice daily, duloxetine 60 mg/day that can be 
administered once daily or as duloxetine 30 mg twice daily, and fluoxetine 40 mg/day that can be 
administered once daily or in divided doses twice daily.  All doses should be taken at approximately 
the same time each day, if possible.
3.2.2
Dose Adjustments
Dose modifications to both brexpiprazole and ADT will be permitted to optimize 
therapeutic benefit according to the rules described below for each treatment.  However, 
the dose of brexpiprazole and the dose of ADT should not both be changed at the same 
visit.
3.2.2.1
Brexpiprazole
Allowable dose modifications to the daily dose of brexpiprazole are summarized in Table 
3.2.2.1-1.  At least 5 days must elapse between dose increases for brexpiprazole.  An 
interval of at least 5 days between dose adjustments is recommended for dose decreases; 
however, the dose of brexpiprazole can be decreased at the investigator’s discretion in a 
step-wise manner at any time after the Week 1 visit as needed for tolerability to a 
minimum of 0.5 mg/day.  Subjects must return to the clinic for unscheduled visits if 
changes to the dose of brexpiprazole (increases or decreases) are required between 
scheduled visits.
Subjects who are unable to tolerate the 0.5 mg/day dose of brexpiprazole must be 
withdrawn from the trial.  However, subjects whose brexpiprazole dose is decreased to 


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0.5 mg/day and who demonstrate adequate tolerability at this dose should be rechallenged 
with a 1 mg/day dose within approximately 6 to 8 weeks after the dose is decreased to 
0.5 mg/day.  If tolerability issues arise following the rechallenge, the dose may be 
decreased again to 0.5 mg/day.  Further rechallenge at 1 mg/day may be performed at the 
investigator’s discretion.  The dose of brexpiprazole can be increased as necessary 
following a dose decrease at any other dose if, in the investigator’s judgment, rechallenge 
with a higher dose is warranted in order to identify an optimum dose for the subject.  
Dose adjustments must ultimately be made based upon the clinical judgment of the 
investigator as it relates to tolerability and therapeutic response.
Table 3.2.2.1-1
Dose Modifications for Brexpiprazole
Dose Increasesa,b
Current Dose of Brexpiprazole
Incremental Increase
Adjusted Brexpiprazole dose
0.5 mg
0.5 mg
1 mg
1 mg
1 mg
2 mg
2 mg
1 mg
3 mg
Dose Decreasesb,c
Current Dose of Brexpiprazole
Incremental Decrease
Adjusted Brexpiprazole dose
0.5 mg
Not permittedd
0.5 mgd
1 mg
0.5 mg
0.5 mg
2 mg
1 mg
1 mg
3 mg
1 mg
2 mg
aAt least 5 days must elapse between dose increases.
bSubjects must return to the clinic for unscheduled visits if changes to the dose of brexpiprazole
(increases or decreases) are required between scheduled visits.
cAn interval of at least 5 days between dose adjustments is recommended for dose decreases; however, 
the investigator may decrease the dose of brexpiprazole at any time after the Week 1 visit for 
tolerability.
dSubjects unable to tolerate 0.5 mg/day of brexpiprazole must be withdrawn from the trial.
3.2.2.2
ADT
It is recommended that the dose of ADT not be changed while the dose of brexpiprazole
is being optimized (ie, no change to ADT up to and including the Week 4 visit).  After the 
Week 4 visit, the dose of ADT can be modified if necessary to achieve optimum efficacy 
and tolerability for the treatment regimen using the following rules:  1) at least 5 days
must elapse between dose increases (either brexpiprazole or ADT), 2) an interval of at 
least 5 days between dose adjustments (either brexpiprazole or ADT) is recommended for 
dose decreases; however, the ADT dose can be decreased at the investigator’s discretion 
at any time as needed for tolerability, and 3) subjects must return to the clinic for 
unscheduled visits if changes to the ADT dose are required between scheduled visits.


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The Sponsor reserves the right to use a generic equivalent should any marketed 
antidepressant become unavailable during the course of the trial.
3.3
Trial Population
The trial population will consist of eligible subjects who, in the investigator’s judgment, 
could potentially benefit from adjunctive treatment with brexpiprazole for MDD 
according to the following criteria:

Subjects who participated in Trial 331-10-227,  Trial 331-10-228 or
Trial 331-13-214 will be eligible for Trial 331-10-238 if they meet one of the 
following conditions:

Subjects who completed participation in the double-blind randomization phase 
(ie, Week 14 visit of phase B) in Trial 331-10-227, Trial 331-10-228 or
Trial 331-13-214 or

Subjects who continued into Phase A+ (were not randomized into Phase B) at the 
end of prospective treatment (ie, Week 8 visit of Phase A) in Trial 331-10-227,  
Trial 331-10-228 or Trial 331-13-214, BUT DID NOT meet criteria for remission 
(defined as a MADRS Total Score of 10) at the Week 14 visit of Phase A+ in 
Trial 331-10-227, Trial 331-10-228 or Trial 331-13-214.

Subjects who participated in a double-blind phase 3 brexpiprazole MDD trial will be
eligible for the 331-10-238 trial if they have completed the last scheduled visit of the 
double-blind phase 3 trial.

Subjects must qualify for Trial 331-10-238 at the last scheduled visit of the prior 
double-blind phase 3 trial and must be able to continue therapy without interruption 
between the double-blind and open-label trials.  Based on the projected enrollment 
estimates for the prior double-blind phase 3 brexpiprazole MDD trials, up to
approximately 3,000 subjects may enroll into Trial 331-10-238.
3.4
Eligibility Criteria
3.4.1
Informed Consent
Written informed consent will be obtained from all subjects (or their guardian or legal 
representative, as applicable for local laws). Consent will be documented on a written 
ICF. The ICF will be approved by the same Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) that approves this protocol.  Each ICF will comply with the
FDA regulations in 21 Code of Federal Regulations (CFR) Part 50, International 
Conference on Harmonization Good Clinical Practice (ICH GCP), and local regulatory 
requirements. The investigator agrees to obtain approval from the sponsor of any written 
ICF used in the trial, prior to submission to the IRB/IEC.


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Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent.  However, informed consent must be obtained and 
documented prior to initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).  
The ICF for the open-label trial may be provided to potential candidates for review and 
discussion toward completion of the prior double-blind phase 3 trial, but the form must 
not be signed until the day of the Screening/Baseline visit for Trial 331-10-238 (ie, the 
last scheduled visit of the prior double-blind phase 3 trial).
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator (or a qualified designee), the 
IRB/IEC-approved written ICF will be signed and dated by both the subject and the 
person obtaining consent (investigator or designee), as well as by any other parties 
required by the IRB/IEC.  The subject will receive a copy of the signed ICF; the original 
shall be kept on file by the investigator.
In addition to the English version of the ICF, the document may also be translated by the
central translation vendor into local languages for use in this trial.  Translation with back-
translation for confirmation will be utilized to ensure accuracy.
3.4.2
Inclusion Criteria
Subjects are required to meet the following inclusion criteria:
Table 3.4.2-1
Inclusion Criteria
All Subjects
1.
Subjects who are able to provide written informed consent and/or consent obtained from a legally 
acceptable representative (as required by IRB/IEC) prior to the initiation of any protocol-required 
procedures.
2.
Ability, in the opinion of the principal investigator, to understand the nature of the trial and follow 
protocol requirements, including the prescribed dosage regimens, tablet/capsule ingestion, and 
discontinuation of prohibited concomitant medication; to read and understand the written word in 
order to complete subject-reported outcomes measures; and to be reliably rated on assessment 
scales.
3
Male and female outpatients 18 to 65 years of age, inclusive, at the time of informed consent for 
Trial 331-10-238.
4
Subjects willing to discontinue all prohibited psychotropic medications starting from the time of 
signing the ICF and during the trial period (refer to Section 4).


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Table 3.4.2-1
Inclusion Criteria
331-10-227,  331-10-228 and 331-13-214 Subjects Only
5.
Subjects who, in the opinion of the investigator, could potentially benefit from administration of 
brexpiprazole as adjunctive therapy to their antidepressant therapy and who meet one of the 
following criteria:
a) Subjects who completed participation in the double-blind randomization phase (ie, Week 14 
visit of Phase B) in Trial 331-10-227, Trial 331-10-228 or Trial 331-13-214 or
b) Subjects who continued into Phase A+ (were not randomized into Phase B) at the end of 
prospective treatment (ie, Week 8 visit of Phase A) in Trial 331-10-227,  Trial 331-10-228 or 
Trial 331-13-214, BUT DID NOT meet criteria for remission (defined as a MADRS Total 
Score of 10) at the Week 14 visit of Phase A+ in Trial 331-10-227,  Trial 331-10-228 or Trial 
331-10-227, Trial 331-10-228 or Trial 331-13-214...
Eligible Subjects From Other Double-Blind Phase 3 Brexipiprazole MDD Trials
6.
Subjects who completed the last scheduled visit of the prior double-blind phase 3 trial, and who in 
the opinion of the investigator, could potentially benefit from administration of brexpiprazole as 
adjunctive therapy to their antidepressant therapy.
3.4.3
Exclusion Criteria
Subjects entering the open-label trial at the last scheduled visit of the prior double-blind 
phase 3 trial will be excluded from Trial 331-10-238 if they meet any of the following 
exclusion criteria.
Table 3.4.3-1
Exclusion Criteria
Sex and Reproductive Status
1.
Sexually active females of childbearing potential (see Section 5.5) and male subjects who are not 
practicing two different methods of birth control with their partner during the trial and for 30 days 
after the last dose of trial medication or who will not remain abstinent during the trial and for 30 
days after the last dose.  If employing birth control, each couple must use two of the following 
precautions:  vasectomy, tubal ligation (subject or partner), vaginal diaphragm, IUD, birth control 
pill, birth control implant, birth control depot injections, condom, or sponge with spermicide.
2.
Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving 
open-label brexpiprazole in Trial 331-10-238.
Administrative
3.
Subjects with a major protocol violation during the course of their participation in the prior double-
blind phase 3 trial.  Minor violations such as occasional visits outside of the acceptable window or 
a missing blood draw will not exclude a subject from participation in Trial 331-10-238; however, 
continual lack of compliance with the visit schedule, trial assessments, or treatment regimen in the 
prior double-blind phase 3 trial would be considered a major violation that would result in 
exclusion from Trial 331-10-238.  The medical monitor should be contacted if the investigator 
is unsure of a subject’s eligibility.
Target Disease
4.
Subjects who have received ECT for the current depressive episode.
5.
Subjects who have had an inadequate response to ECT at any time in the past or who have had a 
vagus nerve stimulation or deep brain stimulation device implanted at any time for management of 
treatment-resistant depression.  Subjects who have had Transcranial Magnetic Stimulation during 
the current major depressive episode. 
6.
Subjects with a current need for involuntary commitment or who have been hospitalized during the 
prior double-blind phase 3 trial for the current major depressive episode.


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Table 3.4.3-1
Exclusion Criteria
7.
Subjects with a current Axis I (DSM-IV-TR) diagnosis of:

Delirium, dementia, amnestic or other cognitive disorder

Schizophrenia, schizoaffective disorder, or other psychotic disorder

Bipolar I or II disorder

Eating disorder (including anorexia nervosa or bulimia)

Obsessive compulsive disorder

Panic disorder

Post-traumatic stress disorder
8.
Subjects with a current Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, 
schizoid, schizotypal or histrionic personality disorder.
9.
Subjects experiencing hallucinations, delusions or any psychotic symptomatology in the current 
depressive episode.
10.
Subjects receiving new onset psychotherapy (individual, group, marriage, or family therapy) during 
the prior double-blind phase 3 trial.
Medical History and Concurrent Diseases
11.
Subjects with a response of “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal 
Ideation with Some Intent to Act, Without Specific Plan) at entry, OR
Subjects with a response of “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal 
Ideation with Specific Plan and Intent) at entry, OR
Subjects with a response of “Yes” on any of  the 5 C-SSRS Suicidal Behavior Items (actual 
attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) at entry, OR 
Subjects who, in the opinion of the investigator (including consideration of responses on the 
C-SSRS throughout the prior double-blind phase 3 trial), present a serious risk of suicide.
Note:  “Entry” is defined as the last scheduled visit of the prior double-blind phase 3 trial.
12.
Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the past 180 
days; including alcohol and benzodiazepines, but excluding caffeine and nicotine.
13.
Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with
medications for at least the past 90 days) and/or an abnormal result for free T4 at 
screening/baseline.  Eligibility of subjects excluded based on an abnormal free T4 result can be 
discussed with the medical monitor if, in the investigator’s judgment, the subject is a suitable 
candidate for the trial.
14.
Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, 
hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders such as any 
history of myocardial infarction, congestive heart failure, HIV seropositive status/acquired 
immunodeficiency syndrome, chronic hepatitis B or C.  Medical conditions that are minor or well-
controlled may be considered acceptable if the condition does not expose the subject to an undue 
risk of a significant adverse event or interfere with assessments of safety or efficacy during the 
course of the trial.  The medical monitor should be contacted in any instance where the investigator 
is uncertain regarding the stability of a subject’s medical condition(s) and the potential impact of 
the condition(s) on trial participation.
15.
Subjects with IDDM (ie, any subjects using insulin) are excluded.  Subjects with non-IDDM may 
be eligible for the trial if their condition is stable as determined by satisfying ALL of the following 
criteria:

Screening/baseline HbA1c < 7.0%, AND

Screening/baseline fasting glucose must be 125 mg/dL, AND

Subject has been maintained on a stable regimen of oral anti-diabetic medication(s) or diabetes 
has been well-controlled by diet during the prior double-blind phase 3 trial, AND

Subject has not had any hospitalizations due to diabetes or complications related to diabetes
during the prior double-blind phase 3 trial, AND

Subject’s diabetes is not newly diagnosed during screening/baseline for Trial 331-10-238.
Continuation of subjects excluded based on abnormal laboratory test results from the 


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Table 3.4.3-1
Exclusion Criteria
screening/baseline visit should be discussed with the medical monitor, if in the investigator's 
judgement the subject is a suitable candidate for the trial.
16.
Subjects with uncontrolled hypertension (DBP > 95 mmHg) or symptomatic hypotension, or 
orthostatic hypotension which is defined as a decrease of 30 mmHg in SBP and/or a decrease of 
20 mmHg in DBP after at least 3 minutes standing compared to the previous supine blood 
pressure, OR development of symptoms.
17.
Subjects with known ischemic heart disease or history of myocardial infarction, congestive heart 
failure (whether controlled or uncontrolled), angioplasty, stenting, or coronary artery bypass 
surgery.
18.
Subjects with epilepsy or a history of seizures, except for a single seizure episode, for instance 
childhood febrile seizure, post traumatic, or alcohol withdrawal.
Physical and Laboratory Results
19.
Subjects with a positive drug screen for cocaine, marijuana, or other illicit drugs are excluded and 
may not be retested or rescreened.  Subjects with a positive urine drug screen resulting from use of 
prescription or OTC medications or products that in the investigator’s documented opinion do not 
signal a clinical condition that would impact the safety of the subject or interpretation of the trial
results may continue evaluation for the trial following consultation and approval by the medical 
monitor. 
20.
The following Screening/baseline laboratory test and ECG results are exclusionary:
1) Platelets 75,000/mm3
2) Hemoglobin 9 g/dL
3) Neutrophils, absolute 1000/mm3
4) AST > 2 ULN
5) ALT > 2 ULN
6) CPK > 3 ULN, unless discussed with and approved by the medical monitor
7) Creatinine 2 mg/dL
8) HbA1c 7.0%
9) Abnormal free T4, unless discussed with and approved by the medical monitor.  (Note: Free T4
is measured only if result for TSH is abnormal.)
10) QTcF 450 msec
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 are medically significant 
and that would impact the safety of the subject or the interpretation of the trial results.  Criteria are 
provided in Appendix 3, Appendix 4, and Appendix 5 to assist investigators in their assessments of 
results that may be potentially medically significant, depending on the subject’s medical history 
and clinical presentation.  Eligibility should be based on the Screening/baseline laboratory test and 
ECG results.  The medical monitor should be contacted if the investigator is unsure of a subject’s 
eligibility. Continuation of subjects excluded based on abnormal laboratory test and ECG results 
should be discussed with the medical monitor, if in the investigator's judgement, the subject is a 
suitable candidate for the trial.
Prohibited Therapies or Medications
21.
Subjects who would be likely to require prohibited concomitant therapy during the trial (see Table 
4.1-1)a.
Allergies and Adverse Drug Reactions
22.
Subjects with a history of neuroleptic malignant syndrome or serotonin syndrome.
23.
Subjects with a history of true allergic response (ie, not intolerance) to more than one class of 
medications.


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Table 3.4.3-1
Exclusion Criteria
Other
24.
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (eg, infectious disease) illness must not be enrolled into this trial. 
25.
Any subject who, in the opinion of the investigator, should not participate in the trial.
ALT = alanine transaminase; AST = aspartate transaminase; CPK = creatine phosphokinase; 
C-SSRS = Columbia-Suicide Severity Rating Scale; DBP = diastolic blood pressure; 
DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision; HbA1c = glycosylated hemoglobin; HIV = human immunodeficiency virus; 
IDDM = insulin-dependent diabetes mellitus; IUD = intrauterine device; NMS = neuroleptic 
malignant syndrome; OTC = over-the-counter; QTcF = QT interval as corrected for heart rate by 
Fridericia’s formula; SBP = systolic blood pressure; T4 = thyroxine; TSH = thyroid-stimulating 
hormone; ULN = upper limit of normal.
aUse of CYP2D6 inhibitors or CYP3A4 inhibitors and inducers is prohibited during the trial.  
Fluoxetine, paroxetine, and duloxetine are protocol-defined ADTs that are also CYP2D6 inhibitors.  
In order to limit the potential higher exposure of brexpiprazole when coadministered with such 
inhibitors, the upper limit of the therapeutic ADT dose is limited to 40 mg for fluoxetine, 50 mg for 
paroxetine CR, and 60 mg for duloxetine.
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 
scheduled visit of the prior double-blind phase 3 trial are not available to assess 
eligibility, the assessment for the affected criteria should be based on the last available 
measurement during the respective 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 3.6.2.1 if there are any clinically significant and/or 
exclusionary values.
3.5
Primary and Secondary Outcome Variables
3.5.1
Primary Outcome Variable
The primary outcome variable is the safety and tolerability of brexpiprazole, which will 
be assessed by examining the frequency and severity of adverse events (AEs).
3.5.2
Secondary Outcome Variables
3.5.2.1
Efficacy Variables
Efficacy variables will be as follows:

Change from baseline in Clinical Global Impression - Severity of Illness scale 
(CGI-S) score;

Mean Clinical Global Impression - Improvement scale (CGI-I) score;

Change from baseline in Sheehan Disability Scale (SDS) score.


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
Change from baseline in the Inventory of Depressive Symptomatology (Self-Report)
(IDS-SR) Total Score
3.5.2.2
Safety Variables
In addition to AEs, safety variables to be examined in this trial will include physical 
examinations, vital signs, body weight, waist circumference, clinical laboratory tests 
(hematology, serum chemistry, urinalysis, and pregnancy tests), ECGs, the Simpson 
Angus Scale (SAS), the Abnormal Involuntary Movement Scale (AIMS), the Barnes 
Akathisia Rating Scale (BARS), the Columbia-Suicide Severity Rating Scale (C-SSRS), 
and the Massachusetts General Hospital Sexual Functioning Questionnaire (MSFQ).
Mean change from baseline and the incidence of potentially clinically relevant abnormal 
values will be calculated for vital signs, body weight, routine laboratory tests (including 
prolactin), and ECG parameters.  Mean change from baseline will be calculated for 
coagulation parameters (prothrombin time [PT], activated partial thromboplastin time 
[aPTT], and International Normalized Ratio [INR]), glycosylated hemoglobin (HbA1c), 
thyroid-stimulating hormone (TSH), waist circumference, and body mass index (BMI; 
derived programmatically from body weight and height measurements).  A central ECG 
service will be utilized to review all ECGs in order to standardize interpretations for the 
safety analysis.  EPS will be evaluated by calculating mean change from baseline on the 
SAS, AIMS, and BARS.  Sexual dysfunction will be evaluated as change from baseline 
in MSFQ score.  The C-SSRS will be used to assess and classify reported suicidal 
behavior.  By-patient listings of physical examination findings will be reviewed as a 
further assessment of safety.
3.5.2.3
Other Outcome Variables
Responses to the Resource Utilization Form (RUF) will be summarized appropriately to 
explore the impact of treatment on health care resources.
3.6
Trial Procedures
The duration of this trial from first subject enrolled to last subject completed is estimated to be 
approximately 57 months, of which approximately 51 months are allotted for rollover of subjects from 
prior double-blind phase 3 brexpiprazole MDD trials.  Individual participation for subjects who complete 
the trial without early withdrawal will be approximately 30 weeks (26 weeks of treatment and 30-day 
follow-up).  Trial assessment time points are summarized in Table 3.6-1.


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Table 3.6-1
Schedule of Assessments
Assessment
Screening/ 
Baselinea
Open-Label Treatment Phase Visit Week (2 days)
Follow-upc
30 (+2) days
1
2
4
8
14
20
26/ETb
ENTRANCE CRITERIA
Informed consentd
X
Inclusion/exclusion criteria
X
Medical history
Xe
EFFICACY
CGI-S
X
X
X
X
X
X
X
X
CGI-If
X
X
X
SDS
X
X
X
IDS-SR
X
X
X
SAFETY
Physical examination
X
X
Waist circumference
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
12-lead ECGh
X
X
X
Clinical laboratory testsi
Xj
Xk
Xk
HbA1c
Xj
Xk
Xk
Drug screen/blood alcoholl
X
X
X
X
X
X
Urine pregnancy test 
(WOCBP only)m
X
X
X
X
X
X
X
X
SAS
X
X
X
X
X
X
X
X
AIMS
X
X
X
BARS
X
X
X
X
X
X
X
X
C-SSRSn
X
X
X
X
X
X
X
X
MSFQ
X
X
Adverse events
Xo
X
X
X
X
X
X
X
X


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Table 3.6-1
Schedule of Assessments
Assessment
Screening/ 
Baselinea
Open-Label Treatment Phase Visit Week (2 days)
Follow-upc
30 (+2) days
1
2
4
8
14
20
26/ETb
Concomitant medicationsp
X
X
X
X
X
X
X
X
X
OTHER
Dose adjustmentsq
X
X
X
X
X
X
RUFr
X
X
Register visit in IVRS/IWRSs
X
X
X
X
X
X
X
X
IMP dispensing
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
IVRS = interactive voice response system; IWRS = interactive web response system; WOCBP = women of childbearing potential.
aScreening for Trial 331-10-238 occurs simultaneously with Baseline at the last scheduled visit of the prior double-blind phase 3 trial.  All assessments listed 
under screening need to be performed at Screening/Baseline of Trial 331-10-238; if any of these assessments were conducted at the last scheduled visit of 
the prior double-blind phase 3 trial, then Screening/Baseline values for those assessments will be derived from that visit and those assessments will not 
need to be repeated at Screening/Baseline of Trial 331-10-238.
bIf a subject discontinues prematurely before Week 26, procedures noted for Week 26 must be completed at the early termination (ET) visit.  Subjects who 
have completed 26 weeks or more, will have the Week 26/ET procedures at their next scheduled visit.  
cConsists of telephone contact or clinic visit (investigator’s discretion) for evaluation of safety and applies to all subjects (completers and early withdrawals).
dInformed consent for Trial 331-10-238 will occur at Screening/Baseline and must be obtained before any trial-related procedures specific to the open-label 
trial are performed.
eUpdate, if necessary.
fImprovement should be based on the subject’s status at the last scheduled visit of the prior double-blind phase 3 trial.
gVital signs include body weight, body temperature, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate.  Blood pressure and heart 
rate will be measured in the following order:  supine, sitting, and standing after the subject has been in each position for at least 3 minutes.  Vital signs 
scheduled for the same visit as blood samples are to be completed before blood is drawn.
hStandard 12-lead ECGs will be performed after the subject has been supine and at rest for 5 minutes prior to the ECG.  A central ECG service will be 
utilized to review 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.  Subjects will be enrolled in Trial 331-10-238 based on the screening/baseline ECG results from the trial site.  If the 
screening/baseline ECG results from the central reader (ie, the last scheduled visit of the prior double-blind phase 3 trial), when available, indicate a QTcF 


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450 msec at screening/baseline, the investigator must contact the medical monitor to discuss the subject’s continued participation in the trial.  ECGs 
scheduled for the same visit as blood samples are to be completed before blood is drawn.
iIncludes hematology (including PT, aPTT, and INR), serum chemistry (including prolactin and TSH, with reflex to free thyroxine [T4] if the result for TSH is 
abnormal), and urinalysis. 
jSubjects must be fasting for a minimum of 8 hours prior to blood draws for screening/baseline laboratory assessments (ie, the last scheduled visit of the prior 
double-blind phase 3 trial).
kClinical laboratory tests should be drawn fasting, if possible, but must be drawn after a minimum 8-hour fast at Week 26/ET.  Vital sign and ECG 
assessments should be completed before any blood samples are collected.
lA urine drug screen and a blood alcohol test are required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator.
mAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with a positive serum pregnancy test result at Screening/Baseline must 
not be enrolled in Trial 331-10-238 and subjects with a positive serum pregnancy test result during the trial must discontinue treatment and be withdrawn 
from the trial.  Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.
n“Since Last Visit” C-SSRS form.
oAE recording will begin with the signing of the ICF for Trial 331-10-238.
pAll prescription and non-prescription medications taken during the trial will be recorded as concomitant medications.  Details of prohibited and restricted 
medications are provided in Section 4.
qAdjustments to the dose of brexpiprazole or ADT are permitted to optimize efficacy and tolerability as described in Section 3.2.  It is recommended that the 
dose of ADT not be changed while the dose of brexpiprazole is being optimized (ie, no change to ADT up to and including the Week 4 visit).  At least 5 
days must elapse between dose increases for brexpiprazole and ADT.  An interval of at least 5 days between dose adjustments is also recommended for 
dose decreases; however, the investigator may decrease the dose of brexpiprazole or ADT as needed for tolerability according to the rules described in 
Section 3.2.2.  Subjects must return to the clinic for unscheduled visits if changes to the dose of brexpiprazole or ADT (increases or decreases) are required 
between scheduled visits.  All eligible subjects entering from prior double-blind phase 3 brexpiprazole MDD trials must be able to continue therapy without 
interruption between the double-blind and open label trials.
rBaseline RUF is completed at Screening/Baseline for all subjects.  The Follow-up RUF (as well as hospitalization questions) is completed at Week 26/ET 
visit.
sThe IVRS/IWRS will be accessed at unscheduled visits if new blister cards are dispensed for dose adjustment of brexpiprazole.


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3.6.1
Schedule of Assessments
3.6.1.1
Screening/Baseline
Subjects entering Trial 331-10-238 must sign the ICF for the open-label trial before any 
procedures specific to Trial 331-10-238 can be performed.  Subjects will retain the same 
subject identification (Subject ID) number assigned in the prior double-blind phase 3 
trial. The following procedures need to be performed at Screening/Baseline of 
Trial 331-10-238; if any of these assessments were conducted at the last scheduled visit 
of the prior double-blind phase 3 trial, then Screening/Baseline values for those 
assessments will be derived from that visit and those assessments will not need to be 
repeated at Screening/Baseline of Trial 331-10-238.

Inclusion/exclusion criteria for Trial 331-10-238 will be reviewed to assure the 
subject’s eligibility.

Medical history will be updated, if necessary, using information from the prior 
double-blind phase 3 trial.

Subjects will submit to a physical examination and assessments of waist 
circumference, vital signs, and ECG.

The investigator (or qualified designee) will administer the CGI-S and CGI-I.

Subjects will complete any Baseline instrument (ie, SDS, IDS-SR, and MSFQ).

An adequately trained and experienced clinician will administer any EPS scale 
(ie, SAS, AIMS, and BARS).

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Concomitant medications will be reviewed to assure that the subject is not receiving 
any prohibited medications.

Subjects will complete the Baseline RUF.

For subjects entering Trial 331-10-238 after completing the last scheduled visit of the
prior double-blind phase 3 trial, a fasting blood sample will be drawn for analysis of 
any clinical laboratory parameter (ie, the clinical laboratory parameters specified in 
Table 3.6.2.1-1) that was not drawn at the last scheduled visit of the prior double-
blind phase 3 trial.

AE recording will begin with the signing of the ICF for Trial 331-10-238.

Trial personnel will call the interactive voice response system (IVRS) or access the 
interactive web response system (IWRS) to register the visit and to obtain blister card 
and ADT bottle number assignments.  The assigned open-label brexpiprazole and 
ADT will be dispensed.  Treatment will begin with brexpiprazole 0.5 mg/day for 
1 week.  The ADT will be the same as the one taken during the prior double-blind
phase 3 trial.  The dose of ADT should not be changed at this time.


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3.6.1.2
Week 1
All subjects will attend a visit at Week 1 (2 days) where the following evaluations will 
be performed:

The investigator (or qualified designee) will administer the CGI-S.

An adequately trained and experienced clinician will administer the SAS and BARS 
to assess EPS.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, 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.

Samples will be obtained for blood alcohol testing.

Urine will be collected for urine screen(s) for drugs of abuse.

Women of childbearing potential (WOCBP) will be given a urine pregnancy test.  
Any positive result must be confirmed by a serum pregnancy test.  WOCBP with a 
positive serum pregnancy test result must discontinue the IMP and be withdrawn 
from the trial.

Drug accountability will be performed for brexpiprazole and ADT.

The dose of brexpiprazole will be increased to 1 mg/day.  Subjects unable to tolerate 
brexpiprazole 1 mg/day may decrease to 0.5 mg/day at any time after the Week 1 
visit.  It is recommended that the dose of ADT not be changed while the dose of 
brexpiprazole is being optimized.  Trial personnel will call the IVRS or access the 
IWRS to register the visit, to enter dose details for brexpiprazole and ADT, and to 
obtain blister card and bottle number assignments.  The assigned open-label 
brexpiprazole and ADT will be dispensed to the subject.

AEs and concomitant medications will be recorded.
3.6.1.3
Week 2
All subjects will attend a visit at Week 2 (2 days) where the following evaluations will 
be performed:

The investigator (or qualified designee) will administer the CGI-S.

An adequately trained and experienced clinician will administer the SAS and BARS 
to assess EPS.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.


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
Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, sitting, and standing after the subject has been in each 
position at least 3 minutes.

WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.  WOCBP with a positive serum pregnancy test result must 
discontinue the IMP and be withdrawn from the trial.

Drug accountability will be performed for brexpiprazole and ADT.

The investigator will adjust the dose of brexpiprazole as necessary as described in 
Section 3.2 to achieve optimal efficacy and tolerability.  It is recommended that the 
dose of ADT not be changed while the dose of brexpiprazole is being optimized.  Any 
subject unable to tolerate the minimum dose of brexpiprazole (ie, 0.5 mg/day) must 
be withdrawn from the trial.  Trial personnel will call the IVRS or access the IWRS to 
register the visit, to enter dose details for brexpiprazole and ADT, and to obtain 
blister card and bottle number assignments.  The assigned open-label brexpiprazole
and ADT will be dispensed to the subject.

AEs and concomitant medications will be recorded.
3.6.1.4
Week 4
All subjects will attend a visit at Week 4 (2 days) where the following evaluations will 
be performed:

The investigator (or qualified designee) will administer the CGI-S.

An adequately trained and experienced clinician will administer the SAS and BARS 
to assess EPS.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, 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.

Samples will be obtained for blood alcohol testing.

Urine will be collected for urine screen(s) for drugs of abuse.

WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.  WOCBP with a positive serum pregnancy test result must 
discontinue the IMP and be withdrawn from the trial.

Drug accountability will be performed for brexpiprazole and ADT.

The investigator will adjust the dose of brexpiprazole as necessary as described in 
Section 3.2 to achieve optimal efficacy and tolerability.  If necessary, the dose of 


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ADT can be changed after the Week 4 visit, but not at the same visit as a change to 
the dose of brexpiprazole (see Section 3.2.2.2).  Any subject unable to tolerate the 
minimum dose of brexpiprazole (ie, 0.5 mg/day) must be withdrawn from the trial.  
Trial personnel will call the IVRS or access the IWRS to register the visit, to enter 
dose details for brexpiprazole and ADT, and to obtain blister card and bottle number 
assignments.  The assigned open-label brexpiprazole and ADT will be dispensed to 
the subject.

AEs and concomitant medications will be recorded.
3.6.1.5
Week 8
All subjects will attend a visit at Week 8 (2 days) where the following evaluations will 
be performed:

The investigator (or qualified designee) will administer the CGI-S.

An adequately trained and experienced clinician will administer the SAS and BARS 
to assess EPS.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, 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.

Samples will be obtained for blood alcohol testing.

Urine will be collected for urine screen(s) for drugs of abuse.

WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.  WOCBP with a positive serum pregnancy test result must 
discontinue the IMP and be withdrawn from the trial.

Drug accountability will be performed for brexpiprazole and ADT.

The investigator will adjust the dose of brexpiprazole as necessary within the range of 
0.5 to 3 mg daily as described in Section 3.2.  If necessary, the dose of ADT can also 
be adjusted (see Section 3.2.2.2).  Trial personnel will call the IVRS or access the 
IWRS to register the visit, to enter dose details for brexpiprazole and ADT, and to 
obtain blister card and bottle number assignments.  The assigned open-label 
brexpiprazole and ADT will be dispensed to the subject.

AEs and concomitant medications will be recorded.


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3.6.1.6
Week 14
All subjects will attend a visit at Week 14 (2 days) where the following evaluations will 
be performed:

The investigator (or qualified designee) will administer the CGI-S and CGI-I.

Waist circumference will be measured.

An adequately trained and experienced clinician will administer the SAS, AIMS, and 
BARS to assess EPS.

The subject will complete the IDS-SR and SDS.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, 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 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 fasting blood draw will be collected for clinical laboratory tests (hematology, 
including PT, aPTT, and INR; and serum chemistry, including prolactin, HbA1c, and 
TSH, with reflex to free T4 if the result for TSH is abnormal).  Vital sign and ECG 
assessments should be completed before any blood samples are collected.

Samples will be obtained for blood alcohol testing.  Additional blood alcohol testing 
may be performed at any other time at the discretion of the investigator.

Urine will be collected for urinalysis and urine screen(s) for drugs of abuse.  
Additional urine drug screens may be performed at any other time at the discretion of 
the investigator.

WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.  WOCBP with a positive serum pregnancy test result must 
discontinue the IMP and be withdrawn from the trial.

Drug accountability will be performed for brexpiprazole and ADT.

The investigator will adjust the dose of brexpiprazole as necessary within the range of 
0.5 to 3 mg daily as described in Section 3.2.  If necessary, the dose of ADT can also 
be adjusted (see Section 3.2.2.2).  Trial personnel will call the IVRS or access the 
IWRS to register the visit, to enter dose details for brexpiprazole and ADT, and to 
obtain blister card and bottle number assignments.  The assigned open-label 
brexpiprazole and ADT will be dispensed to the subject.

AEs and concomitant medications will be recorded.


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3.6.1.7
Week 20
All subjects will attend a visit at Week 20 (2 days) where the following evaluations will 
be performed:

The investigator (or qualified designee) will administer the CGI-S.

An adequately trained and experienced clinician will administer the SAS and BARS 
to assess EPS.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, 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.

WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.  WOCBP with a positive serum pregnancy test result must 
discontinue the IMP and be withdrawn from the trial.

Drug accountability will be performed for brexpiprazole and ADT.

The investigator will adjust the dose of brexpiprazole as necessary within the range of 
0.5 to 3 mg daily as described in Section 3.2.  If necessary, the dose of ADT can also 
be adjusted (see Section 3.2.2.2).  Trial personnel will call the IVRS or access the 
IWRS to register the visit, to enter dose details for brexpiprazole and ADT, and to 
obtain blister card and bottle number assignments.  The assigned open-label 
brexpiprazole and ADT will be dispensed to the subject.

AEs and concomitant medications will be recorded.
3.6.1.8
End of Treatment (Week 26/ET)
The Week 26 visit signifies the end of treatment. Therefore, all subjects will undergo a 
complete evaluation at Week 26 (2 days).  In addition, Week 26 evaluations are to be 
completed, if possible, for any subject withdrawn from the trial prematurely. Since the
original 52 week open-label trial design has been modified as a part of Amendment 3 to 
shorten the duration of the trial to 26 weeks, ongoing subjects who have not reached their 
Week 26 visit will be re-consented and will follow Amendment 3 schedule of 
assessments.  Ongoing subjects who have already completed their Week 26 visit at the 
time Amendment 3 is approved will follow Amendment 3 week 26/ET schedule of 
assessments at their next scheduled visit.  The following activities and assessments will 
occur at Week 26 (or at the ET visit, if applicable):

The investigator (or qualified designee) will administer the CGI-S and CGI-I.


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
An adequately trained and experienced clinician will administer the SAS, AIMS, and 
BARS to assess EPS.

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS 
form.

The subject will complete the MSFQ, SDS, IDS-SR, and the Follow-up RUF.

A complete physical examination (including waist circumference) will be performed.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded.  Blood pressure and heart rate are to be measured in the 
following order:  supine, 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 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 fasting blood draw will be collected for clinical laboratory tests (hematology, 
including PT, aPTT, and INR; and serum chemistry, including prolactin, HbA1c, and 
TSH, with reflex to free T4 if TSH is abnormal).  Vital sign and ECG assessments
should be completed before any blood samples are collected.

Samples will be obtained for blood alcohol testing.

Urine will be collected for urinalysis and urine screen(s) for drugs of abuse.

WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.

Final drug accountability will be performed.

Trial personnel will call the IVRS or access the IWRS to register completion or 
discontinuation from the trial.

AEs and concomitant medications will be recorded.
3.6.1.9
Follow-up
Follow-up safety information (AEs and concomitant medications) will be collected 
30 (+ 2) days after the last dose of open-label medication for all subjects (completers and 
early withdrawals).  Follow-up information can be obtained via telephone contact or 
clinic visit at the investigator’s discretion.
3.6.2
Safety Assessments
3.6.2.1
Clinical Laboratory Tests
As it is unlikely that the final laboratory test results from the last scheduled visit of the 
prior double-blind phase 3 trial will be available at the time of enrollment in 
Trial 331-10-238, the investigator is to review the subject’s most recent laboratory test 
results from the prior double-blind phase 3 trial for compliance with the exclusion criteria 


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and the presence of abnormal laboratory test results that, in the investigator’s judgment, 
are medically significant and would impact the safety of the subject or the interpretation 
of the trial results.  Subjects meeting any of these criteria will be excluded from 
Trial 331-10-238.  Appendix 4 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.  If one or more results from the screening/baseline 
sample are clinically significant and/or exclusionary when the results from the last 
scheduled visit of the prior double-blind phase 3 trial become available, the test(s) should 
be repeated.  The subject may continue to receive trial medication pending results of the 
repeat laboratory tests at the investigator’s discretion.  If the abnormality remains upon 
retest, the medical monitor should be contacted to discuss the subject’s eligibility for 
continued participation in Trial 331-10-238.
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 labs, 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 subjects at the scheduled visits designated 
in Table 3.6-1.  Additional urine and blood samples may be collected for further 
evaluation of safety as warranted by the investigator’s judgment.  Screening/baseline 
laboratory assessments will be performed after a minimum 8-hour fast per the protocol 
instructions for the double-blind phase 3 trials.  All subjects must be fasting for a 
minimum of 8 hours prior to the blood draw at Week 26/ET and should be fasting for a 
minimum of 8 hours prior to all other blood draws during the Treatment Phase, if 
possible.  If a subject is not fasting at a visit other than Week 26/ ET, the blood draw 
should still be performed and the status documented as nonfasting on the laboratory 
requisition sheet.  The Week 26/ET blood draw must be rescheduled to accommodate the 
fasting requirement.  Reports from the central laboratory should be filed with the source 
documents for each subject.  The central laboratory will provide laboratory results to the 
sponsor electronically.


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Table 3.6.2.1-1
Safety Clinical Laboratory Tests
Hematology:
WBC count with differential
RBC count
Hematocrit
Hemoglobin
Platelet count
Urinalysis:
pH
Specific gravity
Protein
Ketones
Glucose
Blood
Microscopic exam (performed only if any part of 
the urinalysis is not negative)
Urine Drug Screens:
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Marijuana
Methadone
Opiates
Phencyclidine
Propoxyphene
Other:
Blood alcohol
Serum Chemistry:
ALP
ALT or SGPT
AST or SGOT
BUN
CPK
Creatinine
LDH
Total bilirubin
Triglycerides 
Cholesterol (total, LDL, and HDL)
Calcium
Chloride
Glucose
Insulin
Magnesium
Bicarbonate
Inorganic phosphorous
Sodium
Potassium
Total protein
Uric acid
GGT
Prolactin
Albumin
Additional Tests:
Urine pregnancy (WOCBP)a
TSH, with reflex to free T4 if TSH is abnormal
PT, aPTT, and INR
HbA1c
ALP = alkaline phosphatase; ALT or SGPT = alanine transaminase; AST or SGOT = aspartate 
transaminase; BUN = blood urea nitrogen; CPK = creatine phosphokinase; GGT = gamma glutamyl 
transferase; HbA1c = glycosylated hemglobin; HDL = high density lipoprotein; LDH = lactic 
dehydrogenase; LDL = low density lipoprotein; RBC = red blood cell.
aAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with a positive 
serum pregnancy test result at Screening/Baseline must not be enrolled and subjects with a positive 
serum pregnancy test result during the trial must discontinue treatment and be withdrawn from the 
trial.
Any value outside the normal range will be flagged for the attention of the investigator 
who must indicate whether or not a flagged value is of clinical significance.  If one or 
more values are questionable, the test(s) may be repeated.  Follow-up unscheduled labs 
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.


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To be eligible for Trial 331-10-238, subjects are not permitted to have laboratory values 
within the following exclusionary ranges:
1) Platelets 75,000/mm3
2) Hemoglobin 9 g/dL
3) Neutrophils, absolute 1000/mm3
4) Aspartate transaminase (AST) > 2 upper limit of normal (ULN)
5) Alanine transaminase (ALT) > 2 ULN
6) Creatine phosphokinase (CPK) > 3 ULN, unless discussed with and approved by 
the medical monitor
7) Creatinine 2 mg/dL
8) HbA1c 7.0%
9) Abnormal free T4, unless discussed with and approved by the medical monitor.  
(Note: Free T4 is measured only if result for TSH is abnormal.)
3.6.2.2
Physical Examination and Vital Sign Assessments
3.6.2.2.1
Physical Examination
The complete physical examination at the last scheduled visit of the prior double-blind
phase 3 trial will serve as the screening/baseline physical examination for the current 
protocol.  A complete physical examination will consist of a review of the following 
body systems:  HEENT, thorax, abdomen, urogenital, extremities, neurological, and skin 
and mucosae.  Repeat measurement of height is not required during Trial 331-10-238 if a 
Screening/Baseline value is available from the prior double-blind phase 3 trial.  Waist 
circumference will be measured at Screening/Baseline, Week 14, and Week 26/ET.  The 
following procedures will aid in the standardization of these measurements:

The subject should be minimally clothed (ie, lightweight clothing; no heavy 
overgarments).

Waist circumference should be recorded before a subject’s meal and at approximately 
the same time at each visit.

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.24


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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 screening/baseline examination should be 
documented as an AE and followed to a satisfactory conclusion.
3.6.2.2.2
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 with uncontrolled hypertension (Screening/Baseline DBP > 95 mmHg) or 
symptomatic hypotension are excluded from the trial as are subjects with orthostatic 
hypotension defined as a decrease of 30 mmHg in SBP and/or a decrease of 
20 mmHg in DBP after at least 3 minutes standing compared to the previous supine 
blood pressure OR development of symptoms (see Table 3.4.3-1).  In addition, subjects 
should be excluded if they have any other vital sign measurement at Screening/Baseline 
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/baseline vital sign result(s) considered to be clinically significant should be 
repeated to confirm the finding(s) before excluding the subject from the trial.  Appendix 
3 is included to assist investigators in their assessments of results that may be potentially 


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medically significant, depending on the subject’s medical history and clinical 
presentation.
3.6.2.3
ECG Assessments
Twelve-lead ECGs will be recorded at the visits specified in Table 3.6-1.  ECG 
recordings will be obtained after the subject has been supine and at rest for at least 
5 minutes.  Additional 12-lead ECGs may be obtained at the investigator’s discretion and 
should always be obtained in the event of an 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, sign, 
and date each ECG reading, noting whether or not any abnormal results are of clinical 
significance.  The ECG will be repeated if any results are considered to be clinically 
significant.
As the results from the central reader will not be available at the Screening/Baseline visit, 
the subject will be enrolled into Trial 331-10-238 based on the local ECG results.  A 
screening/baseline ECG finding of QTc corrected for heart rate by Fridericia’s formula 
(QTcF) 450 msec is exclusionary (see Table 3.4.3-1).  In addition, subjects should be 
excluded if they have any other abnormal ECG finding at Screening/Baseline 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/baseline ECG 
with abnormal result(s) considered to be clinically significant should be repeated to 
confirm the finding(s) before excluding the subject from the trial.  Appendix 5 is 
provided as a guide for determining potentially clinically relevant ECG abnormalities.  If 
the results from the central reader, when available, indicate a screening/baseline 
QTcF 450 msec, the investigator must contact the medical monitor to discuss the 
subject’s continued participation in the trial.
3.6.2.4
Other Safety Assessments
It is required that a trained and experienced clinician administer the safety assessments, 
including the EPS scales (SAS, AIMS, and BARS) and C-SSRS.  The number of raters 
within each trial center should be kept to a minimum.  All efforts will be made to ensure 
that the same clinician administers the scales for a given subject.  Notations in the 
subject’s trial records should substantiate the ratings.  Training and materials for rating 
will be provided by Bracket.


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3.6.2.4.1
Simpson Angus Scale (SAS)
The SAS25 (Appendix 10) 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 electronic case report form (eCRF).
3.6.2.4.2
Abnormal Involuntary Movement Scale (AIMS)
The AIMS26 assessment (Appendix 11) 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 eCRF.
The AIMS Movement Rating Score is defined as the sum of items 1 through 7 (ie, items 
1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, 
trunk movements).
3.6.2.4.3
Barnes Akathisia Rating Scale (BARS)
The BARS27 (Appendix 12) consists of 4 items related to akathisia:  objective 
observation of akathisia by the investigator, subjective feelings of restlessness by the 


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subject, subjective distress due to akathisia, and global clinical assessment of akathisia.  
The first 3 items will be rated on a 4-point scale, with a score of zero representing 
absence of symptoms and a score of 3 representing a severe condition.  The global 
clinical evaluation will be made on a 6-point scale, with zero representing absence of 
symptoms and a score of 5 representing severe akathisia.  To complete this scale, subjects 
will be observed while they are seated and then standing for a minimum of 2 minutes in 
each position.  Symptoms observed in other situations (eg, while engaged in neutral 
conversation or engaged in other activity) may also be rated.  Subjective phenomena are 
to be elicited by direct questioning.  Anticholinergics, propranolol, benzodiazepines, and 
non-benzodiazepine sleep aids are not permitted within 12 hours of scale administration 
(see Section 4).  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 eCRF.
The BARS Global Score is defined as the global clinical assessment of akathisia.
3.6.2.4.4
Suicidality
Suicidality will be monitored during the trial using the C-SSRS.  Subjects completed the 
“Baseline/Screening” C-SSRS form at the beginning of the prior double-blind phase 3 
trial; therefore, only the “Since Last Visit” C-SSRS form will be used in 
Trial 331-10-238.  A copy of the “Since Last Visit” C-SSRS form is provided in 
Appendix 13.
3.6.2.4.5
Sexual Function
The MSFQ28 is a measure of a subject’s self-reported sexual functioning.  It consists of 
5 items that are each rated as one of six defined grades of functioning (Appendix 14).  
The investigator or designated trial personnel should ensure that a subject completes this 
instrument completely and legibly.
3.6.3
Efficacy Assessments
It is required that appropriately trained and qualified individuals administer the CGI-S 
and CGI-I.  The number of raters within each trial center should be kept to a minimum.  
All efforts will be made to ensure that the same clinician administers the scales for a 
given subject.  Notations in the subject’s trial records should substantiate the ratings.  
Training and materials for rating will be provided by Bracket.


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3.6.3.1
Clinical Global Impression - Severity of Illness Scale (CGI-S)
The severity of illness for each subject will be rated using the CGI-S.26  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 6.
3.6.3.2
Clinical Global Impression - Improvement Scale (CGI-I)
The efficacy of trial treatment will be rated for each subject using the CGI-I.26  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 
Screening/Baseline (ie, last scheduled visit of the prior double-blind phase 3 trial).  
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 7.
3.6.3.3
Subject Assessment Recording
3.6.3.3.1
Sheehan Disability Scale (SDS)
The SDS29,30 is a self-rated instrument used to measure the effect of the subject’s 
symptoms on work/school, social life, and family/home responsibilities (Appendix 8).  
The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal 
descriptive anchors simultaneously to assess disability across the three domains.  The 
number most representative of how much each area was disrupted by symptoms is 
marked along the line from 0 = not at all, to 10 = extremely.  Scores of 5 and above are 
associated with significant functional impairment.  In addition to the visual scale, the 
SDS includes two questions related to productivity losses due to the psychiatric 
symptoms and impairment.
3.6.3.3.2
Inventory of Depressive Symptomatology (Self-Report)
The IDS-SR31 is a 30-item self-report measure used to assess core diagnostic depressive 
symptoms as well as atypical and melancholic symptom features of MDD (Appendix 9).  
The investigator or designated trial personnel should ensure that a subject completes this 
instrument completely and legibly.


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3.6.3.3.3
Resource Utilization Form (RUF)
The RUF is a self-report tool designed to collect information regarding the extent of 
medical care sought by subjects while participating in the trial (Appendix 15).  The 
number of hospitalizations and days of hospitalization within the past 12 months will be 
collected on the Baseline Form at Screening/Baseline, including any hospitalizations that 
may have occurred during the subject’s participation in the prior double-blind phase 3 
trial.  The number of visits to various practitioners for mental health and other reasons 
within the 3 months prior to Screening/Baseline (excluding any visits from the prior 
double-blind phase 3 trial) will be collected on the Baseline Form and the number of such 
visits occurring during the trial (excluding visits related to the trial) will be collected on 
the Follow-up Form at Week 26/ET.
3.6.4
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 eCRF page for the last subject completing or 
withdrawing from the trial.
3.7
Stopping Rules, Withdrawal Criteria and Procedures
3.7.1
Entire Trial or Treatment Arm(s)
If the sponsor terminates or suspends the trial for safety or unanticipated other reasons, 
prompt notification will be given to investigators, IRBs/IECs, and regulatory authorities 
in accordance with regulatory requirements.
3.7.2
Individual Center
A particular center may be terminated from the trial at the discretion of the investigator, 
sponsor, or IRB, eg, for non-enrollment of subjects or noncompliance with the protocol.  
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/EC at the site.
3.7.3
Individual Subject
If a subject discontinues from the trial prematurely, the reason must be fully evaluated 
and recorded appropriately in source documents and the eCRF.  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 


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medically necessary.  In addition, subjects meeting the following criteria must be 
withdrawn from the trial:
a) occurrence of any AE, intercurrent illness or abnormality in a laboratory assessment
which, in the opinion of the investigator, warrants the subject’s permanent withdrawal 
from the trial;
b) treatment with a prohibited concomitant medication other than the use of appropriate 
medications for the treatment of AEs under direction of the investigator;
c) subject noncompliance, defined as refusal or inability to adhere to the trial schedule or 
procedures (see Section 3.11, Subject Compliance);
d) at the request of the subject, investigator, sponsor or designee, or regulatory authority;
e) subject becomes pregnant;
f) subject cannot tolerate the minimum dose of brexpiprazole (ie, 0.5 mg/day), the 
minimum protocol-defined therapeutic dose of ADT (see Table 3.2.1.2-1), or requires a 
different ADT; or
g) subject is lost to follow-up.
The investigator will notify the sponsor promptly when a subject is withdrawn.  Subjects 
withdrawn prior to Week 26 must complete the Week 26/ET evaluations at the time of 
withdrawal.  In addition, all subjects who withdraw prematurely from the trial will be 
assessed 30 (+ 2) days after the last dose of IMP for evaluation of safety.  This 
assessment can be accomplished via telephone contact or clinic visit at the investigator’s 
discretion.  Withdrawn subjects will not be replaced.
3.8
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on treatment, 
whether through randomization or open assignment. For the purposes of 
Trial 331-10-238, treatment begins with the first dose of open-label brexpiprazole in the 
Treatment Phase.  Subjects who do not qualify for Trial 331-10-238 at the last scheduled 
visit of the prior double-blind phase 3 trial may not be rescreened.
3.9
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of IMP.  Subjects who are evaluated at the last scheduled 


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visit during the treatment period will be defined as trial completers.  For purposes of this 
trial, subjects who complete the Week 26 visit will be defined as completers.  Protocol-
specified post-treatment follow-up contacts will not qualify as the “last scheduled visit.”  
Subjects who are not completers are defined as those who “discontinued the trial.”
3.10
Definition of Lost to Follow-up
Subjects who cannot be contacted on or before the Week 26 visit during the treatment 
period and who do not have a known reason for discontinuation (eg, withdrew consent or 
AE) will be classified as “lost to follow-up” as the reason for discontinuation.  The site 
will make three 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.
3.11
Subject Compliance
Responsible trial personnel will dispense the IMP (ie, brexpiprazole and ADTs).  
Accountability and compliance verification should be documented in the subject’s trial 
records.  Subjects must be counseled on the importance of taking the IMP as directed at 
all trial visits.  If poor compliance continues (eg, multiple missed doses resulting in less 
than 80% overall compliance at any point in the trial), discontinuation of the subject from 
the trial should be considered.  Subjects who habitually miss visits or habitually attend 
visits outside of the protocol-defined visit window are also noncompliant and should be 
considered for discontinuation.  The medical monitor should be contacted if the 
investigator is uncertain whether a subject's lack of compliance merits discontinuation 
from the trial.
3.12
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, 
subject enrolled in violation of eligibility criteria or concomitant medication criteria), the 
investigator or designee will contact the sponsor’s designee (medical monitor) at the 
earliest possible time by telephone.  Investigator and sponsor (or sponsor’s designee) 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 designated medical 
monitor, and reviewed by the site monitor.


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4
Restrictions
4.1
Prohibited Medications
Concomitant medications taken by subjects who are rolling over into Trial 331-10-238 
from a prior double-blind phase 3 trials should be reviewed for the prohibited 
medications listed in Table 4.1-1.  Any subject taking a prohibited concomitant 
medication should not be enrolled in Trial 331-10-238.
Table 4.1-1
List of Medications Prohibited During the Trial
1.
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including depot or long-acting injectable formulations
b) Anticonvulsants
c) Antidepressants other than the ADTs listed in Table 3.2.1.2-1
d) Mood stabilizers (ie, lithium)
e) Benzodiazepines, except when used to manage treatment emergent AEs such as agitation and
anxietya
f)
Hypnotics, including ramelteon and other non-benzodiazepine sleep aids, except for specific 
medications when used to manage treatment-emergent AEs related to insomniab
g) Stimulants
h) Opioid analgesics, unless permission is obtained from the medical monitor.  Permission for 
opioid use may be considered for a documented and clinically appropriate indication 
(eg, episodic pain condition, tooth extraction) if prescribed at a medically appropriate dose and 
frequency.
i)
Nutritional supplements and non-prescription herbal preparations with CNS effects 
(eg, St. John’s Wort, omega-3 fatty acids, kava extracts, GABA supplements, etc)
2.
Investigational agents
3.
CYP2D6 inhibitors or CYP3A4 inhibitors and inducers.  Selected CYP2D6 inhibitorsc are: 
celecoxib, hydroxyzine, chloroquine, methadone, chlorpheniramine, moclobemide, clemastine, 
clomipramine, pyrilamine, diphenhydramine, quinidine, terbinafine, halofantrine, tripelennamine.  
Selected CYP3A4 inhibitors are: amiodarone, fluvoxamine, amprenavir, indinavir, aprepitant, 
itraconazole, chloramphenicol, ketoconazole, cimetidine, nefazodone, clarithromycin, nelfinavir, 
clotrimazole (if used orally), quinupristin/dalfopristin, delavirdine, ritonavir, diltiazem, saquinavir, 
erythromycin, troleandomycin, fluconazole, verapamil.  Selected CYP3A4 inducers are: 
carbamazepine, oxcarbazepine, phenytoin, dexamethasone, primidone, efavirenz, rifampin, 
nevirapine, St. John’s Wort, phenobarbitol, troglitazone.  The medical monitor should be consulted 
for any questions regarding the potential for pharmacokinetic interactions with concomitant 
medications used by subjects during the trial.
4.
Barbiturates, except for the treatment of migraine headaches, provided that in the opinion of the 
investigator the dosing is medically appropriate.
GABA = gamma-aminobutyric acid.
aAdministration of specific oral benzodiazepines is permitted for the short-term management of 
treatment emergent AEs such as anxiety and agitation up to a maximum of 6 mg/day lorazepam (or 
equivalent) in divided doses.  Short-acting benzodiazepines are to be used whenever possible.  In 
countries where no short-acting benzodiazepines are commercially available, use of oral diazepam or 
clonazepam may be acceptable if prior authorization is obtained from the medical monitor.  The 
following guide should be used to determine approximate lorazepam equivalents:  1 mg lorazepam = 
15 mg oxazepam = 0.5 mg alprazolam = 5 mg diazepam = 0.5 mg clonazepam.  The prescribed 
benzodiazepine should be discontinued as soon as the AE for which it was initiated subsides, as per 


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the investigator’s discretion to avoid any withdrawal effects.  Benzodiazepines must not be 
administered within 12 hours prior to scheduled efficacy and safety assessments, including EPS 
scales.  Investigators are encouraged to delay scale administration until 12 hours have elapsed, if at all 
possible.  However, if delaying administration of efficacy and safety scales is not feasible, the scales 
should still be administered and the use of benzodiazepine documented, including a notation of the 
drug name, dose, and time of administration on the eCRF.
bNon-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 eCRF.
cFluoxetine, paroxetine, and duloxetine are protocol-defined ADTs that are also CYP2D6 inhibitors.  In 
order to limit the potential higher exposure of brexpiprazole when coadministered with such 
inhibitors, the upper limit of the therapeutic ADT dose is limited to 40 mg for fluoxetine, 50 mg for 
paroxetine CR, and 60 mg for duloxetine (see Section 4.2.1).
4.2
Other Restrictions
4.2.1
Restricted Therapies and Precautions
The subject’s best medical interests should guide the investigator in the management of 
conditions that are pre-existing or that develop during the trial (intercurrent illness or 
AEs).  The investigator should examine the acceptability of all concomitant medications 
not explicitly prohibited.  In order to ensure that appropriate concomitant therapy is 
administered, it is essential that subjects be instructed not to take any medications (either 
self-administered non-prescription drugs or prescription therapy prescribed by another 
physician) without prior consultation with the investigator.  In particular, the investigator 
should caution the subject about concomitant use of the following during the trial:

Non-steroidal anti-inflammatory drugs, aspirin, or other drugs that interfere with 
coagulation since the combined use of psychotropic drugs that interfere with 
serotonin reuptake and these agents has been associated with an increased risk of 
upper gastrointestinal bleeding.32

Triptans (eg, sumatriptan, naratriptan, almotriptan, frovatriptan, rizatriptan, eletriptan, 
and zolmitriptan), linezolid, and methylene blue since there have been rare 
post-marketing reports of serotonin syndrome or serotonin syndrome-like reactions 
(eg, mental status changes, hyperreflexia, autonomic effects, lack of coordination, and 
diarrhea) following the concomitant use of SSRIs or SNRIs and these drugs.33,34,35


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Electroconvulsive therapy was prohibited during the prior double-blind phase 3 trials and 
is also prohibited for the duration of Trial 331-10-238.  Transcranial magnetic stimulation 
is also prohibited.  In addition, subjects may not undergo implantation of a device for 
vagus nerve stimulation or deep brain stimulation during the trial.
Use of intramuscular benzodiazepines and continual use of oral benzodiazepines are
prohibited throughout the trial.  However, administration of specific oral benzodiazepines 
is permitted for the short-term management of treatment emergent AEs such as anxiety 
and agitation up to a maximum of 6 mg/day lorazepam (or equivalent) in divided doses.  
Short-acting benzodiazepines are to be used whenever possible.  In countries where no 
short-acting benzodiazepines are commercially available, use of oral diazepam or 
clonazepam may be acceptable if prior authorization is obtained from the medical 
monitor.  The following guide should be used to determine approximate lorazepam 
equivalents:  1 mg lorazepam = 15 mg oxazepam = 0.5 mg alprazolam = 5 mg diazepam 
= 0.5 mg clonazepam.  The prescribed benzodiazepine should be discontinued as soon as 
the AE for which it was initiated subsides, as per the investigator’s discretion to avoid 
any withdrawal effects.
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 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.
Anticholinergics are permitted for the treatment of EPS up to a maximum of 4 mg/day 
benztropine or its equivalent and propranolol is permitted for akathisia or tremor up to a 
maximum of 20 mg three times daily (total of 60 mg/day).  Sites should only utilize 
medications that are approved for these indications in their respective countries.
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 eCRF.


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Fluoxetine, paroxetine, and duloxetine are protocol-defined ADTs in this trial; however, 
they are also CYP2D6 inhibitors.  Data from Trial 331-08-207 and Trial 331-08-208 
indicate that coadministration of CYP2D6 inhibitors with brexpiprazole can cause 
potentially higher plasma concentrations of brexpiprazole (up to 2-fold).  In order to limit 
the potential higher exposure of brexpiprazole when coadministered with such inhibitors, 
the upper limit of the therapeutic ADT dose is limited to 40 mg for fluoxetine, 50 mg for 
paroxetine CR, and 60 mg for duloxetine.  The investigator should consider the potential 
for higher brexpiprazole plasma concentrations when adjusting the dose of brexpiprazole
for subjects who are receiving fluoxetine, paroxetine CR, or duloxetine as the assigned 
ADT.
All trial personnel should be familiar with the content of the Investigator Brochure 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
Subjects may only receive psychotherapy (eg, individual, group, marriage, or family 
therapy) if they initiated the therapy at least 42 days before enrollment in the prior 
double-blind phase 3 trial, participated in the therapy regularly during the prior 
double-blind phase 3 trial, and commit to maintain their participation during the course of 
Trial 331-10-238, or unless permission is obtained from the medical monitor.
Consumption of grapefruit, grapefruit products, Seville oranges, or Seville orange 
products within 72 hours prior to dosing and during the trial is prohibited.  Subjects will 
be instructed to refrain from drinking alcoholic beverages or using illicit drugs during 
participation in the trial.  The investigator may request a blood or urine drug screen at any 
time during the trial if there is a suspicion of illicit drug use.


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5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related.
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE.  For the purpose of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between the drug and 
the AE.  Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any AE caused by a drug.
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 or the 
sponsor, 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 or substantial disruption of the ability to 
conduct normal life functions.

requires in-patient hospitalization or prolongs an existing hospitalization  
NOTE: A pre-scheduled hospitalization is not considered an SAE; however, 
SAE forms must be completed for all other hospitalizations, including 
hospitalization for psychiatric reasons.  Psychosocial hospitalizations 
(eg, homelessness or need for shelter that is unrelated to the subject’s underlying 
psychiatric condition) should not be reported as SAEs.

congenital anomaly/birth defect

other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above, eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Non-serious adverse events are all AEs that do not meet the criteria for a "serious" AE.
If a subject is experiencing an extrapyramidal symptom, the specific extrapyramidal 
symptom must be indicated on the AE page of the eCRF.  Examples of AEs that are 
considered extrapyramidal symptoms include, but are not limited to:  generalized rigidity, 


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hyperkinesia, dyskinesia, bradykinesia, akinesia, dystonia, hypertonia, akathisia, tremor, 
flexed posture, involuntary muscle contractions, athetosis, and chorea.  If a subject is 
experiencing two 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 eCRF instead of the 
individual symptoms.  Permitted treatments for EPS are described in Section 4.2.1.
Immediately Reportable Event (IRE):

Any SAE

Any AE that necessitates discontinuation of IMP.

Potential Hy’s Law cases (any increase of AST or ALT 3 times the upper 
normal limit with an increase in total bilirubin 2 times the upper normal limit).

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 INC 
Research.  Pregnancy will only be documented on the AE eCRF if there is an 
abnormality or complication.
Clinical Laboratory 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 determined by the investigator 
to be an abnormal change from baseline for that subject, this is considered an AE. 
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF.  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 causal relationship.


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Possibly related: There is a reasonable causal relationship between the IMP and the 
AE.  Dechallenge is lacking or unclear.
Unlikely related: There is a temporal relationship to IMP administration, but there is 
not a reasonable causal relationship between the IMP and the AE.
Not Related: 
There is no temporal or reasonable relationship to the IMP
administration.
Investigators will assess IMP causality based on brexpiprazole.
5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  In order to 
avoid bias in eliciting AEs, subjects should be asked the following non-leading question: 
"How have you felt since your last visit?"  All AEs (serious and non-serious) reported by 
the subject must be recorded on the source documents and on the eCRFs provided by the 
sponsor or designee.
Note:  Normal pregnancy is not an AE and should not be recorded on the eCRFs; 
guidelines outlined in Section 5.5 should be followed for pregnancy reporting.
In addition, INC Research (Appendix 2) must be notified immediately by telephone or 
fax of any immediately reportable events 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 (IRE)
The investigator must immediately (ie, within 24 hours) report any serious adverse event, 
potential Hy’s law cases, or confirmed pregnancy by telephone or by fax to INC 
Research as outlined in Appendix 2 after either the investigator or site personnel become 
aware of the event.  An Immediately Reportable Event (IRE) form must be completed 
and transmitted per the instructions in the Operations Manual.  (Please note that the IRE
form is NOT the AE eCRF.)
Non-serious events that require discontinuation of IMP (including laboratory 
abnormalities) should be reported to INC Research within 3 working days.  The IRE form 
must be completed and sent by fax or overnight courier to INC Research.
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.


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5.4
Potential Hy’s Law Cases
For a subject that experiences an elevation in AST or ALT that is 3 times the upper 
normal limit, a total bilirubin level should also be evaluated. If the total bilirubin is 
2 times the upper normal limit, confirmatory repeat laboratory samples should be 
drawn within 48 to 72 hours of the initial draw.  If these values are confirmed, trial 
personnel will complete an IRE form with all values listed and also report the event as an 
AE on the eCRFs.  Please note: If the subject was enrolled into the trial with non-
exclusionary elevated transaminase levels at baseline, please discuss any potential drug-
induced liver injury events with the Medical Monitor.
5.5
Pregnancy
WOCBP and men who are sexually active must use an effective method of birth control 
during the course of the trial and for at least 30 days after the last dose in a manner such 
that risk of failure is minimized.  Unless the subject is sterile (ie, women who have had 
an oophorectomy and/or hysterectomy or have been postmenopausal for at least 
12 consecutive months; or men who have had orchidectomy) or remains abstinent, two of 
the following precautions must be used: vasectomy or tubal ligation (subject and 
partner), vaginal diaphragm, intrauterine device, birth control pills, birth control depot 
injection, birth control implant, condom or sponge with spermicide.  Any single method 
of birth control, including vasectomy and tubal ligation, may fail, leading to pregnancy.
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
trial participation for WOCBP.  The topics should generally include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Prior to trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an ICF stating that the above-mentioned risk factors 
and the consequences were discussed with her.


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During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
If a subject or investigator suspects that the subject may be pregnant prior to IMP
administration, 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 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 withdrawn from 
the trial.  Exceptions to trial discontinuation may be considered for life-threatening 
conditions only after consultations with the Drug Safety and Pharmacovigilance 
Department of INC Research (see Appendix 2 for contact information).
The investigator must immediately notify INC Research of any pregnancy associated 
with IMP exposure, including at least 30 days after the last dose for female subjects and 
the female partner(s) of a male subject and record the event on the IRE form and forward 
it to INC Research.  INC Research will forward Pregnancy Surveillance Form(s) for 
monitoring the outcome of the pregnancy.
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered if indicated.  In addition, the 
investigator must report to INC Research, 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 six months.
5.6
Follow-up of Adverse Events
For this trial, information on AEs will be followed for up to 30 (+ 2) days after the last 
dose of IMP has been administered.
5.6.1
Follow-up of Non-serious Adverse Events
Non-serious AEs that are identified on the last scheduled contact must be recorded on the 
AE eCRF with the current status noted.  All non-serious events that are ongoing at this 
time will be recorded as ongoing on the eCRF.


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5.6.2
Follow-up of Post Trial Serious Adverse Events
Serious adverse events that are identified on the last scheduled contact must be 
recorded on the AE eCRF page and reported to INC Research 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, or 
the subject is lost to follow-up.  Resolution means the subject has returned to the baseline 
state of health, or 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 INC Research up to the point the event has been resolved.
This trial requires that subjects be actively monitored for SAEs up to 30 (+ 2) days after 
discharge from the trial.
5.6.3
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 INC Research.  This may include SAEs
that are captured on follow-up visit or telephone contact or at any other time point after 
the defined trial period (ie, up to last scheduled contact). The investigator should follow 
related SAEs identified after the last scheduled contact until the events are resolved, or 
the subject is lost to follow-up.  The investigator should continue to report any significant 
follow-up information to INC Research up to the point the event has been resolved.
6
Pharmacokinetic Analysis
Not Applicable
7
Statistical Analysis
7.1
Primary and Secondary Outcome Variable Analysis
7.1.1
Data Sets for Analysis
The following analysis samples are defined for this trial:
Enrolled Sample:  comprises all subjects who sign an ICF for the trial.
Safety Sample:  comprises those subjects who receive at least one dose of open-label 
brexpiprazole as adjunctive therapy to one of the allowed ADTs.


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Efficacy Sample:  comprises those subjects in the Safety Sample who have at least one 
postbaseline efficacy evaluation of CGI-S.
The Safety Sample will be used for all baseline and safety summaries.
The Efficacy Sample will be used for the CGI-S summaries.
The observed cases (OC) dataset will consist of the actual observations recorded at each 
visit and will be used to present summaries per trial week.
The last-observation-carried-forward (LOCF) data set will include data recorded at a 
given visit in the Treatment Phase or, if no observation is recorded at that visit, data 
carried forward from the previous visit in the Treatment Phase.  Data collected prior to or 
on the first day of Treatment Phase dosing will not be carried forward or averaged with 
Treatment Phase data to impute missing values for the LOCF data set.
7.1.2
Handling of Missing Data
In order to assess sensitivity of results due to missing data, two types of analyses will be 
performed for analyses by visit:  LOCF and OC.  The LOCF and OC data sets are defined 
in Section 7.1.1.  The OC data set will be used for analyses at each visit and the LOCF 
data set will be used for the last visit analyses.
7.1.3
Primary Outcome Analysis
The primary safety analysis is the frequency and severity of AEs (see Section 7.4.1).
7.1.4
Secondary Outcome Analysis
Secondary efficacy endpoints are as follows:
1) Change from baseline in CGI-S score, by trial week and at the last visit;
2) Mean CGI-I score, by trial week and at the last visit;
3) Change from baseline in SDS score, by trial week and at the last visit;
4) Change from baseline in IDS-SR Total Score, by trial week and at the last visit.
Descriptive statistics will be provided for each endpoint.  The analysis will be carried out 
on the Efficacy Sample.  Descriptive statistics will be summarized at each trial visit using 
the OC data set and at the last visit using the LOCF data set.
7.2
Sample Size
The sample size is not based on statistical power considerations.  The trial population will 
be derived from eligible subjects from the prior double-blind phase 3 brexpiprazole MDD 


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trials.  Therefore, the number of eligible subjects will be limited by the number of 
subjects enrolled into these protocols.  Based on the projected enrollment estimates for 
the prior double-blind phase 3 trials, up to approximately 3,000 subjects may enroll into 
Trial 331-10-238.
7.3
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).
7.4
Safety Analyses
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, body weight, waist circumference, and BMI.  In addition, data from the following 
safety scales will be evaluated:  SAS, AIMS, BARS, C-SSRS, and MSFQ.  Analyses 
regarding safety and tolerability will be conducted based on the Safety Sample, which is 
defined in Section 7.1.1.  In general, baseline measurements of safety variables are 
defined as their last measurements prior to the first dose of open-label brexpiprazole.
7.4.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  The incidence of the following events will be 
summarized:
a) TEAEs by severity
b) Potentially drug-related TEAEs
c) TEAEs with an outcome of death
d) Serious TEAEs
e) Discontinuations due to TEAEs
7.4.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements, prolactin concentrations, coagulation parameters (PT, aPTT, and INR), 
HbA1c, and TSH will be provided.  In addition, potentially clinically significant results in 
laboratory tests identified using prospectively defined criteria will be summarized.


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7.4.3
Physical Examination and Vital Signs Data
By-patient listings will be provided for physical examination.  Summary statistics for 
changes from baseline in vital signs will be provided.  Potentially clinically significant 
results in vital signs will also be summarized.
7.4.4
ECG Data
Mean change from baseline and incidence of clinically significant changes will be 
calculated for ECG parameters.
For the analysis of QT and QTc, data from three consecutive complexes (representing 
three consecutive heart beats) will be measured to determine average values.  The 
following QT corrections will be used for reporting purposes in the clinical study report:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett formula: 
QTcB=QT/(RR)0.5
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula: QTcF=QT/(RR)0.33
3) QTcN is the length of the QT interval corrected for heart rate by the FDA
Neuropharm Division formula:  QTcN=QT/(RR)0.37
7.4.5
Other Safety Data
Descriptive statistics will be provided for the SAS, AIMS, BARS, and MSFQ scales.  
Change from baseline in body weight will be summarized by descriptive statistics, as 
well as incidence of clinically significant changes in body weight.  Descriptive statistics 
will also be provided for change from baseline in waist circumference and BMI.  
Descriptive statistics will be summarized at each visit using the OC data set and at the 
last visit using the LOCF data set.
Suicidality monitored during the trial using the C-SSRS will be summarized as number 
and percentage of subjects reporting any suicidal behavior, ideation, behavior by type 
(4 types), ideation by type (5 types), and treatment-emergent suicidal behavior and 
ideation.
7.5
Other Outcomes
The percentage of subjects hospitalized for exacerbation of symptoms (including 
emergency department visits) will be tabulated as a measure of healthcare resource 


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utilization.  The frequency of outpatient visits to various healthcare providers (eg, 
primary care physician, psychiatrists, other mental health practitioners, etc.) not required 
per the protocol will also be examined.
8
Trial Drug Management
8.1
Packaging and Labeling
Trial drugs will be provided to the investigator(s) by the sponsor (or designated agent).  
The IMP will consist of open-label brexpiprazole and open-label ADTs.  Open-label 
brexpiprazole will be supplied as 0.5, 1, 2, and 3-mg tablets packaged in weekly blister 
cards, each containing sufficient tablets for 7 (+ 2 days).  Blister cards will contain single 
tablet strengths (ie, brexpiprazole 0.5, 1, 2, or 3 mg/day) and subjects will take 1 tablet 
daily.  When accessed by the site, the IVRS or IWRS will assign a specific blister card 
number to be dispensed to a subject.  New weekly blister cards will be dispensed at each 
scheduled visit and at unscheduled visits if the dose of brexpiprazole is changed.
Each blister card used in the trial will be given an identifying number and will be labeled 
to clearly disclose the blister card number, Subject ID (to be filled in by the site 
staff/investigator), subject’s initials or other unique identifier, name of the investigator (to 
be filled in by the site staff/investigator), site number (to be filled in by the site 
staff/investigator), subject’s initials (to be filled in by the site staff/investigator), date 
dispensed (to be filled in by the site staff/investigator), compound ID, protocol number, 
the sponsor's name and address, instructions for use, route of administration, and 
appropriate precautionary statements.  Once a blister card has been assigned to a subject
via the IVRS or IWRS, it cannot be dispensed to another subject.
ADTs will be supplied as bulk drug in commercial packaging (eg, bottles) with an 
ancillary trial-specific label that will be positioned such that it will not obscure the 
original commercial label.  The sponsor reserves the right to use a generic equivalent, 
should any marketed antidepressant become unavailable during the course of the trial.  
Each ADT bottle used in the trial will be labeled to clearly disclose the bottle number, 
Subject ID, subject’s initials, protocol number, ADT drug name, the sponsor's name and 
address, instructions for use, route of administration, and appropriate precautionary 
statements.  Once an ADT bottle has been assigned to a subject via the IVRS or IWRS, it 
cannot be dispensed to another subject.  The amount of open-label ADT dispensed to a 
subject at each visit will be contingent upon the prescribed daily dose of ADT as well as 
the duration between trial visits.  Subjects must remain on the same ADT for the duration 


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of the trial (ie, Screening/Baseline through Week 26/ET).  Any subject who cannot 
tolerate the minimum protocol-defined therapeutic dose of ADT (see Table 3.2.1.2-1) or 
who is required to change from one ADT to another must be withdrawn from the trial.
8.2
Storage
Trial drugs will be stored in a securely locked cabinet or enclosure.  Access will be 
limited to the investigators and their designees.  Neither investigators nor any designees 
may provide trial drugs to any subject not participating in this protocol.
Brexpiprazole should be stored according to the storage conditions indicated on the 
clinical label.  The open-label ADTs should be stored as per the individual 
manufacturers’ label recommendations on the package insert or the ADT clinical label.  
The clinical site staff will maintain a temperature log in the drug storage area recording 
the temperature at least once each working day.
8.3
Accountability
The investigator, or designee, must maintain an inventory record of trial drugs (including 
brexpiprazole and ADTs) received, dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused and/or partially used IMP
(including brexpiprazole and ADTs) must be returned to Otsuka Pharmaceutical 
Development & Commercialization, Inc. (OPDC) (or a designated contractor).
All IMP returned to OPDC (or the designated contractor) must be accompanied by the 
appropriate documentation and be clearly identified by protocol number and trial site 
number.  Returned supplies should be in the original containers (eg, blister cards and 
ADT commercial packaging).  The assigned trial monitor will facilitate the return of 
unused and/or 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:


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
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
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 sponsor through and including reconciliation and up to 
destruction, including subject dosing.  The investigator or designee must notify the 
sponsor (or sponsor’s designee) within 24 hours of becoming aware of the PQC by e-mail 
or telephone and according to the procedure outlined below:  

Online – Send information required for reporting purposes (listed below) to 

Phone -
Call Center at 
.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of compliant

Reporter identification (eg, subject, investigator, site, etc)

Reporter contact information (eg, address, phone number, e-mail address.)

ID of material (product/compound name, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return


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8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return.  If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by OAPI-EQC.  
It should be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to OAPI-EQC for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of Product Quality complaints will be handled by OAPI 
EQC-QM group.
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.
9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

The date of the visit and the corresponding Visit in the trial schedule;

General subject status remarks, including any significant medical findings.  The 
severity, frequency, and duration of any AEs and the investigator's assessment of 
relationship to the IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of all clinicians who made an entry in the progress 
notes.


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In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. Any changes to information in the trial progress notes or other source 
documents will be initialed and dated on the day the change is made by a site trial staff 
member authorized to make the change.  Changes will be made by striking a single line 
through erroneous data, and clearly entering the correct data (eg, wrong data right data).  
If the reason for the change is not apparent, a brief explanation for the change will be 
written in the source documentation by the clinician.
Information from the trial progress notes and other source documents will be data entered 
by investigative site personnel directly onto eCRFs in the sponsor’s electronic data 
capture system.
9.3
File Management at the Trial Site
The investigator will ensure that the trial center file is maintained in accordance with 
Section 8 of the ICH GCP 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 
three periods:

A period of at least 2 years following 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 the sponsor 
or designated agent 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 the eCRF data on the 
CD-ROM and any data clarification forms received from the sponsor (or sponsor’s 


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designee).  Such documentation is subject to inspection by the sponsor, sponsor’s 
designee, and relevant regulatory agencies.  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 (or designee) in writing.
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in a detailed 
and orderly manner in accordance with established research principles, the ICH GCP 
Guideline, FDA regulations and applicable regulatory requirements and local laws.  As 
part of a concerted effort to fulfill these obligations (maintain current personal knowledge 
of the progress of the trial), the sponsor's monitors or designee will visit the site during
the trial, as well as communicate frequently via telephone and written communications.
10.2
Auditing
The sponsor's Quality Management Unit (or representative) may conduct trial site audits.  
Audits will include, but are not be limited to, drug supply, presence of required 
documents, the informed consent process, and comparison of eCRFs with source 
documents.  The investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator 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, the ICH 
GCP Guideline, and all other applicable local laws and regulatory requirements. Each 
trial site will seek approval by an IRB or EC according to regional requirements. The 
IRB/IEC will evaluate the ethical, scientific and medical appropriateness of the trial. 
Further, in preparing and handling eCRFs, the investigator, subinvestigator, and their 
staff will take measures to ensure adequate care in protecting subject privacy. To this 
end, a subject number and subject identification code will be used to identify each 
subject.


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12
Confidentiality
All information generated in this trial will be considered highly confidential and will not 
be disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  However, authorized regulatory officials and sponsor personnel (or 
their representatives) will be allowed full access to inspect and copy the records.  All 
IMPs, subject bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by the sponsor.
Subjects will be identified only by initials and unique subject numbers in eCRFs.  Per 
country regulations, if subject initials cannot be collected, another unique identifier will 
be used.  Their full names may, however, be made known to a regulatory agency or other 
authorized officials if necessary.
13
Amendment Policy
The investigator will not make any changes to this protocol without prior written consent 
from the sponsor (or sponsor’s designee) and subsequent approval by the IRB/IEC.  Any 
permanent change to the protocol, whether it be 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.  Except for 
non-substantial (ie, administrative) amendments, investigators will wait for IRB/IEC 
approval of the amended protocol before implementing the change(s).  Administrative 
amendments are defined as having no effect on the safety or physical or mental integrity
of subjects, the conduct or management of the trial, the scientific value of the trial or the 
quality or safety of IMP(s) used in the trial.  However, a protocol change intended to 
eliminate an apparent immediate hazard to subjects should be implemented immediately, 
followed by IRB/IEC notification within 5 working days.  The sponsor (or sponsor’s 
designee) will submit protocol amendments to the FDA or other regulatory agencies.
When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written ICF will require similar modification.  In such 
cases, after approval of the new ICF by the IRB/IEC, repeat informed consent will be 
obtained from subjects in a timely manner before expecting continued participation in the 
trial.


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14
References
1
Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, et al. Recurrence after 
recovery from Major Depressive Disorder during 15 years of observational follow-up. 
Am J Psychiatry. 1999;156:1000-6.
2
Eaton WW, Shao H, Nestadt G, Lee BH, Bienvenu OJ, Zandi P. Population-based 
study of first onset and chronicity in Major Depressive Disorder. Arch Gen 
Psychiatry. 2008;65:513-20.
3
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. 
Evaluation of outcomes with citalopram for depression using measurement-based 
care in STAR*D:  Implications for clinical practice. Am J Psychiatry. 2006;163:28-
40.
4
Moller HJ. Outcomes in major depressive disorder: the evolving concept of remission 
and its implications for treatment. World J Biol Psychiatry. 2008;9:102-14.
5
Mulder RT, Frampton CM, Luty SE, Joyce PR. Eighteen months of drug treatment 
for depression: Predicting relapse and recovery. J Affect Disord. 2009;114:263-70.
6
Judd LL, Schettler PJ, Akiskal HS. The prevalence, clinical relevance, and public 
health significance of subthreshold depressions. Psychiatr Clin North Am. 
2002;25:685-98.
7
McIntyre RS, O'Donovan C. The human cost of not achieving full remission in 
depression. Can J Psychiatry. 2004;49(Suppl 1):10S-16S.
8
Sobocki P, Jonsson B, Angst J, Rehnberg C. Cost of depression in Europe. J Ment 
Health Policy Econ. 2006;9:87-98.
9
American Psychiatric Association. Practice Guideline for the Treatment of Patients 
with Major Depressive Disorder, Second Edition. Arlington, VA: American 
Psychiatric Association; 2000.
10 Trivedi MH, Thase ME, Osuntokun O, Henley DB, Case M, Watson SB, et al. An 
integrated analysis of olanzapine/fluoxetine combination in clinical trials of 
treatment-resistant depression. J Clin Psychiatry. 2009;70:387-96.
11 Bauer M, El-Khalili N, Dato C, Szamosi J, Eriksson H. A pooled analysis of two 
randomised, placebo-controlled studies of extended release quetiapine fumarate 
adjunctive to antidepressant therapy in patients with major depressive disorder. J 
Affect Disord. 2010;127:19-30.
12 Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon J, et al. The 
efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder. 
A second multicenter, randomized, double-blind, placebo-controlled study. J Clin 
Psychopharmacol. 2008;28:156-65.
13 Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, et 
al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive 
disorder:  A multicenter, randomized, double-blind, placebo-controlled study. J Clin 
Psychiatry. 2007;68:843-853.


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14 Mahmoud RA, Pandina GJ, Turkoz I, Kosik-Gonzalez C, Canuso CM, Kujawa MJ, et 
al. Risperidone for treatment-refractory major depressive disorder: a randomized trial. 
Ann Intern Med. 2007;147:593-602.
15 Reynolds GP, Kirk SL. Metabolic side effects of antipsychotic drug treatment -
pharmacological mechanisms. Pharmacol Ther. 2010;125:169-79.
16 Sharpley AL, Attenburrow ME, Hafizi S, Cowen PJ. Olanzapine increases slow wave 
sleep and sleep continuity in SSRI-resistant depressed patients. J Clin Psychiatry. 
2005;66(4):450-4.
17 Miller DD. Atypical antipsychotics: Sleep, sedation, and efficacy. Prim Care 
Companion J Clin Psychiatry. 2004;6(Suppl 2):3-7.
18 Ohno Y. New insight into the therapeutic role of 5-HT1A receptors in central nervous 
system disorders. Cent Nerv Syst Agents Med Chem. 2010;10:148-57.
19 OPC-34712 Investigator's Brochure, Otsuka Pharmaceutical Development & 
Commercialization, Inc. Version No. 6, 03 Mar 2011.
20
. A phase 2, multicenter, randomized, double-blind, placebo-controlled 
study of the safety and efficacy of OPC-34712 as adjunctive therapy in the treatment
of patients with major depressive disorder. Otsuka Clinical Study Report for Protocol 
331-08-211, issued 23 Mar 2011.
21
. A phase 2, 6-week, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy, safety, and tolerability of oral OPC-34712 
once daily and aripiprazole once daily for treatment of hospitalized adult patients with 
acute schizophrenia. Otsuka Clinical Study Report for Protocol 331-07-203, issued 09 
Mar 2011.
22 Blier P and Szabo SR. Potential mechanisms of action of atypical antipsychotic 
medications in treatment-resistant depression and anxiety. J Clin Psychiatry.  
2005;66(Suppl 8):30-40.
23 Trivedi MH, Hollander E, Nutt D, Blier P. Clinical evidence and potential 
neurobiological underpinnings of unresolved symptoms of depression. J Clin 
Psychiatry. 2008;69:246-58.
24 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.
25 Simpson GN, Angus JWS. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand. 1970;212(Suppl 44):S11-S19.
26 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.
27 Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 
1989;154:672 6.


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28 Labbate LA, Lare SB. Sexual dysfunction in male psychiatric outpatients: validity of 
the Massachusetts General Hospital Sexual Functioning Questionnaire. Psychother 
Psychosom. 2001;70:221-5.
29 Sheehan DV. The Anxiety Disease. New York: Charles Scribner & Sons; 1983.
30 Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin 
Psychopharmacol. 1996;11(Suppl 3):89-95.
31 Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of 
Depressive Symptomatology (IDS):  Psychometric properties. Psychol Med. 
1996;26:477-86.
32 Loke YK, Trivedi AN, Singh S. Meta-analysis:  gastrointestinal bleeding due to 
interaction between selective serotonin uptake inhibitors and non-steroidal anti-
inflammatory drugs. Aliment Pharmacol Ther. 2008;27:31-40.
33 US Food and Drug Administration [homepage on the Internet]. Rockville, MD:  FDA 
Public Health Advisory 2006 19 Jul [cited 24 Oct 2011]. Available at 
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandPro
viders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm
124349.htm
34 US Food and Drug Administration [homepage on the Internet]. Rockville, MD:  FDA 
Drug Safety Communication 2011 26 Jul [updated 2011 21 Oct; cited 24 Oct 2011]. 
Available at 
www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPr
oducts/ucm265479.htm
35 US Food and Drug Administration [homepage on the Internet]. Rockville, MD:  FDA 
Drug Safety Communication 2011 26 Jul [updated 2011 21 Oct; cited 24 Oct 2011]. 
Available at 
www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPr
oducts/ucm265476.htm


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Appendix 1
Names of Sponsor Personnel
Primary Medical Contact:
, 
 
, 
.
Phone 
Mobile 
 
Backup Medical Contact:
, 
, 
Phone 
Fax 
E-mail 
 
:
. 
, 
, 
Phone 
Fax 
Primary Clinical Contact:
Phone: 
Fax: 
1
Mobile: 
email: 
 
Backup Clinical Contacts:
.
Phone 


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Fax 
, 
 
Phone 
Fax 


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Appendix 2
Institutions Concerned With the Trial
Clinical Research Organization
INC Research
3201 Beechleaf Court, Suite 600
Raleigh, NC  27604-1547
USA
Safety Reporting
Please report SAEs, AEs requiring discontinuation of drug product, and pregnancies to 
INC Research Pharmacovigilance & Drug Safety as follows:
Country
Safety Fax Line
United States
Canada
France
Germany
Hungary
Poland
Romania
Russia
Slovakia
Ukraine
All other countries
Medical Monitors
North America:
Primary:
, 
r
, 
Phone:  
Mobile:  
Fax:  
E-mail: 


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Backup:
Phone: 
 
Mobile: 
 
Fax: 
E-mail:  
EU:
Phone:  
Mobile:  
Fax:  
E-mail: 
Clinical Lab - ECG Central Reader
eResearch Technology
1818 Market Street, Suite 1000
Philadelphia, PA  19103-3638
USA
Central Laboratory
Covance Laboratories
8211 SciCor Drive
Indianapolis, IN 46214
USA
Subject Recruitment/Retention
INC Research
3201 Beechleaf Court, Suite 600
Raleigh, NC  27604-1547
USA


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Materials for Subject Recruitment/Retention
Southport Graphics
210 James Jackson Avenue
Cary, NC, 27513
USA
Phone:  (919) 650-3822
Electronic Data Capture
Medidata Solutions
79 5th Avenue, 8th floor
New York, NY  10003
USA
Rater Training
Bracket
575 East Swedesford Road, Suite 200
Wayne, PA 19087
USA
IVRS/IWRS
S-Clinica
6, chaussée de Boondael
B-1050 Brussels, Belgium
Translation Agency
Global Language Solutions, Inc.
25 Enterprise, Suite 500
Aliso Viejo, CA 92656
USA
Central IRB
Schulman Associates IRB
4445 Lake Forest Drive
Suite 300
Cincinnati, OH 45242
USA


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Appendix 3
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Heart Rateb
> 120 bpm
< 50 bpm
15 bpm increase
15 bpm decrease
Systolic Blood Pressureb
> 180 mmHg
< 90 mmHg
20 mmHg increase
20 mmHg decrease
Diastolic Blood Pressureb
> 105 mmHg
< 50 mmHg
15 mmHg increase
15 mmHg decrease
Orthostatic Hypotension
20 mmHg decrease in systolic blood 
pressure and a 25 bpm increase in 
heart rate from supine to 
sitting/standing
Not Applicable
(baseline status not considered)
Weight
-
7% increase
7% decrease
a In 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.
b As 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 4
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 5
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 study entry
ST/T Morphological
Myocardial Ischemia
all
not present present
Symmetrical T-wave inversion
all
not present present
Increase in QTc
QTcF 450 msec 
(males and females)
a In 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.
b No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
c No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
d No current diagnosis of left bundle branch block or right bundle branch block.


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Appendix 6
Clinical Global Impression - Severity of Illness Scale (CGI-S)
Considering your total clinical experience with this particular population, how mentally 
ill is the patient at this time? 
0 = Not assessed
4 = Moderately ill
1 = Normal, not at all ill
5 = Markedly ill
2 = Borderline mentally ill
6 = Severely ill
3 = Mildly ill
7 = Among the most extremely ill patients


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Appendix 7
Clinical Global Impression - Improvement Scale (CGI-I)
Rate total improvement whether or not in your judgment it is due entirely to drug 
treatment.  Compared to his/her condition at the last scheduled visit of the prior double-
blind phase 3 trial (ie, prior to enrollment into Trial 331-10-238), how much has patient 
changed?
0 = Not assessed
4 = No change
1 = Very much improved
5 = Minimally worse
2 = Much improved
6 = Much worse
3 = Minimally improved
7 = Very much worse


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Appendix 8
Sheehan Disability Scale (SDS)
Instructions to the investigator:
The Sheehan Disability Scale is a measurement of functional disability and impairment 
due to psychiatric symptoms. It consists of 3 functional impairment items and 2 items 
related to productivity losses due to the symptoms and impairment.
The Sheehan Disability Scale is a self rated questionnaire and should be administered to 
the patient to be completed on his/her own without the presence or influence of study 
investigator/nurse or other individuals.
You should instruct the patient to report the disability and impairment experienced during 
the past week due to his/her symptoms. Emphasize that you will not interfere with the 
completion or have any comments to the patient’s responses.
Please note that a questionnaire that has been completed by the patient is considered as 
source data and cannot be amended by the investigator or any other individual.
Reference: 
Sheehan DV. The Anxiety Disease. New York. Charles Scribner and Sons, 1983
Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. International Clinical 
Psychopharmacology 1996;11:89-95.


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SHEEHAN DISABILITY SCALE
A BRIEF, PATIENT RATED, MEASURE OF DISABILITY AND IMPAIRMENT
Please mark ONE circle for each scale.
DAYS LOST
On how many days in the last week did your symptoms cause you to miss school or work 
or leave you unable to carry out your normal daily responsibilities?________
DAYS UNDERPRODUCTIVE
On how many days in the last week did you feel so impaired by your symptoms, that 
even though you went to school or work, your productivity was reduced?________
Copyright 1983, 2010 David V. Sheehan.  All rights reserved.  Reproduced with permission of the 
author
WORK* / SCHOOL
The symptoms have disrupted your work / school work:
0
1
2
3
4
5
6
7
8
9
10
Not at all
Mildly
Moderately
Markedly
Extremely
I have not worked / studied at all during the past week for reasons unrelated to disorder.
* Work includes paid, unpaid volunteer work or training
SOCIAL LIFE
The symptoms have disrupted your social life / leisure activities:
0
1
2
3
4
5
6
7
8
9
10
Not at all
Mildly
Moderately
Markedly
Extremely
FAMILY LIFE / HOME RESPONSIBILITIES
The symptoms have disrupted your family life / home responsibilities:
0
1
2
3
4
5
6
7
8
9
10
Not at all
Mildly
Moderately
Markedly
Extremely


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Appendix 9
Inventory of Depressive Symptomatology (Self-Report) (IDS-
SR)
Please circle the one response to each item that best describes you for the past seven days.
1.
Falling Asleep:
0
I never take longer than 30 minutes to fall asleep.
1
I take at least 30 minutes to fall asleep, less than 
half the time.
2
I take at least 30 minutes to fall asleep, more than 
half the time.
3
I take more than 60 minutes to fall asleep, more 
than half the time.
2.
Sleep During the Night:
0
I do not wake up at night.
1
I have a restless, light sleep with a few brief 
awakenings each night.
2
I wake up at least once a night, but I go back to 
sleep easily.
3
I awaken more than once a night and stay awake 
for 20 minutes or more, more than half the time.
3.
Waking Up Too Early:
0
Most of the time, I awaken no more than 30 
minutes before I need to get up.
1
More than half the time, I awaken more than 30 
minutes before I need to get up.
2
I almost always awaken at least one hour or so 
before I need to, but I go back to sleep eventually.
3
I awaken at least one hour before I need to, and 
can’t go back to sleep.
4.
Sleeping Too Much:
0
I sleep no longer than 7-8 hours/night, without 
napping during the day.
1
I sleep no longer than 10 hours in a 24-hour period 
including naps.
2
I sleep no longer than 12 hours in a 24-hour period 
including naps.
3
I sleep longer than 12 hours in a 24-hour period 
including naps.
5.
Feeling Sad:
0
I do not feel sad.
1
I feel sad less than half the time.
2
I feel sad more than half the time.
3
I feel sad nearly all of the time.
6.
Feeling Irritable:
0
I do not feel irritable.
1
I feel irritable less than half the time.
2
I feel irritable more than half the time.
3
I feel extremely irritable nearly all of the time.
7.
Feeling Anxious or Tense:
0
I do not feel anxious or tense.
1
I feel anxious (tense) less than half the time.
2
I feel anxious (tense) more than half the time.
3
I feel extremely anxious (tense) nearly all of 
the time.
8.
Response of Your Mood to Good or Desired Events:
0
My mood brightens to a normal level which 
lasts for several hours when good events occur.
1
My mood brightens but I do not feel like my 
normal self when good events occur.
2
My mood brightens only somewhat to a rather 
limited range of desired events.
3
My mood does not brighten at all, even 
when very good or desired events occur in 
my life.
9.
Mood in Relation to the Time of Day:
0
There is no regular relationship between my 
mood and the time of day.
1
My mood often relates to the time of day 
because of environmental events (e.g., being 
alone, working).
2
In general, my mood is more related to the time 
of day than to environmental events.
3
My mood is clearly and predictably better or 
worse at a particular time each day.
9A. Is your mood typically worse in the morning, 
afternoon or night?  (circle one)
9B. Is your mood variation attributed to the 
environment? (yes or no) (circle one)
10. The Quality of Your Mood:
0
The mood (internal feelings) that I experience 
is very much a normal mood.
1
My mood is sad, but this sadness is pretty much 
like the sad mood I would feel if someone close 
to me died or left.
2
My mood is sad, but this sadness has a rather 
different quality to it than the sadness I would 
feel if someone close to me died or left.
3
My mood is sad, but this sadness is different 
from the type of sadness associated with 
grief or loss.
Reprinted with permission from A. John Rush Jr., M.D.


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Please complete either 11 or 12 (not both)
11. Decreased Appetite:
0
There is no change in my usual appetite.
1
I eat somewhat less often or lesser amounts of 
food than usual.
2
I eat much less than usual and only with personal 
effort.
3
I rarely eat within a 24-hour period, and only 
with extreme personal effort or when others 
persuade me to eat.
12. Increased Appetite:
0
There is no change from my usual appetite.
1
I feel a need to eat more frequently than usual.
2
I regularly eat more often and/or greater amounts 
of food than usual.
3
I feel driven to overeat both at mealtime and 
between meals.
Please complete either 13 or 14 (not both)
13. Decreased Weight (Within the Last Two Weeks):
0
I have not had a change in my weight.
1
I feel as if I’ve had a slight weight loss.
2
I have lost 2 pounds or more.
3
I have lost 5 pounds or more.
14. Increased Weight (Within the Last Two Weeks):
0
I have not had a change in my weight.
1
I feel as if I’ve had a slight weight gain.
2
I have gained 2 pounds or more.
3
I have gained 5 pounds or more.
15. Concentration/Decision Making:
0
There is no change in my usual capacity to 
concentrate or make decisions.
1
I occasionally feel indecisive or find that my 
attention wanders.
2
Most of the time, I struggle to focus my attention 
or to make decisions.
3
I cannot concentrate well enough to read or 
cannot make even minor decisions.
16. View of Myself:
0
I see myself as equally worthwhile and deserving 
as other people.
1
I am more self-blaming than usual.
2
I largely believe that I cause problems for others.
3
I think almost constantly about major and minor 
defects in myself.
17. View of My Future:
0
I have an optimistic view of my future.
1
I am occasionally pessimistic about my future, 
but for the most part I believe things will get 
better.
2
I’m pretty certain that my immediate future 
(1-2 months) does not hold much promise of 
good things for me.
3
I see no hope of anything good happening to 
me anytime in the future.
18. Thoughts of Death or Suicide:
0
I do not think of suicide or death.
1
I feel that life is empty or wonder if it’s worth 
living.
2
I think of suicide or death several times a 
week for several minutes.
3
I think of suicide or death several times a day 
in some detail, or I have made specific plans 
for suicide or have actually tried to take my 
life.
19. General Interest:
0
There is no change from usual in how 
interested I am in other people or activities.
1
I notice that I am less interested in people or 
activities.
2
I find I have interest in only one or two of my 
formerly pursued activities.
3
I have virtually no interest in formerly pursued 
activities.
20. Energy Level:
0
There is no change in my usual level of 
energy.
1
I get tired more easily than usual.
2
I have to make a big effort to start or finish my 
usual daily activities (for example, shopping, 
homework, cooking or going to work).
3
I really cannot carry out most of my usual 
daily activities because I just don’t have the 
energy.
21. Capacity for Pleasure or Enjoyment (excluding 
sex):
0
I enjoy pleasurable activities as much as usual.
1
I do not feel my usual sense of enjoyment 
from pleasurable activities.
2
I rarely get a feeling of pleasure from any 
activity.
3
I am unable to get any pleasure or enjoyment 
from anything.
Reprinted with permission from A. John Rush Jr.,M.D.


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22. Interest in Sex (Please Rate Interest, not Activity):
0
I’m just as interested in sex as usual.
1
My interest in sex is somewhat less than usual or I 
do not get the same pleasure from sex as I used to.
2
I have little desire for or rarely derive pleasure 
from sex.
3
I have absolutely no interest in or derive no 
pleasure from sex.
23. Feeling slowed down:
0
I think, speak, and move at my usual rate of speed.
1
I find that my thinking is slowed down or my voice 
sounds dull or flat.
2
It takes me several seconds to respond to most 
questions and I’m sure my thinking is slowed.
3
I am often unable to respond to questions without 
extreme effort.
24. Feeling restless:
0
I do not feel restless.
1
I’m often fidgety, wring my hands, or need to shift 
how I am sitting.
2
I have impulses to move about and am quite 
restless.
3
At times, I am unable to stay seated and need to 
pace around.
25. Aches and pains:
0
I don’t have any feeling of heaviness in my arms or 
legs and don’t have any aches or pains.
1
Sometimes I get headaches or pains in my stomach, 
back or joints but these pains are only sometime 
present and they don’t stop me from doing what I 
need to do.
2
I have these sorts of pains most of the time.
3
These pains are so bad they force me to stop what I 
am doing.
26. Other bodily symptoms:
0
I don’t have any of these symptoms:  heart 
pounding fast, blurred vision, sweating, hot and 
cold flashes, chest pain, heart turning over in my 
chest, ringing in my ears, or shaking.
1
I have some of these symptoms but they are mild 
and are present only sometimes.
2
I have several of these symptoms and they bother 
me quite a bit.
3
I have several of these symptoms and when they 
occur I have to stop doing whatever I am doing.
27. Panic/Phobic symptoms:
0
I have no spells of panic or specific fears 
(phobia) (such as animals or heights).
1
I have mild panic episodes or fears that do not 
usually change my behavior or stop me from 
functioning.
2
I have significant panic episodes or fears that 
force me to change my behavior but do not stop 
me from functioning.
3
I have panic episodes at least once a week or 
severe fears that stop me from carrying on my 
daily activities.
28. Constipation/diarrhea:
0
There is no change in my usual bowel habits.
1
I have intermittent constipation or diarrhea 
which is mild.
2
I have diarrhea or constipation most of the time 
but it does not interfere with my day-to-day 
functioning.
3
I have constipation or diarrhea for which I take 
medicine or which interferes with my day-to-
day activities.
29. Interpersonal Sensitivity:
0
I have not felt easily rejected, slighted, 
criticized or hurt by others at all.
1
I have occasionally felt rejected, slighted, 
criticized or hurt by others.
2
I have often felt rejected, slighted, criticized or 
hurt by others, but these feelings have had only 
slight effects on my relationships or work.
3
I have often felt rejected, slighted, criticized or 
hurt by others and these feelings have impaired 
my relationships and work.
30. Leaden Paralysis/Physical Energy:
0
I have not experienced the physical sensation of 
feeling weighted down and without physical 
energy.
1
I have occasionally experienced periods of 
feeling physically weighted down and without 
physical energy, but without negative effect on 
work, school, or activity level.
2
I feel physically weighted down (without 
physical energy) more than half the time.
3
I feel physically weighted down (without 
physical energy) most of the time, several 
hours per day, several days per week.
Which 3 items (questions) were the easiest to understand?
________________
Thank you
Range 0-84
Score:
_________________
Reprinted with permission from A. John Rush Jr., M.D.


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Appendix 10
Simpson Angus Scale (SAS)
Circle the appropriate score for each item:
1.
GAIT
The patient is examined as he walks into the examining room; his gait, the swing of arms, his 
general posture; all form the basis for an overall score for this item.  This is rated as follows:
0
Normal
1
Mild diminution in swing while the patient is walking 
2
Obvious diminution in swing suggesting shoulder rigidity
3
Stiff gait with little or no arm swing noticeable
4
Rigid gait with arms slightly pronated; or stooped-shuffling gait with propulsion and retropulsion.
2.
ARM DROPPING
The patient and the examiner both raise their arms to shoulder height and let them fall to their sides, 
in a normal subject a stout slap is heard as the arms hit the sides.  In the patient with extreme 
Parkinson's syndrome, the arms fall very slowly.
0
Normal, free fall with loud slap and rebound
1
Fall slowed slightly with less audible contact and little rebound
2
Fall slowed, no rebound
3
Marked slowing, no slap at all
4
Arms fall as though against resistance; as though through glue
3.
SHOULDER SHAKING
The subject's arms are bent at a right angle at the elbow and taken one at a time by the examiner 
who grabs one hand and also clasps the other around the patient's elbow.  The subject's upper arm is 
pushed to and fro and the humerus is externally rotated.  The degree of resistance from normal to 
extreme rigidity is scored as follows:
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
4.
ELBOW RIGIDITY
The elbow joints are separately bent at right angles and passively extended and flexed, with the 
subject's biceps observed and simultaneously palpated.  The resistance to the procedure is rated.  
(The presence of cogwheel rigidity is noted separately.)
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint


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5.
WRIST RIGIDITY
The wrist is held in one hand and then the fingers held by the examiner's other hand with the wrist 
moved to extension, and both ulnar and radial deviation.  The resistance to this procedure is rated:
0
Normal
1
Slight stiffness and resistance
2
Moderate stiffness and resistance
3
Marked rigidity with difficulty in passive movement
4
Extreme stiffness and rigidity with almost a frozen joint
6.
HEAD ROTATION
The patient sits or stands and is told that you are going to move his head from side to side, that it 
will not hurt and that he should try and relax.  (Questions about pain in the cervical area or difficulty 
in moving his head should be obtained to avoid causing any pain.)  Clasp the patient's head between 
the two hands with fingers on back of the neck.  Gently rotate the head in a circular motion 3 times 
and evaluate the muscular resistance to the movement.
0
Loose, no resistance
1
Slight resistance to movement although the time to rotate may be normal
2
Resistance is apparent and time of rotation is slowed
3
Resistance is obvious and rotation is slowed
4
Head appears stiff and rotation is difficult to carry out
7.
GLABELLA TAP
Subject is told to open his eyes and not to blink.  The glabella region is tapped at a steady, rapid 
speed.  The number of times patient blinks in succession is noted:
0
0-5 blinks
1
6-10 blinks
2
11-15 blinks
3
16-20 blinks
4
21 and more blinks
8.
TREMOR
Patient is observed walking into examining room and then is examined for this item:
0
Normal
1
Mild finger tremor, obvious to sight and touch
2
Tremor of hand or arm occurring spasmodically
3
Persistent tremor of one or more limbs
4
Whole body tremor
9.
SALIVATION
Patient is observed while talking and then asked to open his mouth and elevate his tongue.  The 
following ratings are given:
0
Normal
1
Excess salivation so that pooling takes place if the mouth is open and the tongue raised
2
Excess salivation is present and might occasionally result in difficulty in speaking
3
Speaking with difficulty because of excess salivation
4
Frank drooling


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10.
AKATHISIA
Patient is observed for restlessness.  If restlessness is noted, ask: "Do you feel restless or jittery 
inside; is it difficult to sit still?"  Subjective response is not necessary for scoring but patient report 
can help make the assessment.
0
No restlessness reported or observed
1
Mild restlessness observed
2
Moderate restlessness observed
3
Restlessness is frequently observed
4
Restlessness persistently observed
Adapted and used with permission by Simpson GN and Angus JWS, “A Rating Scale for Extrapyramidal 
Side Effects,” Acta Psychiatr Scand, 1970, 212 (Suppl 44):11-9.


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Appendix 11
Abnormal Involuntary Movement Scale (AIMS)
Movement ratings: rate highest severity observed.  Rate 
movements that occur upon activation one less than those 
observed spontaneously.
Code for items 1-7:
0 = None
1 = Minimal, may be extreme normal
2 = Mild
3 = Moderate
4 = Severe
(Circle One)
FACIAL AND 
ORAL 
MOVEMENTS:
1.
MUSCLES OF FACIAL EXPRESSION e.g. 
movements of forehead, eyebrows, periorbital area, 
cheeks; include frowning, blinking, smiling, grimacing
0
1
2
3
4
2.
LIPS AND PERIORAL AREA e.g. puckering, pouting, 
smacking.
0
1
2
3
4
3.
JAW e.g. biting, clenching, chewing, mouth opening, 
lateral movement.
0
1
2
3
4
4.
TONGUE Rate only increase in movement both in and 
out of mouth, not inability to sustain movement.
0
1
2
3
4
EXTREMITY 
MOVEMENTS:
5.
UPPER (ARMS, WRISTS, HANDS, FINGERS)
include choreic movements (i.e. rapid, objectively 
purposeless, irregular, spontaneous), athetoid movements 
(i.e. slow, irregular, complex, serpentine).  Do not 
include tremor (i.e. repetitive, regular, rhythmic).
0
1
2
3
4
6.
LOWER (LEGS, KNEES, ANKLES, TOES) e.g. 
lateral knee movement, foot tapping, heel dropping, foot 
squirming, inversion and eversion of foot
0
1
2
3
4
TRUNK
MOVEMENTS:
7.
NECK, SHOULDERS, HIPS e.g. rocking, twisting, 
squirming, pelvic gyrations
0
1
2
3
4
GLOBAL
JUDGMENTS:
8.
Severity of abnormal movements
None, normal
0
Minimal
1
Mild
2
Moderate
3
Severe
4
9.
Incapacitation due to abnormal movements
None, normal
0
Minimal
1
Mild
2
Moderate
3
Severe
4
10. Patient's awareness of abnormal movements
Rate only subject’s report.
No awareness
0
Aware, no distress
1
Aware, mild distress
2
Aware, moderate distress
3
Aware, severe distress
4
DENTAL
STATUS:
11. Any current problems with teeth and/or dentures?
No
0
Yes
1
12. Does patient usually wear dentures?
No
0
Yes
1
Guy, W. ed. ECDEU Assessment Manual for Psychopharmacology. US Dept of HEW, Publication No. 
(Adm): 76-338, 1976


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Appendix 12
Barnes Akathisia Rating Scale (BARS)
Rating scale for drug-induced akathisia (Barnes Akathisia Rating Scale)
Instructions
Patient should be observed while they are seated, and then standing while engaged in 
neutral conversation (for a minimum of two minutes in each position).  Symptoms 
observed in other situations, for example while engaged in activity on the ward, may also 
be rated.  Subsequently, the subjective phenomena should be elicited by direct 
questioning.
Objective
0
Normal, occasional fidgety movements of the limbs
1
Presence of characteristic restless movements: shuffling or tramping movements of 
the legs/feet, or swinging one leg while sitting, and/or rocking from foot to foot or 
"walking on the spot" when standing, but movements present for less than half the 
time observed
2 
Observed phenomena, as described in (1) above, which are present for at least half 
the observation period
3
Patient is constantly engaged in characteristic restless movements, and/or has the 
inability to remain seated or standing without walking or pacing, during the time 
observed
Subjective
Awareness of restlessness
0
Absence of inner restlessness
1
Non-specific sense of inner restlessness
2
The patient is aware of an inability to keep the legs still, or a desire to move the 
legs, and/or complains of inner restlessness aggravated specifically by being 
required to stand still
3
Awareness of intense compulsion to move most of the time and/or reports strong 
desire to walk or pace most of the time
Distress related to restlessness
0 
No distress
1 
Mild
2
Moderate
3 
Severe


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Global clinical assessment of akathisia
0 
Absent.  No evidence of awareness of restlessness.  Observation of characteristic 
movements of akathisia in the absence of a subjective report of inner restlessness 
or compulsive desire to move the legs should be classified as pseudoakathisia
1 
Questionable.  Non-specific inner tension and fidgety movements
2 
Mild akathisia.  Awareness of restlessness in the legs and/or inner restlessness 
worse when required to stand still.  Fidgety movements present, but characteristic 
restless movements of akathisia not necessarily observed.  Condition causes little 
or no distress
3 
Moderate akathisia.  Awareness of restlessness as described for mild akathisia
above, combined with characteristic restless movements such as rocking from foot 
to foot when standing.  Patient finds the condition distressing
4 
Marked akathisia.  Subjective experience of restlessness includes a compulsive 
desire to walk or pace.  However, the patient is able to remain seated for at least 
five minutes.  The condition is obviously distressing
5 
Severe akathisia.  The patient reports a strong compulsion to pace up and down 
most of the time.  Unable to sit or lie down for more than a few minutes.  Constant 
restlessness which is associated with intense distress and insomnia
Reproduced from:  A rating scale for drug-induced akathisia.  T.R.E. Barnes, British Journal of Psychiatry
(1989), 154, 672-676.
1989 The Royal College of Psychiatrists.


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Appendix 13
Columbia-Suicide Severity Rating Scale (C-SSRS)
COLUMBIA-SUICIDE SEVERITY RATING SCALE
(C-SSRS)
Since Last Visit
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended to be used by individuals who have received training in its 
administration. The questions contained in the Columbia-Suicide Severity Rating 
Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual 
administering the scale.
Definitions of behavioral suicidal events in this scale are based on those used in 
The Columbia Suicide History Form, developed by John Mann, MD and Maria 
Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), 
New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. 
(Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal behavior: 
utility and limitations of research instruments. In M.B. First [Ed.] Standardized 
Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact 
., 
 
; inquiries and training 
requirements contact 


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2008 The Research Foundation for Mental Hygiene, Inc.
SUICIDAL IDEATION
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the 
answer to question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 
is “yes”, complete “Intensity of Ideation” section below.
Since Last 
Visit
1.  Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe:
Yes       No
□    □
2.  Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) 
without thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes      No
 □    □
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is 
different than a specific plan with time, place or method details worked out (e.g.,  thought of method to kill self but 
not a specific plan).  Includes person who would say, “I thought about taking an overdose but I never made a specific 
plan as to when, where or how I would actually do it…..and I would never go through with it.”
Have you been thinking about how you might do this?
If yes, describe:
Yes      No
 □    □
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed 
to “I have the thoughts but I definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
Yes       No
 □    □
5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it 
out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this 
plan?
  
If yes, describe:
Yes      No
 □    □


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


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


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


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Appendix 14
Massachusetts General Hospital Sexual Functioning 
Questionnaire (MSFQ)
Please answer all questions by circling the correct answer or the answer which seems the most appropriate
to you (consider “normal” the time in your life prior to the past month when you were most satisfied with 
your sexual functioning).
a) How has your interest in sex been over the past month?
1
2
3
4
5
6
greater
normal
minimally
moderately
markedly
totally
than normal
diminished
diminished
diminished
absent
b) How has your ability to get sexually aroused or excited been over the past 
month?
1
2
3
4
5
6
greater
normal
minimally
moderately
markedly
totally
than normal
diminished
diminished
diminished
absent
c) How has your ability to achieve orgasm been over the past month?
1
2
3
4
5
6
greater
normal
minimally
moderately
markedly
totally
than normal
diminished
diminished
diminished
absent
d) (for men only) How has your ability to get and maintain an erection been over 
the past month?
1
2
3
4
5
6
greater
normal
minimally
moderately
markedly
totally
than normal
diminished
diminished
diminished
absent
e) How would you rate your overall sexual satisfaction over the past month?
1
2
3
4
5
6
greater
normal
minimally
moderately
markedly
totally
than normal
diminished
diminished
diminished
absent
Copyright 1998, Depression and Clinical Research Program, Massachusetts General Hospital
(Derived from the Arizona Sexual Experiences Scale and from the Guided Interview Questionnaire by 
Segraves and Segraves).


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Appendix 15
Resource Utilization Form (RUF)
BASELINE
We are interested in how often you have sought medical care or were hospitalized for any 
type of condition.  (Note:  Do not include any research visits.)  Please refer to your 
personal calendar.  Enter 0 if there were no visits (Question 1) or no hospitalizations 
(Questions 2 to 5).
1. In the past 3 months, how many visits did you make to any of the following?
Number of visits
a.
A primary care doctor
  visits
b. Psychiatrist
  visits
c.
Counselor, psychologist or other mental health professional
  visits
d. Physicians other than your primary care doctor or 
  visits
mental health professional
e.
An emergency room or urgent care facility for the treatment
  visits
of your emotions, nerves, or mental health
f.
An emergency room or urgent care facility for any other reason?
  visits
2. In the past 12 months, how many times were you hospitalized for the treatment of 
your emotions, nerves, or mental health?
(Enter 0 if there were no hospitalizations.)
  number of times hospitalized
3. In the past 12 months, how many times were you hospitalized for any other reason?
(Enter 0 if there were no hospitalizations.)
  number of times hospitalized
4. IF YOU WERE HOSPITALIZED in the past 12 months, for how
many days were you in the hospital for your emotions, nerves, 
or mental health?
  days hospitalized
5. IF YOU WERE HOSPITALIZED in the past 12 months, for how many days were 
you hospitalized for any other reasons?
  days hospitalized


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FOLLOW-UP
We are interested in how often you have sought medical care for any type of condition 
since you started the study.  (Note:  Do not include any research visits.)  Please refer to 
your personal calendar.  Enter 0 if no visits were made.
1. Since you started the study, how many visits did you make to any of the following?
Number of visits
a.
A primary care doctor
  visits
b. Psychiatrist
  visits
c.
Counselor, psychologist or other mental health professional
  visits
d. Physicians other than your primary care doctor or 
  visits
mental health professional
e.
An emergency room or urgent care facility for the treatment
  visits
of your emotions, nerves or mental health
f.
An emergency room or urgent care facility for any other reason?
  visits


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Appendix 16
Protocol Amendment(s)/Administrative Change(s)
Amendment Number:
1
Issue Date:
23 November 2011
PURPOSE:
The sponsor has determined the need for a formal amendment to the original protocol 
approved on 11 May 2011 to add additional clarity to trial procedures and to make
several administrative changes.
BACKGROUND:
1.
Clarification of trial procedures
1) Clarify dosing schedule of duloxetine 40 mg/day (once daily or 20 mg twice daily).
2) Clarify interval between dose adjustments by changing description from “at least one 
week” to “at least 5 days” and revise wording regarding rechallenge after dose is 
decreased to 0.5 mg/day.
3) Clarify that the serum pregnancy test is the definitive test for determining pregnancy, 
irrespective of urine pregnancy test result.
4) Clarify that subjects who are sterile (ie, women who have had an oophorectomy 
and/or hysterectomy or have been postmenopausal for at least 12 consecutive months; 
or men who have had orchidectomy) are not required to use two different methods of 
birth control.
5) Per recent posting from FDA, add linezolid and methylene blue to list of drugs that 
may result in serotonin syndrome if coadministered with SSRIs or SNRIs.
2.
Administrative changes and correction of typographical errors

1) Replace OPC-34712 with approved generic name (ie, brexpiprazole)

2) Add EudraCT number

3) Update primary medical contact for OPDC personnel

4) Change name of United BioSource Corporation to Bracket

5) Update address of Schulman Associates IRB.
MODIFICATIONS TO PROTOCOL:

Bold and underlined text:
Changed text

Bold and strikethrough text:
Deleted text


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
Bold and italicized text:
Added text
TITLE PAGE
Brexpiprazole (OPC-34712)
Protocol No. 331-10-238
IND No.  103,958
EudraCT No. 2011-001351-37
Sponsor Representatives:
Phone 
Fax 
E-mail 
Phone 
Fax 
E-mail 
Issue Date:
11 May 2011
Date of Amendment 1:
23 November 2011
Entire protocol, Footnote
27 May 2011
23 November 2011
SYNOPSIS, Name of Product:
Name of Company:  Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Product:  Brexpiprazole (OPC-34712)
Protocol #331-10-238
IND #103,958
EudraCT #2011-001351-37
SYNOPSIS, Objective(s):
Primary:  To assess the long-term safety and tolerability of oral OPC-34712 (hereafter 
referred to by the generic name “brexpiprazole”) as adjunctive therapy in the treatment 
of adults with MDD.
Secondary:  To assess the long-term efficacy of oral OPC-34712 brexpiprazole as 
adjunctive therapy in the treatment of adults with MDD.


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SYNOPSIS, Trial Design, Paragraph 1, Sentences 1 and 3:
This is a multicenter, 52-week, open-label trial designed to assess the long-term safety, 
tolerability, and efficacy of adjunctive OPC-34712 brexpiprazole in depressed adults on 
concurrent antidepressant therapy (ADT).  The trial will be conducted on an outpatient 
basis.  Enrollment into the trial will be drawn from eligible subjects who have completed 
one of the double-blind, phase 3 efficacy trials (ie, Trial 331-10-227 or Trial 331-10-228) 
and who, in the investigator’s judgment, could potentially benefit from adjunctive 
treatment with oral OPC-34712 brexpiprazole for MDD.
SYNOPSIS, Trial Design, Paragraph 3, Treatment Phase, Sentence 1:
Eligible subjects will receive daily treatment with open-label OPC-34712 brexpiprazole
and ADT as described in the Investigational Medicinal Product, Dose, Formulation, 
Mode of Administration section.
SYNOPSIS, Subject Population, Paragraph 1, Sentence 1:
The subject population will consist of eligible subjects who, in the investigator’s 
judgment, could potentially benefit from adjunctive treatment with OPC-34712
brexpiprazole for MDD and who meet one of the following conditions:
SYNOPSIS, Investigational Medicinal Product, Dose, Formulation, Mode of 
Administration, Paragraph 1:
Trial medication (ie, investigational medicinal product [IMP]) will be provided to the 
investigator(s) by the sponsor (or designated agent) and will consist of open-label OPC-
34712 brexpiprazole and open-label ADTs.
SYNOPSIS, Investigational Medicinal Product, Dose, Formulation, Mode of 
Administration, OPC-34712, Paragraph 1 and bulleted list:
OPC-34712 Brexpiprazole:  Open-label OPC-34712 brexpiprazole will be supplied as 
0.5, 1, 2, and 3-mg tablets packaged in weekly blister cards, each containing sufficient 
tablets for 7 (+ 2 days).  Blister cards will be dispensed at each scheduled visit and at 
unscheduled visits if the dose of OPC-34712 brexpiprazole is changed.  All doses of 
OPC-34712 brexpiprazole should be taken orally once daily and can be administered 
without regard to meals.  For convenience, OPC-34712 brexpiprazole may be taken 
with the first daily dose of ADT.
All subjects will be dosed as follows:

The first dose of open-label OPC-34712 brexpiprazole will be taken one day after 
the last dose is taken for the double-blind, phase 3 efficacy trial so that adjunctive 
treatment will continue without interruption.  It is anticipated that the last dose of the 
double-blind, phase 3 efficacy trial will be taken the day of the Week 14 visit of Trial 


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331-10-227 or Trial 331-10-228 (ie, the day of the Screening/Baseline visit for the 
open-label trial).  Subjects will initiate open-label dosing with brexpiprazole
0.5 mg/day OPC-34712 for 1 week.  Subjects unable to tolerate brexpiprazole
0.5 mg/day OPC-34712 must be withdrawn from the trial.

The dose of brexpiprazole OPC-34712 will be increased to 1 mg/day at the Week 1 
visit.  Subjects unable to tolerate brexpiprazole 1 mg/day OPC-34712 may decrease 
to 0.5 mg/day at any time after the Week 1 visit.

Investigators may further increase the dose to brexpiprazole 2 mg/day OPC-34712
and then to brexpiprazole 3 mg/day OPC-34712, with an interval of at least one 
week 5 days between dose increases.  An interval of at least one week 5 days
between dose adjustments is recommended for dose decreases; however, the dose of 
brexpiprazole OPC-34712 can be decreased at the investigator’s discretion in a step-
wise manner at any time after the Week 1 visit as needed for tolerability to a 
minimum of 0.5 mg/day.  Dose adjustments must ultimately be made based upon the 
clinical judgment of the investigator as it relates to tolerability and therapeutic 
response.

Subjects who tolerate a reduced dose of brexpiprazole 0.5 mg/day OPC-34712
should be rechallenged with brexpiprazole 1 mg/day OPC-34712 at least once 
during the trial.  In addition, the dose of brexpiprazole OPC-34712 can be re-
escalated as necessary following any dose decrease if, in the investigator’s judgment, 
rechallenge with a higher dose is warranted in order to identify an optimum dose for 
the subject.  Subjects must return to the clinic for unscheduled visits if changes to the 
dose of brexpiprazole OPC-34712 (increases or decreases) are required between 
scheduled visits.
SYNOPSIS, Investigational Medicinal Product, Dose, Formulation, Mode of 
Administration, ADT, Paragraph 1, Sentences 3 and 4:
It is recommended that the dose of ADT not be changed while the dose of brexpiprazole
OPC-34712 is being optimized (ie, no change to ADT up to and including the Week 4 
visit).  After the Week 4 visit, the dose of ADT can be modified if necessary to achieve 
optimum efficacy and tolerability for the treatment regimen using the following rules:  1) 
at least one week 5 days must elapse between dose increases (either brexpiprazole
OPC-34712 or ADT), 2) an interval of at least one week 5 days between dose 
adjustments (either brexpiprazole OPC-34712 or ADT) is recommended for dose 
decreases; however, the ADT dose can be decreased at the investigator’s discretion at any 
time as needed for tolerability, and 3) subjects must return to the clinic for unscheduled 
visits if changes to the ADT dose are required between scheduled visits.
SYNOPSIS, Investigational Medicinal Product, Dose, Formulation, Mode of 
Administration, ADT, Paragraph 3:


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All doses of ADT will be administered orally once daily except for duloxetine 40 mg/day 
that is can be administered once daily or as duloxetine 20 mg twice daily, duloxetine 
60 mg/day that can be administered once daily or as duloxetine 30 mg twice daily, and 
fluoxetine 40 mg/day that can be administered once daily or in divided doses twice daily.
SYNOPSIS, Criteria for Evaluation, Primary Outcome Variable:
The primary outcome variable is the safety and tolerability of brexpiprazole OPC-34712
which will be assessed by examining the frequency and severity of adverse events (AEs).
List of Abbreviations and Definitions of Terms:
EudraCT
European Clinical Trial Data Base
Investigational 
medicinal product 
(IMP)
For the purposes of this protocol, IMP refers to all trial medication 
supplied to the sites by the sponsor (or designated agent) and 
includes bottles of protocol-specified ADTs and blister cards 
containing brexpiprazole OPC-34712.
Section 1, Introduction, Paragraph 3:
OPC-34712 (hereafter referred to by the generic name “brexpiprazole”) is an organic 
compound synthesized by Otsuka Pharmaceutical Co, Ltd, that is a 
 at 
, 
, and 
, an 
antagonist at 
, and has a 
 for 
 and 
  Details of the receptor affinity profile of OPC-
34712 brexpiprazole are summarized in Section 1.1.1.  Activity at dopamine and 
serotonin receptors has been shown to be useful in the treatment of psychiatric disorders, 
eg, schizophrenia and bipolar mania.  Hence, OPC-34712 brexpiprazole is expected to 
be a promising antipsychotic agent.  As the relative activity at these and other receptors 
appears to be related to the side effect profiles of antipsychotic drugs,15,16,17,18 OPC-
34712 brexpiprazole may have the potential to exhibit improved safety compared to 
other agents.  The more potent antagonism at 5-HT2A receptors for OPC-34712
brexpiprazole relative to aripiprazole may afford a more favorable profile with respect to 
sleep quality; whereas, the low binding affinities for histamine and muscarinic receptors 
suggest that OPC-34712 brexpiprazole may have less potential to cause H1-receptor-
related weight gain than olanzapine.  Preclinical data also suggest that OPC-34712
brexpiprazole will have lower potential for hyperprolactinemia than risperidone.  


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Results from initial phase 2 trials showed OPC-34712 brexpiprazole to be well tolerated 
by subjects with MDD and schizophrenia (see Section 1.3).
Section 1.1.1, Efficacy Pharmacology:
OPC-34712 Brexpiprazole functions as a partial agonist at the D2 receptor.  In in vitro 
assay systems based on forskolin-induced cyclic AMP accumulation and calcium (Ca2+) 
mobilization in human dopamine D2L receptor-expressing cells, its intrinsic activity at 
the D2 receptor was slightly lower than that of aripiprazole, another D2 receptor partial 
agonist.  OPC-34712 Brexpiprazole inhibited apomorphine (APO)-induced 
hyperlocomotion, APO-induced stereotyped behavior, and conditioned avoidance 
response in rats, which are predictive animal models for antipsychotic-like efficacy.  The 
inhibitory effects of OPC-34712 brexpiprazole were more potent than those of 
aripiprazole.  Moreover, in contrast to the D2 receptor antagonist risperidone, OPC-
34712 brexpiprazole did not increase plasma prolactin levels in reserpine-treated rats, 
thus demonstrating a D2 receptor partial agonistic profile in vivo.  Despite its lower 
intrinsic activity at the D2 receptor, the in vivo catalepsy liability of OPC-34712
brexpiprazole, an index of EPS, was similar to that of aripiprazole, but still lower than 
that of the typical antipsychotic haloperidol.  Furthermore, OPC-34712 brexpiprazole
showed high binding affinity for the 5-HT2A receptor and dose-dependently inhibited 
()-2,5-dimethoxy-4-iodoamphetamine-induced head twitch response in rats, indicating 
that the compound has 5-HT2A receptor antagonistic activity; the effect of OPC-34712
brexpiprazole was more potent than that of aripiprazole.  In addition, OPC-34712
brexpiprazole exhibited high binding affinities for the D3 and 5-HT1A receptors, acting 
as a partial agonist at these receptors.
Section 1.1.2, Safety Pharmacology:
In safety pharmacology studies in rats at an oral dose of 30 mg/kg or higher, OPC-34712
brexpiprazole induced pharmacologically mediated clinical signs considered to be due to 
depression of the central nervous system (CNS) and dose-dependent decreases in body 
temperature.  When orally administered at up to 30 mg/kg in conscious male beagle dogs, 
OPC-34712 brexpiprazole showed no effect on respiratory parameters or heart rate at 
any dose tested.  OPC-34712 Brexpiprazole decreased blood pressure 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.  OPC-34712 Brexpiprazole inhibited human ether-a-
go-go related gene (hERG) current in Chinese hamster ovary cells (CHO-K1) at 
concentrations of 10−8 mol/L or higher, with a 50% inhibitory concentration of 1.17 


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10−7 mol/L.  The mechanism for the blood pressure decreasing effect of OPC-34712
brexpiprazole was suggested to result from a blockade of the 1-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 OPC-34712
brexpiprazole on monophasic action potential parameters in halothane-anesthetized 
dogs.  OPC-34712 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 OPC-34712 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.
Section 1.2.1, Pharmacokinetics/pharmacodynamics:
The pharmacokinetics of single and multiple doses of OPC-34712 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 OPC-34712 brexpiprazole
and thus is considered as an inactive metabolite.  Both OPC-34712 brexpiprazole and 
DM-3411 pharmacokinetics were linear following single oral doses of brexpiprazole 0.2 
to 8 mg OPC-34712 to healthy subjects.  The terminal phase elimination half-life of 
OPC-34712 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 OPC-34712 brexpiprazole and at 
approximately 10 to 24 hours postdose for DM-3411.  In healthy subjects, administration 
of single-dose OPC-34712 brexpiprazole with a high-fat meal did not affect its rate and 
extent of absorption.
Steady state pharmacokinetics also appeared to be linear following multiple daily doses 
of OPC-34712 brexpiprazole in the range of 0.5 to 2 mg to healthy subjects.  The 
accumulation factor based on maximum (peak) plasma concentration (Cmax) and area 
under the concentration-time curve calculated to the last observable concentration at time 
t (AUCt) was approximately 4 times.  After multiple dose administration of OPC-34712
brexpiprazole (1 to 12 mg/day) to subjects with schizophrenia or schizoaffective 
disorder, OPC-34712 brexpiprazole and DM-3411 mean terminal elimination half-life 


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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, OPC-34712 brexpiprazole was shown to be 
metabolized by CYP3A4 and CYP2D6 isozymes and was not an inhibitor of CYP3A4, 
CYP2B6, CYP2D6, or P-glycoprotein.  Coadministration of potent CYP3A4 or CYP2D6 
inhibitors with OPC-34712 brexpiprazole resulted in about a 2-fold higher exposure and 
about a 1.5-fold increase in the terminal elimination half life of OPC-34712
brexpiprazole.  Of note, administration of OPC-34712 brexpiprazole with fluoxetine, 
paroxetine, or duloxetine (MDD medications coadministered in this trial) may potentially 
increase OPC-34712 brexpiprazole plasma concentrations by up to 2-fold.
In a single-dose trial in healthy subjects, approximately 46.0% and 24.6% of 
administered radioactivity following an oral dose of 14C-OPC-34712 brexpiprazole was 
excreted in feces and urine, respectively.  In this same trial, OPC-34712 brexpiprazole
did not preferentially bind to red blood cells.  OPC-34712 Brexpiprazole showed high 
protein binding in human serum (99.8%) in vitro.
The binding of OPC-34712 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 OPC-
34712 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 pharmacokinetic/pharmacodynamic (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 OPC-34712 brexpiprazole will result in at least 80% to 
90% D2/D3 receptor occupancy.
Additional information on the pharmacokinetics/pharmacodynamics of OPC-34712
brexpiprazole and its metabolites in humans can be found in the Investigator Brochure.19
Section 1.2.2, Major Depressive Disorder
The efficacy of OPC-34712 brexpiprazole as adjunctive therapy for the treatment of
MDD has been studied in one completed placebo-controlled trial (Trial 331-08-211).  An 
additional placebo-controlled efficacy trial (Trial 331-09-222) and one long-term open-
label safety trial (Trial 331-08-212) are ongoing.  Trial 331-08-211 was a multicenter, 
randomized, double-blind, placebo-controlled trial designed to assess the safety and 


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efficacy of OPC-34712 brexpiprazole (0.15 to 2 mg daily) as adjunctive treatment to an 
assigned open-label ADT in subjects with MDD who have demonstrated an incomplete 
response to prospective treatment with the same ADT.  Subjects with an incomplete 
response after 8 weeks of treatment with single-blind placebo plus open-label ADT were 
randomized to 6 weeks of double-blind treatment with either OPC-34712 brexpiprazole-
plus-ADT or placebo-plus-ADT.  Responders continued to receive placebo-plus-ADT for 
an additional 6 weeks.  Randomized subjects received brexpiprazole 0.15 mg/dayOPC-
34712, 0.50 0.25 mg/day OPC-34712, 1.5 0.50 mg/day OPC-34712, or matching 
placebo.  Subjects randomized to the brexpiprazole 0.50 0.25 mg/day OPC-34712 and 
brexpiprazole 1.5 0.50 mg/day OPC-34712 arms were titrated to the target doses (0.50 
and 1.5 mg, respectively) over a 2-week period.  Dose adjustments were permitted after 
the subjects received 1 week of treatment at the target dose.  Subjects who could not 
tolerate the lowest dose (brexpiprazole 0.15, 0.25, or 1.0 mg/day OPC-34712or 
matching placebo, respectively) were to be discontinued from the trial.  In this trial, 
adjunctive OPC-34712 brexpiprazole dosed at 1.5 0.50 mg/day was superior to 
adjunctive placebo with respect to the primary endpoint (change from Week 8 to Week 
14 in Montgomery Asberg Depression Rating Scale [MADRS] Total Score) and several 
secondary efficacy endpoints.20  Ongoing Trial 331-09-222 is of similar design to Trial 
331-08-211, but is exploring an expanded dose range (brexpiprazole 1 to 
3 mg/dayOPC-34712).
Section 1.2.3, Schizophrenia, Sentence 2:
The outcome of this trial suggests an active dose range of brexpiprazole 1 to 6 mg/day 
OPC-34712 for the treatment of schizophrenia.21
Section 1.2.4, Other Indications, Sentences 1 and 2:
OPC-34712 Brexpiprazole is being investigated in a proof-of-concept trial in adult 
ADHD (Trial 331-08-213).  This is a multicenter, randomized, double-blind, placebo-
controlled, flexible-dose trial in which adults with ADHD who have an incomplete/partial 
response to stimulant therapy in a prospective treatment phase are randomized to double-
blind treatment with either OPC-34712 brexpiprazole-plus-stimulant or placebo-plus-
stimulant.
Section 1.3, Known and Potential Risks and Benefits, Paragraph 1, Sentences 1, 4, and 5:


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As of 31 Dec 2010, 14 clinical trials involving OPC-34712 brexpiprazole have been 
completed worldwide, including 10 in the United States (US), 1 in multiple countries 
(including the US), 2 in Japan, and 1 in Korea.  
OPC-34712 Brexpiprazole has been well tolerated by healthy volunteers at single doses 
up to 6 mg and at multiple doses up to 2 mg/day.  In patient trials, OPC-34712
brexpiprazole has been well tolerated at multiple doses up to 12 mg/day in subjects with 
schizophrenia or schizoaffective disorder, up to 4 mg/day in subjects with MDD who 
received concomitant ADT, and up to 4 mg/day in adults with ADHD who received 
concomitant stimulant therapy.
Section 1.3, Known and Potential Risks and Benefits, Paragraph 2, Sentences 1 and 2:
In the 11 completed phase 1 and 2 clinical trials performed under the US IND (two phase 
2 trials, one phase 1b trial, and eight phase 1 trials), 673/973 (69.2%) subjects who 
received OPC-34712 brexpiprazole either alone or coadministered with another 
marketed medication reported at least one treatment-emergent adverse event (TEAE) 
compared to 158/253 (62.5%) subjects who received placebo either alone or 
coadministered with another marketed medication.  The most common TEAEs reported 
for OPC-34712 brexpiprazole in the completed trials (5% in the total OPC-34712
brexpiprazole group and more than the total placebo group) were headache (10.6%), 
dizziness (8.0%), anxiety (7.1%), akathisia (7.0%), and nausea (5.5%).  
Section 1.3, Known and Potential Risks and Benefits, Paragraph 3, Sentences 3 and 4:
The incidence of serious TEAEs (fatal and non-fatal) that were reported during treatment 
with OPC-34712 brexpiprazole administered either alone or coadministered with 
another medication (19/973 subjects, 2.0%) was comparable to placebo administered 
either alone or coadministered with another medication (4/253 subjects, 1.6%).  
Furthermore, treatment with OPC-34712 brexpiprazole does not appear to promote 
suicidal behavior in subjects with MDD or schizophrenia.
Section 1.3, Known and Potential Risks and Benefits, Paragraph 4:
OPC-34712 Brexpiprazole did not result in any consistent, clinically relevant changes in 
laboratory values, vital signs (blood pressure or heart rate), or electrocardiogram (ECG) 
parameters in the completed phase 1 and 2 clinical trials in subjects with MDD or 
schizophrenia.  Statistically significant increases in weight were observed with OPC-
34712 brexpiprazole relative to placebo in both sample populations.  OPC-34712
Brexpiprazole exhibited a favorable profile with respect to movement disorders in 
subjects with MDD at doses up to 3 mg/day (Trial 331-09-221) and in subjects with 


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schizophrenia at doses up to 12 mg/day (Trial 331-08-205).  In the dose-ranging trial that 
enrolled subjects who were experiencing an acute exacerbation of schizophrenia (Trial 
331-07-203), an increase in the incidence of EPS was observed at the highest dose (ie, 
brexpiprazole 5.0 1.0 mg/day OPC-34712).
Section 2.1, Trial Rationale, Paragraph 1, Sentence 4:
As OPC-34712 brexpiprazole demonstrated antagonism at 5-HT2A receptors, the 
attenuated response to SSRIs may be reversed with coadministration of OPC-34712
brexpiprazole and SSRIs, thus enhancing clinical outcomes.
Section 2.1, Trial Rationale, Paragraph 2:
Because the management of MDD may require prolonged administration of ADT(s) with 
or without an augmenting agent, safety monitoring for longer than the period required to 
achieve initial response is warranted.  In the OPC-34712 brexpiprazole clinical 
development program for MDD, phase 2 and phase 3 trials examined the 6-week safety 
and efficacy of OPC-34712 brexpiprazole augmentation of ADTs.  For phase 2, subjects 
who completed either of the trials had the option to enroll into an open-label rollover trial 
in which they received OPC-34712 brexpiprazole for up to 52 weeks (Trial 331-08-
212).  The current trial (Trial 331-10-238) provides an open-label rollover option for the 
double-blind phase 3 trials (ie, Trial 331-10-227 and Trial 331-10-228) and will expand 
on the knowledge gained in these trials by assessing the long-term safety, tolerability, and 
efficacy of OPC-34712 brexpiprazole when administered concomitantly with 
antidepressant medications.
Section 2.2, Dosing Rationale, Paragraph 1:
A dose range of brexpiprazole 0.5 to 3 mg/day OPC-34712 was selected for the current 
open-label trial to encompass the dose range of the double-blind efficacy trials (ie, 
brexpiprazole 1 to 3 mg/day OPC-34712) and to include an option for a reduced dose 
for tolerability (ie, 0.5 mg/day) in order to maximize subject retention in the long-term 
trial.  Therapeutic dose ranges of ADT are based on product labels and clinical practice.  
Data from phase 1 drug interaction trials (Trial 331-08-207 and Trial 331-08-208) 
indicated that coadministration of CYP2D6 inhibitors (eg, paroxetine, fluoxetine, and 
duloxetine) with OPC-34712 brexpiprazole could cause potentially higher plasma 
concentrations of OPC-34712 brexpiprazole (up to 2-fold).  In order to limit the 
potential higher exposure of OPC-34712 brexpiprazole when coadministered with such 
inhibitors, the upper limit of the therapeutic ADT dose is limited to 40 mg for fluoxetine, 
50 mg for paroxetine CR, and 60 mg for duloxetine in the current trial.


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Section 2.3, Trial Objectives:
Primary:
To assess the long-term safety and tolerability of oral OPC-34712
brexpiprazole as adjunctive therapy in the treatment of adults with MDD.
Secondary:
To assess the long-term efficacy of oral OPC-34712 brexpiprazole as 
adjunctive therapy in the treatment of adults with MDD.
Section 3.1, Type/Design of Trial, Paragraph 1, Sentences 1 and 3:
This is a multicenter, 52-week, open-label trial designed to assess the long-term safety, 
tolerability, and efficacy of adjunctive OPC-34712 brexpiprazole in depressed adults on 
concurrent antidepressant therapy (ADT).  The trial will be conducted on an outpatient 
basis.  Enrollment into the trial will be drawn from eligible subjects who have completed 
one of the double-blind, phase 3 efficacy trials (ie, Trial 331-10-227 or Trial 331-10-228) 
and who, in the investigator’s judgment, could potentially benefit from adjunctive 
treatment with oral OPC-34712 brexpiprazole for MDD.
Section 3.1, Type/Design of Trial, Paragraph 3, Treatment Phase, Sentence 1:
Eligible subjects will receive daily treatment with open-label OPC-34712 brexpiprazole
and ADT as described in Section 3.2.
Figure 3.1-1, Population and treatment group descriptions:
Section 3.2.1.1, OPC-34712 Brexpiprazole:
The first dose of open-label OPC-34712 brexpiprazole will be taken one day after the 
last dose is taken for the double-blind, phase 3 efficacy trial so that adjunctive treatment
will continue without interruption.  It is anticipated that the last dose of the double-blind, 
phase 3 efficacy trial will be taken the day of the Week 14 visit of Trial 331-10-227 or 
Open-label OPC-34712 Brexpiprazole (0.5 to 3 mg/day) + ADT
Eligible subjects who 
completed one of the 
double-blind phase 3 
trials (ie, Trial 331-10-
227 or Trial 331-10-228) 
and who could 
potentially benefit from 
adjunctive treatment with 
OPC-34712
brexpiprazole for MDD 
per investigator


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Trial 331-10-228 (ie, the day of the Screening/Baseline visit for the open-label trial).  
Subjects will initiate open-label dosing with brexpiprazole 0.5 mg/day OPC-34712 for 1 
week.  Subjects unable to tolerate brexpiprazole 0.5 mg/day OPC-34712 must be 
withdrawn from the trial.  The dose of OPC-34712 brexpiprazole will be increased to 
1 mg/day at the Week 1 visit.  Subjects unable to tolerate brexpiprazole 1 mg/day 
OPC-34712 may decrease to 0.5 mg/day at any time after the Week 1 visit.
Investigators may further increase the dose to brexpiprazole 2 mg/day OPC-34712 and 
then to brexpiprazole 3 mg/day OPC 34712, with an interval of at least one week 5 
days between dose increases.  An interval of at least one week 5 days between dose 
adjustments is recommended for dose decreases; however, the dose of OPC-34712
brexpiprazole can be decreased at the investigator’s discretion in a step-wise manner at 
any time after the Week 1 visit as needed for tolerability to a minimum of 0.5 mg/day.  
Dose adjustments must ultimately be made based upon the clinical judgment of the 
investigator as it relates to tolerability and therapeutic response.  Subjects must return to 
the clinic for unscheduled visits if changes to the dose of OPC-34712 brexpiprazole
(increases or decreases) are required between scheduled visits.  The dosing schedule is 
summarized in Table 3.2.1.1-1.  Additional information on dose adjustments is provided 
in Section 3.2.2.1.
All doses of OPC-34712 brexpiprazole should be taken orally once daily and can be 
administered without regard to meals.  For convenience, OPC-34712 brexpiprazole may 
be taken with the first daily dose of ADT.
Table 3.2.1.1-1
Dosing Schedule for OPC-34712 Brexpiprazole
IMP
Trial Visit
Screening/ 
Baseline
Week 1a
Week 2b
Week 4b
Visits at Weeks 8, 14, 20, 26, 32, 
38, and 44b
OPC-34712
Brexpiprazole
(mg/day)c
0.5
1
0.5, 1 or 2
0.5, 1, 2 or 3
0.5, 1, 2, or 3
ADTd
Final dose 
from double-
blind trial
No changee
No changee
No changee
Change to ADT dose is permitted as 
described in Section 3.2.2.2.
aSubjects unable to tolerate brexpiprazole 1 mg/day OPC-34712 may decrease to 0.5 mg/day at any 
time after the Week 1 visit.
bStep-wise increases in the dose of OPC-34712 brexpiprazole must be separated by at least one week
5 days.  Although step-wise decreases in the OPC-34712 brexpiprazole dose are permitted at any 
time after the Week 1 visit to a minimum of 0.5 mg/day, an interval of at least one week 5 days
between dose adjustments is recommended.  See Section 3.2.2.1 for additional information on dose 
adjustments.  Subjects must return to the clinic for unscheduled visits if changes to the dose of OPC-
34712 brexpiprazole (increases or decreases) are required between scheduled visits.


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cSubjects unable to tolerate the minimum dose of OPC-34712 brexpiprazole (ie, 0.5 mg/day) must be 
withdrawn from the trial.
dThroughout Trial 331-10-238, the subject must remain on the same ADT that was assigned in the 
double-blind phase 3 trial (ie, Trial 331-10-227 or Trial 331-10-228).
eIt is recommended that the dose of ADT not be changed while the dose of OPC-34712 brexpiprazole
is being optimized.
Section 3.2.1.2, ADT, Sentence 7:
All doses of ADT will be administered orally once daily except for duloxetine 40 mg/day 
that is can be administered once daily or as duloxetine 20 mg twice daily, duloxetine 
60 mg/day that can be administered once daily or as duloxetine 30 mg twice daily, and 
fluoxetine 40 mg/day that can be administered once daily or in divided doses twice daily.
Table 3.2.1.2-1, Footnote a:
aAll doses are to be administered orally once daily except for duloxetine 40 mg/day that is can be
administered once daily or as duloxetine 20 mg twice daily, duloxetine 60 mg/day that can be 
administered once daily or as duloxetine 30 mg twice daily, and fluoxetine 40 mg/day that can be 
administered once daily or in divided doses twice daily.  All doses should be taken at approximately 
the same time each day, if possible.
Section 3.2.2, Dose Adjustments
Dose modifications to both OPC-34712 brexpiprazole and ADT will be permitted to 
optimize therapeutic benefit according to the rules described below for each treatment.  
However, the dose of OPC-34712 brexpiprazole and the dose of ADT should not both 
be changed at the same visit.
Section 3.2.2.1, OPC-34712 Brexpiprazole
Allowable dose modifications to the daily dose of OPC-34712 brexpiprazole are 
summarized in Table 3.2.2.1-1.  At least one week 5 days must elapse between dose 
increases for OPC-34712 brexpiprazole.  An interval of at least one week 5 days
between dose adjustments is recommended for dose decreases; however, the dose of 
OPC-34712 brexpiprazole can be decreased at the investigator’s discretion in a step-
wise manner at any time after the Week 1 visit as needed for tolerability to a minimum of 
0.5 mg/day.  Subjects must return to the clinic for unscheduled visits if changes to the 
dose of OPC-34712 brexpiprazole (increases or decreases) are required between 
scheduled visits.
Subjects who are unable to tolerate the 0.5-mg/day dose of OPC-34712 brexpiprazole
must be withdrawn from the trial.  However, subjects whose OPC-34712 brexpiprazole


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dose is decreased to 0.5 mg/day and who demonstrate adequate tolerability at this dose 
should be rechallenged with a 1-mg/day dose within approximately 6 to 8 weeks after 
starting the dose is decreased to 0.5 mg/day dose.  If tolerability issues arise following 
the rechallenge, the dose may be decreased again to 0.5 mg/day.  Further rechallenge at 
1 mg/day may be performed at the investigator’s discretion.  The dose of OPC-34712
brexpiprazole can be re-escalated as necessary following a dose decrease at any other 
dose if, in the investigator’s judgment, rechallenge with a higher dose is warranted in 
order to identify an optimum dose for the subject.  Dose adjustments must ultimately be 
made based upon the clinical judgment of the investigator as it relates to tolerability and 
therapeutic response.
Table 3.2.2.1-1
Dose Modifications for OPC-34712 Brexpiprazole
Dose Increasesa,b
Current Dose of OPC-34712
Brexpiprazole
Incremental Increase
Adjusted OPC-34712
Brexpiprazole dose
0.5 mg
0.5 mg
1 mg
1 mg
1 mg
2 mg
2 mg
1 mg
3 mg
Dose Decreasesb,c
Current Dose of OPC-34712
Brexpiprazole
Incremental Decrease
Adjusted OPC-34712
Brexpiprazole dose
0.5 mg
Not permittedd
0.5 mgd
1 mg
0.5 mg
0.5 mg
2 mg
1 mg
1 mg
3 mg
1 mg
2 mg
aAt least one week 5 days must elapse between dose increases.
bSubjects must return to the clinic for unscheduled visits if changes to the dose of OPC-34712
brexpiprazole (increases or decreases) are required between scheduled visits.
cAn interval of at least one week 5 days between dose adjustments is recommended for dose decreases; 
however, the investigator may decrease the dose of OPC-34712 brexpiprazole at any time after the 
Week 1 visit for tolerability.
dSubjects unable to tolerate 0.5 mg/day of OPC-34712 brexpiprazole must be withdrawn from the trial.
Section 3.2.2.2, ADT:
It is recommended that the dose of ADT not be changed while the dose of OPC-34712
brexpiprazole is being optimized (ie, no change to ADT up to and including the Week 4 
visit).  After the Week 4 visit, the dose of ADT can be modified if necessary to achieve 
optimum efficacy and tolerability for the treatment regimen using the following rules:  
1) at least one week 5 days must elapse between dose increases (either OPC-34712


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brexpiprazole or ADT), 2) an interval of at least one week 5 days between dose 
adjustments (either OPC-34712 brexpiprazole or ADT) is recommended for dose 
decreases; however, the ADT dose can be decreased at the investigator’s discretion at any 
time as needed for tolerability, and 3) subjects must return to the clinic for unscheduled 
visits if changes to the ADT dose are required between scheduled visits.
Section 3.3, Trial Population, Paragraph 1, Sentence 1:
The trial population will consist of eligible subjects who, in the investigator’s judgment, 
could potentially benefit from adjunctive treatment with OPC-34712 brexpiprazole for 
MDD and who meet one of the following conditions:
Table 3.4.2-1, Criterion 3:
3.
Subjects who, in the opinion of the investigator, could potentially benefit from administration of 
OPC-34712 brexpiprazole as adjunctive therapy to their antidepressant therapy and who meet one 
of the following criteria:
a) Subjects who completed participation in the Double-blind Randomization Phase (ie, Week 14 
visit of Phase B) in Trial 331-10-227 or Trial 331-10-228 or
b) Subjects who met criteria for a response at the end of prospective treatment (ie, Week 8 visit of 
Phase A) in Trial 331-10-227 or Trial 331-10-228, BUT DID NOT meet criteria for remission 
(defined as a MADRS Total Score of 10) at the Week 14 visit of Phase A+ in Trial 331-10-
227 or Trial 331-10-228.
Table 3.4.3-1, Criterion 2 and Footnote a:
2.
Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving 
open-label OPC-34712 brexpiprazole in Trial 331-10-238.
aUse of CYP2D6 inhibitors or CYP3A4 inhibitors and inducers is prohibited during the trial.  
Fluoxetine, paroxetine, and duloxetine are protocol-defined ADTs that are also CYP2D6 inhibitors.  
In order to limit the potential higher exposure of OPC-34712 brexpiprazole when coadministered 
with such inhibitors, the upper limit of the therapeutic ADT dose is limited to 40 mg for fluoxetine, 
50 mg for paroxetine CR, and 60 mg for duloxetine.
Section 3.5.1, Primary Outcome Variable:
The primary outcome variable is the safety and tolerability of OPC-34712 brexpiprazole
which will be assessed by examining the frequency and severity of adverse events (AEs).
Table 3.6-1, Footnotes o, s and u:
oAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with a positive 
urine and serum pregnancy test results at Screening/Baseline must not be enrolled in Trial 331-10-
238. and Ssubjects with a positive urine and serum pregnancy test results during the trial must 
discontinue treatment and be withdrawn from the trial.  Pregnancy tests can be performed at any point 
during the trial if pregnancy is suspected.


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sAdjustments to the dose of OPC-34712 brexpiprazole or ADT are permitted to optimize efficacy and 
tolerability as described in Section 3.2.  It is recommended that the dose of ADT not be changed 
while the dose of OPC-34712 brexpiprazole is being optimized (ie, no change to ADT up to and 
including the Week 4 visit).  At least one week 5 days must elapse between dose increases for OPC-
34712 brexpiprazole and ADT.  An interval of at least one week 5 days between dose adjustments is 
also recommended for dose decreases; however, the investigator may decrease the dose of OPC-
34712 brexpiprazole or ADT as needed for tolerability according to the rules described in Section 
3.2.2.  Subjects must return to the clinic for unscheduled visits if changes to the dose of OPC-34712
brexpiprazole or ADT (increases or decreases) are required between scheduled visits.
uThe IVRS/IWRS will be accessed at unscheduled visits if new blister cards are dispensed for dose 
adjustment of OPC-34712 brexpiprazole.
Section 3.6.1.1, Screening/Baseline, Bullet 7:

Trial personnel will call the interactive voice response system (IVRS) or access the 
interactive web response system (IWRS) to register the visit and to obtain blister card 
and ADT bottle number assignments.  The assigned open-label OPC-34712
brexpiprazole and ADT will be dispensed.  Treatment will begin with brexpiprazole
0.5 mg/day OPC-34712 for 1 week.  The ADT will be the same as the one taken 
during the double-blind phase 3 trial (ie, Trial 331-10-227 of Trial 331-10-228).  The 
dose of ADT should not be changed at this time.
Section 3.6.1.2, Week 1, Bullets 10, 11, and 12:

Women of childbearing potential (WOCBP) will be given a urine pregnancy test.  
Any positive result must be confirmed by a serum pregnancy test.  WOCBP with a 
positive urine and serum pregnancy test results must discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be performed for OPC-34712 brexpiprazole and ADT.

The dose of OPC-34712 brexpiprazole will be increased to 1 mg/day.  Subjects 
unable to tolerate brexpiprazole 1 mg/day OPC-34712 may decrease to 0.5 mg/day 
at any time after the Week 1 visit.  It is recommended that the dose of ADT not be 
changed while the dose of OPC-34712 brexpiprazole is being optimized.  Trial 
personnel will call the IVRS or access the IWRS to register the visit, to enter dose 
details for OPC-34712 brexpiprazole and ADT, and to obtain blister card and bottle 
number assignments.  The assigned open-label OPC-34712 brexpiprazole and ADT 
will be dispensed to the subject.

Section 3.6.1.3, Week 2, Bullets 6, 7 and 8:

WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.  WOCBP with a positive urine and serum pregnancy test 
results must discontinue the IMP and be withdrawn from the trial.

Drug accountability will be performed for OPC-34712 brexpiprazole and ADT.


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
The investigator will adjust the dose of OPC-34712 brexpiprazole as necessary as 
described in Section 3.2 to achieve optimal efficacy and tolerability.  It is 
recommended that the dose of ADT not be changed while the dose of OPC-34712
brexpiprazole is being optimized.  Any subject unable to tolerate the minimum dose 
of OPC-34712 brexpiprazole (ie, 0.5 mg/day) must be withdrawn from the trial.  
Trial personnel will call the IVRS or access the IWRS to register the visit, to enter 
dose details for OPC-34712 brexpiprazole and ADT, and to obtain blister card and 
bottle number assignments.  The assigned open-label OPC-34712 brexpiprazole and 
ADT will be dispensed to the subject.

Section 3.6.1.4, Week 4, Bullets 9, 10 and 11:

WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.  WOCBP with a positive urine and serum pregnancy test 
results must discontinue the IMP and be withdrawn from the trial.

Drug accountability will be performed for OPC-34712 brexpiprazole and ADT.

The investigator will adjust the dose of OPC-34712 brexpiprazole as necessary as 
described in Section 3.2 to achieve optimal efficacy and tolerability.  If necessary, the 
dose of ADT can be changed after the Week 4 visit, but not at the same visit as a 
change to the dose of OPC-34712 brexpiprazole (see Section 3.2.2.2).  Any subject 
unable to tolerate the minimum dose of OPC-34712 brexpiprazole (ie, 0.5 mg/day) 
must be withdrawn from the trial.  Trial personnel will call the IVRS or access the 
IWRS to register the visit, to enter dose details for OPC-34712 brexpiprazole and 
ADT, and to obtain blister card and bottle number assignments.  The assigned open-
label OPC-34712 brexpiprazole and ADT will be dispensed to the subject.

Section 3.6.1.5, Week 8, Bullets 11, 12 and 13:

WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.  WOCBP with a positive urine and serum pregnancy test 
results must discontinue the IMP and be withdrawn from the trial.

Drug accountability will be performed for OPC-34712 brexpiprazole and ADT.

The investigator will adjust the dose of OPC-34712 brexpiprazole as necessary 
within the range of 0.5 to 3 mg daily as described in Section 3.2.  If necessary, the 
dose of ADT can also be adjusted (see Section 3.2.2.2).  Trial personnel will call the 
IVRS or access the IWRS to register the visit, to enter dose details for OPC-34712
brexpiprazole and ADT, and to obtain blister card and bottle number assignments.  
The assigned open-label OPC-34712 brexpiprazole and ADT will be dispensed to 
the subject.

Section 3.6.1.6, Long-term Treatment Visits (Weeks 14, 20, 26, 32, 38, and 44), Bullets 
7, 8 and 9 after Paragraph 1:


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
WOCBP will be given a urine pregnancy test.  Any positive result must be confirmed 
by a serum pregnancy test.  WOCBP with a positive urine and serum pregnancy test 
results must discontinue the IMP and be withdrawn from the trial.

Drug accountability will be performed for OPC-34712 brexpiprazole and ADT.

The investigator will adjust the dose of OPC-34712 brexpiprazole as necessary 
within the range of 0.5 to 3 mg daily as described in Section 3.2.  If necessary, the 
dose of ADT can also be adjusted (see Section 3.2.2.2).  Trial personnel will call the 
IVRS or access the IWRS to register the visit, to enter dose details for OPC-34712
brexpiprazole and ADT, and to obtain blister card and bottle number assignments.  
The assigned open-label OPC34712 brexpiprazole and ADT will be dispensed to the 
subject.

Table 3.6.2.1-1, Footnote a:
aAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with a positive 
urine and serum pregnancy test results at Screening/Baseline must not be enrolled in Trial 331-10-
238. and Ssubjects with a positive urine and serum pregnancy test results during the trial must 
discontinue treatment and be withdrawn from the trial.
Section 3.6.2.4, Other Safety Assessments, Sentence 5:
Training and materials for rating will be provided by United BioSource Corporation
Bracket.
Section 3.6.3, Efficacy Assessments, Sentence 5:
Training, certification, and materials for rating will be provided by United BioSource 
Corporation Bracket.
Section 3.7.3, Individual Subject, Item f:
f) subject cannot tolerate the minimum dose of OPC-34712 brexpiprazole (ie, 
0.5 mg/day), the minimum protocol-defined therapeutic dose of ADT (see 
Table 3.2.1.2-1), or requires a different ADT; or
Section 3.8, Screen Failures, Sentence 2:
For the purposes of Trial 331-10-238, treatment begins with the first dose of open-label 
OPC-34712 brexpiprazole in the Treatment Phase.
Section 3.11, Subject Compliance, Sentence 1:
Responsible trial personnel will dispense the IMP (ie, OPC-34712 brexpiprazole and 
ADTs).
Table 4.1-1, Footnote c:


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cFluoxetine, paroxetine, and duloxetine are protocol-defined ADTs that are also CYP2D6 inhibitors.  In 
order to limit the potential higher exposure of OPC-34712 brexpiprazole when coadministered with 
such inhibitors, the upper limit of the therapeutic ADT dose is limited to 40 mg for fluoxetine, 50 mg 
for paroxetine CR, and 60 mg for duloxetine (see Section 4.2.1).
Section 4.2.1, Restricted Therapies and Precautions, Bullet 2 after Paragraph 1:

Triptans (eg, sumatriptan, naratriptan, almotriptan, frovatriptan, rizatriptan, eletriptan, 
and zolmitriptan), linezolid, and methylene blue since there have been rare post-
marketing reports of serotonin syndrome or serotonin syndrome-like reactions (eg, 
mental status changes, weakness, hyperreflexia, autonomic effects, and lack of 
coordination, and diarrhea) following the concomitant use of SSRIs or SNRIs and 
triptans these drugs.33,34,35
Section 4.2.1, Restricted Therapies and Precautions, Paragraphs 7 and 8:
Fluoxetine, paroxetine, and duloxetine are protocol-defined ADTs in this trial; however, 
they are also CYP2D6 inhibitors.  Data from Trial 331-08-207 and Trial 331-08-208 
indicate that coadministration of CYP2D6 inhibitors with OPC-34712 brexpiprazole
can cause potentially higher plasma concentrations of OPC-34712 brexpiprazole (up to 
2-fold).  In order to limit the potential higher exposure of OPC-34712 brexpiprazole
when coadministered with such inhibitors, the upper limit of the therapeutic ADT dose is 
limited to 40 mg for fluoxetine, 50 mg for paroxetine CR, and 60 mg for duloxetine.  The 
investigator should consider the potential for higher OPC-34712 brexpiprazole plasma 
concentrations when adjusting the dose of OPC-34712 brexpiprazole for subjects who 
are receiving fluoxetine, paroxetine CR, or duloxetine as the assigned ADT.
All trial personnel should be familiar with the content of the Investigator Brochure for 
OPC-34712 brexpiprazole in order to manage the subject’s condition adequately and 
select appropriate concomitant medications, if needed.
Section 5.1, Definitions, Last sentence:
Investigators will assess IMP causality based on OPC-34712 brexpiprazole.
Section 5.5, Pregnancy, Paragraph 1, Sentence 2:
Unless the subject and his/her partner(s) are is sterile (ie, women who have had an 
oophorectomy and/or hysterectomy or have been postmenopausal for at least 12 
consecutive months; or men who have had orchidectomy) or remains abstinent, two of 
the following precautions must be used:  vasectomy, tubal ligation, vaginal diaphragm, 
intrauterine device, birth control pills, birth control depot injection, birth control implant, 
condom or sponge with spermicide.


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Section 7.1.1, Data Sets for Analysis, Safety Sample definition:
Safety Sample:  comprises those subjects who receive at least one dose of open-label 
OPC-34712 brexpiprazole as adjunctive therapy to one of the allowed ADTs.
Section 7.4, Safety Analyses, Last sentence:
In general, baseline measurements of safety variables are defined as their last 
measurements prior to the first dose of open-label OPC-34712 brexpiprazole.
Section 8.1, Packaging and Labeling, Paragraph 1:
Trial drugs will be provided to the investigator(s) by the sponsor (or designated agent).  
The IMP will consist of open-label OPC-34712 brexpiprazole and open-label ADTs.  
Open-label OPC-34712 brexpiprazole will be supplied as 0.5, 1, 2, and 3-mg tablets 
packaged in weekly blister cards, each containing sufficient tablets for 7 (+ 2 days).  
Blister cards will contain single tablet strengths (ie, brexpiprazole 0.5, 1, 2, or 3 mg/day 
OPC-34712) and subjects will take 1 tablet daily.  When accessed by the site, the IVRS 
or IWRS will assign a specific blister card number to be dispensed to a subject.  New 
weekly blister cards will be dispensed at each scheduled visit and at unscheduled visits if 
the dose of OPC-34712 brexpiprazole is changed.
Section 8.2, Storage, Paragraph 2, Sentence 1:
OPC-34712 Brexpiprazole should be stored according to the storage conditions 
indicated on the clinical label.  
Section 8.3, Accountability:
The investigator, or designee, must maintain an inventory record of trial drugs (including 
OPC-34712 brexpiprazole and ADTs) received, dispensed, administered, and returned.
Section 8.4, Returns and Destruction, Paragraph 1:
Upon completion or termination of the trial, all unused and/or partially used IMP 
(including OPC-34712 brexpiprazole and ADTs) must be returned to Otsuka 
Pharmaceutical Development & Commercialization, Inc. (OPDC) (or a designated 
contractor).
Section 14, References:
33
US Food and Drug Administration [homepage on the Internet]. Rockville, MD:  
FDA Public Health Advisory 2006 19 Jul [updated 2006 24 Nov; cited 4 Nov 2008
24 Oct 2011]. Available at 


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34
US Food and Drug Administration [homepage on the Internet]. Rockville, MD:  
FDA Drug Safety Communication 2011 26 Jul [updated 2011 21 Oct; cited 24 Oct 
2011]. Available at 
35
US Food and Drug Administration [homepage on the Internet]. Rockville, MD:  
FDA Drug Safety Communication 2011 26 Jul [updated 2011 21 Oct; cited 24 Oct 
2011]. Available at 
Appendix 1, Names of Sponsor Personnel, Primary Medical Contact:
Phone 
Fax 
Appendix 2, Institutions Concerned With the Trial
Rater Training
United BioSource Corporation
Specialty Clinical Services
Bracket
575 East Swedesford Road, Suite 200
Wayne, PA 19087
USA
Central IRB
Schulman Associates IRB
4290 Glendale-Mulford Road
4445 Lake Forest Drive
Suite 300
Cincinnati, OH 45242
USA


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Add:
Appendix 16
Protocol Amendment(s)/Administrative Change(s)
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects as a result of this protocol amendment.


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Amendment Number:
2
Issue Date:
16 November 2012
PURPOSE:
The sponsor has determined the need for a formal amendment to amendment 1 approved 
on 23 November 2011 to allow enrollment of eligible subjects who completed the last 
scheduled visit of a double-blind phase 3 brexpiprazole MDD trial, to remove the
definitions of incomplete response and response, to match the specifications for potential 
Hy’s Law cases, to clarify that the contraceptive methods of vasectomy and tubal ligation 
apply to the subject and partner, to update study duration and the estimated number of 
enrolled subjects, and to make administrative changes.
BACKGROUND:
1.
Enrollment of subjects who completed the last scheduled visit of a double-
blind phase 3 brexpiprazole MDD trial
1) Add subjects who completed the last scheduled visit of double-blind phase 3 
brexpiprazole MDD trials as those eligible for enrollment into Trial 331-10-238
2) Add statement that all assessments listed under screening need to be performed at 
Screening/Baseline of Trial 331-10-238; and that if any of these assessments were 
conducted at the last scheduled visit of the prior double-blind phase 3 trial, then 
Screening/Baseline values for those assessments will be derived from that visit and 
those assessments will not need to be repeated at Screening/Baseline of Trial 331-10-
238
2.
Definitions of incomplete response and response

1) Remove the definitions for incomplete response and response for Trial 331-10-
227 and Trial 331-10-228
3.
Hy’s Law specifications

1) Update the specifications for potential Hy’s Law cases 
4.
Contraceptive methods of vasectomy and tubal ligation
1) Clarify that that the contraceptive methods of vasectomy and tubal ligation apply to 
the subject and partner


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5.
Study duration and number of enrolled subjects
1) Update the study duration to approximately 63 months, of which approximately 51
months are allotted for rollover of subjects from the prior double-blind phase 3 trials
2) Update number of estimated enrolled subjects to 3,000
6.
Administrative changes and correction of typographical errors
1) Update primary and backup medical contact for OPDC personnel

2) Remove safety reporting information for Czech Republic and add safety reporting 
information for “All Other Countries”
MODIFICATIONS TO PROTOCOL:

Bold and underlined text:
Changed text

Bold and strikethrough text:
Deleted text

Bold and italicized text:
Added text
TITLE PAGE
Issue Date:
11 May 2011
Date of Amendment 1:
23 November 2011
Date of Amendment 2:
16 November 2012
Entire protocol, Footnote
23 November 2011
16 November 2012
SYNOPSIS, Trial Design, Paragraph 1, Sentence 3:
This is a multicenter, 52-week, open-label trial designed to assess the long-term safety, 
tolerability, and efficacy of adjunctive brexpiprazole in depressed adults on concurrent 
antidepressant therapy (ADT).  The trial will be conducted on an outpatient basis.  
Enrollment into the trial will be drawn from eligible subjects who have completed the 
last scheduled visitone of thea double-blind, phase 3 efficacy brexpiprazole MDD trials
(ie, Trial 331-10-227 or Trial 331-10-228) and who, in the investigator’s judgment, 
could potentially benefit from adjunctive treatment with oral brexpiprazole for MDD.
SYNOPSIS, Trial Design, Paragraph 3, Screening/Baseline, Sentences 1 and 3:


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Subjects will be screened for eligibility at the last scheduled visit of the prior double-
blind phase 3 trialof Trial 331-10-227 or Trial 331-10-228 (ie, Week 14).  Subjects will 
sign a separate informed consent form for participation in Trial 331-10-238 before any 
procedures specific to the open-label trial are performed.  The assessments from the last 
scheduled visit of the prior double-blind phase 3 trialWeek 14 visit of Trial 331-10-227 
or Trial 331-10-228 will serve as the baseline measures for Trial 331-10-238 for any 
assessment that is not unique to the open-label trial.
SYNOPSIS, Trial Design, Paragraph 3, Follow-up:
Subjects will be followed up for safety via telephone contact or clinic visit 30 (+ 2) days 
after the last dose of open-label medication.
SYNOPSIS, Subject Population:
The subject population will consist of eligible subjects who, in the investigator’s 
judgment, could potentially benefit from adjunctive treatment with brexpiprazole for 
MDD according to the following criteriaand who meet one of the following 
conditions: 

Subjects who participated in Trial 331-10-227 or Trial 331-10-228 only will be 
eligible for the 331-10-238 study if they meet one of the following conditions:

Subjects who completed participation in the double-blind randomization phase 
(ie, Week 14 visit of Phase B) in Trial 331-10-227 or Trial 331-10-228 or

Subjects who met criteria for a response continued into Phase A+ (were not 
randomized into Phase B) at the end of prospective treatment (ie, Week 8 visit of 
Phase A) in Trial 331-10-227 or Trial 331-10-228, BUT DID NOT meet criteria 
for remission (defined as a Montgomery Asberg Depression Rating Scale
MADRS Total Score of 10) at the Week 14 visit of Phase A+ in Trial 331-10-
227 or Trial 331-10-228.

Subjects who participated in another double-blind phase 3 brexpiprazole MDD trial 
will be eligible for the 331-10-238 study if they have completed the last scheduled 
visit of the prior double-blind phase 3 trial.

Subjects must qualify for Trial 331-10-238 at the last scheduled visit of the prior 
double-blind phase 3 trial and must be able to continue therapy without interruption 
between the double-blind and open label trials.  Based on the projected enrollment 
estimates for the prior double-blind phase 3 brexpiprazole MDD trials (ie, Trial 331-
10-227 and Trial 331-10-228), up to approximatelyup to 12803,000 subjects may 
enroll into Trial 331-10-238.
SYNOPSIS, Investigational Medicinal Product, Dose, Formulation, Mode of 
Administration, Brexpiprazole, bulleted list, Paragraph 1, Sentences 1 and 2:

The first dose of open-label brexpiprazole will be taken one day after the last dose 
is taken for the prior double-blind, phase 3 brexpiprazole MDDefficacy trial so 
that adjunctive treatment will continue without interruption.  It is anticipated that 


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the last dose of the double-blind, phase 3 brexpiprazole MDDefficacy trial will be 
taken the day of the last scheduled visitWeek 14 visit of Trial 331-10-227 or 
Trial 331-10-228, (ie, the day of the Screening/Baseline visit for the open-label 
trial).
SYNOPSIS, Investigational Medicinal Product, Dose, Formulation, Mode of 
Administration, ADT, Paragraph 1, Sentences 1 and 2:
ADT:  During the Treatment Phase of Trial 331-10-238, subjects will remain on the same 
assigned open-label ADT from the prior double-blind, phase 3 brexpiprazole 
MDDefficacy trial (ie, Trial 331-10-227 or Trial 331-10-228).  The initial dose of ADT 
will be the same as the ADT dose taken on the last scheduled visit of the prior double-
blind phase 3 trialTrial 331-10-227 or Trial 331-10-228.
SYNOPSIS, Trial Duration, Sentence 1:
The duration of this trial from first subject enrolled to last subject completed is estimated 
to be approximately 3063 months, of which approximately 1751 months are allotted for 
rollover of subjects from the prior double-blind phase 3 brexpiprazole MDD trials (ie, 
Trial 331-10-227 or Trial 331-10-228).
List of Abbreviations and Definitions of Terms:
Incomplete 
response
A term employed to assess prospective response to ADT 
during Phase A of the double-blind phase 3 trials (ie, Trial 
331-10-227 and Trial 331-10-228) as part of eligibility criteria 
for entrance into Phase B.  Incomplete response is defined as 
< 50% reduction in depressive symptom severity between 
baseline and the Week 8 visit as measured by the 17-item 
Hamilton Depression Rating Scale (HAM-D17) Total Score; 
AND a HAM-D17 Total Score 14 at the Week 8 visit; AND a 
Clinical Global Impression - Improvement scale (CGI-I) score 
3 at the Week 8 visit.  Note:  The visit of interest for this 
definition is the Week 8 visit of the double-blind phase 3 trial 
(ie, Trial 331-10-227 and Trial 331-10-228).


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Response
A term employed to assess prospective response to ADT 
during Phase A of the double-blind phase 3 trials (ie, Trial 
331-10-227 and Trial 331-10-228) and representing the logical
complement of “incomplete response.”  Response is defined as 
50% reduction in depressive symptom severity between 
baseline and the Week 8 visit as measured by the HAM-D17 
Total Score; OR a HAM-D17 Total Score of < 14 at the Week 
8 visit; OR a CGI-I score of < 3 at the Week 8 visit.  Note:  
The visit of interest for this definition is the Week 8 visit of 
the double-blind phase 3 trial (ie, Trial 331-10-227 and Trial 
331-10-228).
Section 2.1, Trial Rationale, Paragraph 2, Sentence 4:
The current trial (Trial 331-10-238) provides an open-label rollover option for the
double-blind phase 3 brexpiprazole MDD trials (ie, Trial 331-10-227 andTrial 331-10-
228) and will expand on the knowledge gained in these trials by assessing the long-term 
safety, tolerability, and efficacy of brexpiprazole when administered concomitantly with 
antidepressant medications.
Section 3.1, Type/Design of Trial, Paragraph 1, Sentence 3:
This is a multicenter, 52-week, open-label trial designed to assess the long-term safety, 
tolerability, and efficacy of adjunctive brexpiprazole in depressed adults on concurrent 
ADT.  The trial will be conducted on an outpatient basis.  Enrollment into the trial will be 
drawn from eligible subjects who have completed onethe last scheduled visit of the 
double-blind, phase 3 efficacy brexpiprazole MDD trials (ie, Trial 331-10-227 or Trial 
331-10-228) and who, in the investigator’s judgment, could potentially benefit from 
adjunctive treatment with oral brexpiprazole for MDD.
Section 3.1, Type/Design of Trial, Paragraph 3, Screening/Baseline, Sentences 1 and 3:
Subjects will be screened for eligibility at the last scheduled visit of the prior double-
blind phase 3 trial Trial 331-10-227 or Trial 331-10-228 (ie, Week 14).  Subjects will 
sign a separate informed consent form for participation in Trial 331-10-238 before any 
procedures specific to the open-label trial are performed.  The assessments from the last 
scheduled visit of the prior double-blind phase 3 trial (Week 14 visit of Trial 331-10-
227 or Trial 331-10-228) will serve as the baseline measures for Trial 331-10-238 for 
any assessment that is not unique to the open-label trial.
Section 3.1, Type/Design of Trial, Paragraph 3, Follow-up:
Subjects will be followed up for safety via telephone contact or clinic visit 30 (+ 2) days 
after the last dose of open-label medication.
Figure 3.1-1, Population and screening/baseline visit descriptions:


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Section 3.2.1.1, Brexpiprazole, Paragraph 1, Sentence 2:
The first dose of open-label brexpiprazole will be taken one day after the last dose is 
taken for the prior double-blind, phase 3 efficacy trial so that adjunctive treatment will 
continue without interruption.  It is anticipated that the last dose of the double-blind, 
phase 3 efficacy trial will be taken the day of the last scheduled visitWeek 14 visit of 
Trial 331-10-227 or Trial 331-10-228, (ie, the day of the Screening/Baseline visit for the 
open-label trial).
Table 3.2.1.1-1, Footnote d:
dThroughout Trial 331-10-238, the subject must remain on the same ADT that was 
assigned in the prior double-blind phase 3 trial (ie, Trial 331-10-227 or Trial 331-10-
228).
Section 3.2.1.2, ADT, Sentences 1 and 3:
Eligible subjects who 
completed the last 
scheduled visitone of 
thea double-blind phase 
3 brexpiprazole MDD
trials (ie, Trial 331-10-
227 or Trial 331-10-228)
and who could 
potentially benefit from 
adjunctive treatment with 
brexpiprazole for MDD 
per investigator
Last scheduled visit of a
double-blind phase 3 
brexpiprazole MDD
Ttrial 331-10-227 or 
Trial 331-10-228
a
Occurs simultaneously with the last scheduled visit of a double-blind 
phase 3 brexpiprazole MDD Ttrial 331-10-227 or Trial 331-10-228.


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During the Treatment Phase of Trial 331-10-238, subjects will remain on the same 
assigned open-label ADT from the prior double-blind, phase 3 efficacy trial (ie, Trial 
331-10-227 or Trial 331-10-228).  Numbered ADT bottles to be dispensed to the subject 
will be assigned by the IVRS or IWRS.  The initial dose of ADT for the open-label trial 
will be the same as the ADT dose taken on the last scheduled visit of the prior double-
blind phase 3 trial.
Section 3.2.2.1, Brexpiprazole, Paragraph 2:
Subjects who are unable to tolerate the 0.5 -mg/day dose of brexpiprazole must be 
withdrawn from the trial.  However, subjects whose brexpiprazole dose is decreased to 
0.5 mg/day and who demonstrate adequate tolerability at this dose should be rechallenged 
with a 1 -mg/day dose within approximately 6 to 8 weeks after the dose is decreased to 
0.5 mg/day.  If tolerability issues arise following the rechallenge, the dose may be 
decreased again to 0.5 mg/day.  Further rechallenge at 1 mg/day may be performed at the 
investigator’s discretion.  The dose of brexpiprazole can be increasedre-escalated as 
necessary following a dose decrease at any other dose if, in the investigator’s judgment, 
rechallenge with a higher dose is warranted in order to identify an optimum dose for the 
subject.  Dose adjustments must ultimately be made based upon the clinical judgment of 
the investigator as it relates to tolerability and therapeutic response.
Section 3.2.2.2, ADT, Paragraph 2:
The Sponsor reserves the right to use a generic equivalent should any marketed 
antidepressant become unavailable during the course of the trial.
Section 3.3, Trial Population, Paragraphs 1, 2, 4, 5, 6, and 7:
The subject trial population will consist of eligible subjects who, in the investigator’s 
judgment, could potentially benefit from adjunctive treatment with brexpiprazole for 
MDD according to the following criteriaand who meet one of the following 
conditions: 

Subjects who participated in Trial 331-10-227 or Trial 331-10-228 will be eligible 
for the 331-10-238 study if they meet one of the following conditions:

Subjects who completed participation in the Ddouble-blind Rrandomization 
Pphase (ie, Week 14 visit of Phase B) in Trial 331-10-227 or Trial 331-10-228 or

Subjects who met criteria for a response continued into Phase A+ (were not 
randomized into Phase B) at the end of prospective treatment (ie, Week 8 visit of 
Phase A) in Trial 331-10-227 or Trial 331-10-228, BUT DID NOT meet criteria 
for remission (defined as a Montgomery Asberg Depression Rating Scale 
MADRS Total Score of 10) at the Week 14 visit of Phase A+ in Trial 331-10-
227 or Trial 331-10-228.


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
Subjects who participated in another double-blind phase 3 brexpiprazole MDD trial 
will be eligible for the 331-10-238 study if they have completed the last scheduled 
visit of the prior double-blind phase 3 trial.

Subjects must qualify for Trial 331-10-238 at the last scheduled visit of the prior 
double-blind phase 3 trial and must be able to continue therapy without interruption 
between the double-blind and open label trials.  Based on the projected enrollment 
estimates for the prior double-blind phase 3 brexpiprazole MDD trials (ie, Trial 331-
10-227 and Trial 331-10-228), up to approximatelyup to 12803,000 subjects may 
enroll into Trial 331-10-238.
Section 3.4.1, Informed Consent, Paragraph 2, Sentence 3:
The ICF for the open-label trial may be provided to potential candidates for review and 
discussion toward completion of the prior double-blind phase 3 trial, but the form must 
not be signed until the day of the Screening/Baseline visit for Trial 331-10-238 (ie, the 
the last scheduled visit of the prior double-blind phase 3 trialWeek 14 visit of Trial 
331-10-227 or Trial 331-10-228).
Table 3.4.2-1, Inclusion Criteria 3, 4, 5, and 6:
All Subjects
3.54.
Male and female outpatients 18 to 65 years of age, inclusive, at the time of informed consent for 
Trial 331-10-238.
4.65.
Subjects willing to discontinue all prohibited psychotropic medications starting from the time of 
signing the ICF and during the trial period (refer to Section 4).
331-10-227 and 331-10-228 Subjects Only
5.3.
Subjects who, in the opinion of the investigator, could potentially benefit from administration of 
brexpiprazole as adjunctive therapy to their antidepressant therapy and who meet one of the 
following criteria:
a) Subjects who completed participation in the dDouble-blind rRandomization pPhase (ie, Week 
14 visit of Phase B) in Trial 331-10-227 or Trial 331-10-228 or
b) Subjects who met criteria for a response continued into Phase A+ (were not randomized 
into Phase B) at the end of prospective treatment (ie, Week 8 visit of Phase A) in Trial 331-10-227 
or Trial 331-10-228, BUT DID NOT meet criteria for remission (defined as a MADRS Total Score 
of 10) at the Week 14 visit of Phase A+ in Trial 331-10-227 or Trial 331-10-228.
Eligible Subjects From Other Double-Blind Phase 3 Brexipiprazole MDD Trials
6.4.
Subjects who completed participationthe last scheduled visit of the prior double-blind phase 3 
trial and who in the opinion of the investigator, could potentially benefit from administration of 
brexpiprazole as adjunctive therapy to their antidepressant therapy.
Section 3.4.3, Exclusion Criteria, Paragraph 1:
Subjects entering the open-label trial at the last scheduled visit of the prior double-blind 
phase 3 trialof Trial 331-10-227 or Trial 331-10-228 (ie, Week 14) will be excluded 
from Trial 331-10-238 if they meet any of the following exclusion criteria.
Table 3.4.3-1, Exclusion Criteria 1, 3, 6, 10, 11, 15, and 20:


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Sex and Reproductive Status
1.
Sexually active females of childbearing potential (see Section 5.5) and male subjects who are not 
practicing two different methods of birth control with their partner during the trial and for 30 days 
after the last dose of trial medication or who will not remain abstinent during the trial and for 30 
days after the last dose.  If employing birth control, each couple must use two of the following 
precautions:  vasectomy, tubal ligation (subject or partner), vaginal diaphragm, IUD, birth control 
pill, birth control implant, birth control depot injections, condom, or sponge with spermicide.
Administrative
3.
Subjects with a major protocol violation during the course of their participation in the prior double-
blind phase 3 trial (ie, Trial 331-10-227 or Trial 331-10-228).  Minor violations such as 
occasional visits outside of the acceptable window or a missing blood draw will not exclude a 
subject from participation in Trial 331-10-238; however, continual lack of compliance with the 
visit schedule, trial assessments, or treatment regimen in the prior double-blind phase 3 trial (ie, 
Trial 331-10-227 or Trial 331-10-228) would be considered a major violation that would result in 
exclusion from Trial 331-10-238.  The medical monitor should be contacted if the investigator 
is unsure of a subject’s eligibility.
Target Disease
6.
Subjects with a current need for involuntary commitment or who have been hospitalized during the 
prior double-blind phase 3 trialTrial 331-10-227 or Trial 331-10-228 for the current major 
depressive episode.
10.
Subjects receiving new onset psychotherapy (individual, group, marriage, or family therapy) during 
the prior double-blind phase 3 trialTrial 331-10-227 or Trial 331-10-228.
Medical History and Concurrent Diseases
11.
Subjects with a response of “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal 
Ideation with Some Intent to Act, Without Specific Plan) at entry, OR
Subjects with a response of “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal 
Ideation with Specific Plan and Intent) at entry, OR
Subjects with a response of “Yes” on any of  the 5 C-SSRS Suicidal Behavior Items (actual 
attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) at entry, OR 
Subjects who, in the opinion of the investigator (including consideration of responses on the 
C-SSRS throughout the prior double-blind phase 3 trialTrial 331-10-227 or Trial 331-10-228), 
present a serious risk of suicide.
Note:  “Entry” is defined as the last scheduled visit of the prior double-blind phase 3 trialWeek 
14 of Trial 331-10-227 or Trial 331-10-228.
15.
Subjects with IDDM (ie, any subjects using insulin) are excluded.  Subjects with non-IDDM may 
be eligible for the trial if their condition is stable as determined by satisfying ALL of the following 
criteria:

Screening/baseline HbA1c < 7.0%, AND

Screening/baseline fasting glucose must be 125 mg/dL, AND

Subject has been maintained on a stable regimen of oral anti-diabetic medication(s) or diabetes 
has been well-controlled by diet during the prior double-blind phase 3 trialTrial 331-10-227 
or Trial 331-10-228, AND

Subject has not had any hospitalizations during Trial 331-10-227 or Trial 331-10-228 due to 
diabetes or complications related to diabetes during the prior double-blind phase 3 trialTrial 
331-10-227, or Trial 331-10-228, AND

Subject’s diabetes is not newly diagnosed during screening/baseline for Trial 331-10-238.
Physical and Laboratory Results
20.
The following laboratory test and ECG results are exclusionary:
1) Platelets 75,000/mm3
2) Hemoglobin 9 g/dL
3) Neutrophils, absolute 1000/mm3
4) AST > 2 ULN


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5) ALT > 2 ULN
6) CPK > 3 ULN, unless discussed with and approved by the medical monitor
7) Creatinine 2 mg/dL
8) HbA1c 7.0%
9) Abnormal free T4, unless discussed with and approved by the medical monitor.  (Note: Free T4
is measured only if result for TSH is abnormal.)
10) QTcF 450 msec
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 are medically significant 
and that would impact the safety of the subject or the interpretation of the trial results.  Criteria are 
provided in Appendix 3, Appendix 4, and Appendix 5 to assist investigators in their assessments of 
results that may be potentially medically significant, depending on the subject’s medical history 
and clinical presentation.  Eligibility should be based on the last available measurement during the 
prior double-blind phase 3 trialTrial 331-10-227 or Trial 331-10-228.  The medical monitor 
should be contacted if the investigator is unsure of a subject’s eligibility.
22.
Subjects with a history of neuroleptic malignant syndrome (NMS) or serotonin syndrome.
Section 3.4.3, Exclusion Criteria, Paragraph 2, Sentence 2:
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 
scheduled visit of the prior double-blind phase 3 trial (ie, Week 14 of Trial 331-10-227 
or Trial 331-10-228) are not available to assess eligibility, the assessment for the 
affected criteria should be based on the last available measurement during the respective 
double-blind trial.
Section 3.6, Trial Procedures, Sentence 1:
The duration of this trial from first subject enrolled to last subject completed is estimated 
to be approximately 6330 months, of which approximately 5117 months are allotted for 
rollover of subjects from the prior double-blind phase 3 brexpiprazole MDD trials (ie, 
Trial 331-10-227 or Trial 331-10-228).


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Table 3.6-1
Schedule of Assessments
Assessment
Screening/ 
Baselinea
Open-Label Treatment Phase Visit Week (2 days)
Follow-upc
30 (+2) days
1
2
4
8
14
20
26
32
38
44
52/ETb
ENTRANCE CRITERIA
Informed consentd
X
Inclusion/exclusion criteria
X
Medical history
Xe
EFFICACY
CGI-S
Xf
X
X
X
X
X
X
X
X
X
X
X
CGI-Igf
X
X
X
X
X
X
X
X
X
X
X
SDS
Xf
X
X
X
IDS-SR
Xfq
X
X
X
X
X
X
SAFETY
Physical examination
Xf
X
X
X
Waist circumference
Xf
X
X
X
X
X
X
X
X
Vital signshg
Xf
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGih
Xf
X
X
X
X
X
X
X
Clinical laboratory testsji
Xf,kj
Xlk
Xlk
Xlk
Xlk
Xlk
Xlk
Xlk
ACTH, cortisol, and HbA1c
Xm
Xlk
Xlk
Xlk
Xlk
Xlk
Xlk
Xlk
Drug screen/blood alcoholnl
Xf
X
X
X
X
X
X
X
Urine pregnancy test 
(WOCBP only)om
Xf
X
X
X
X
X
X
X
X
X
X
X
SAS
Xf
X
X
X
X
X
X
X
X
X
X
X
AIMS
Xf
X
X
X
X
X
X
X
X
X
X
X
BARS
Xf
X
X
X
X
X
X
X
X
X
X
X
C-SSRSpn
Xf
X
X
X
X
X
X
X
X
X
X
X
MSFQ
Xf
X
X
X
X
X


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Table 3.6-1
Schedule of Assessments
Assessment
Screening/ 
Baselinea
Open-Label Treatment Phase Visit Week (2 days)
Follow-upc
30 (+2) days
1
2
4
8
14
20
26
32
38
44
52/ETb
Adverse events
Xqo
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationsrp
X
X
X
X
X
X
X
X
X
X
X
X
X
OTHER
Dose adjustmentssq
X
X
X
X
X
X
X
X
X
X
RUFtr
X
X
X
X
Register visit in IVRS/IWRSus
X
X
X
X
X
X
X
X
X
X
X
X
IMP dispensing
X
X
X
X
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
X
X
X
X
IVRS = interactive voice response system; IWRS = interactive web response system; WOCBP = women of childbearing potential.
aScreening for Trial 331-10-238 occurs simultaneously with Baseline at the last scheduled visit of the prior double-blind trialWeek 14 visit of Trial 331-10-
227 or Trial 331-10-228.  All assessments listed under screening need to be performed at Screening/Baseline of Trial 331-10-238; if any of these 
assessments were conducted at the last scheduled visit of the prior double-blind phase 3 trial, then Screening/Baseline values for those assessments will 
be derived from that visit and those assessments will not need to be repeated at Screening/Baseline of Trial 331-10-238.
bIf a subject discontinues prematurely before Week 52, procedures noted for Week 52 must be completed at the early termination (ET) visit.
cConsists of telephone contact or clinic visit (investigator’s discretion) for evaluation of safety and applies to all subjects (completers and early withdrawals).
dInformed consent for Trial 331-10-238 will occur at Screening/Baseline and must be obtained before any trial-related procedures specific to the open-label 
trial are performed.
eUpdate, if necessary.
fScreening/Baseline value will be obtained from the Week 14 visit of Trial 331-10-227 or Trial 331-10-228.
gfImprovement should be based on the subject’s status at the last scheduled visit of the prior double-blind phase 3 trial (ie, the Week 14 visit of Trial 331-
10-227 or Trial 331-10-228).
hgVital signs include body weight, body temperature, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate.  Blood pressure and heart 
rate will be measured in the following order:  supine, sitting, and standing after the subject has been in each position for at least 3 minutes.  Vital signs 
scheduled for the same visit as blood samples are to be completed before blood is drawn.
ihStandard 12-lead ECGs will be performed after the subject has been supine and at rest for 5 minutes prior to the ECG.  A central ECG service will be 
utilized to review 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.  Subjects will be enrolled in Trial 331-10-238 based on the screening/baseline ECG results from the trial site.  If the 


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screening/baseline ECG results from the central reader (ie, Week 14 visit of Trial 331-10-227 or Trial 331-10-228the last scheduled visit of the prior 
double-blind phase 3 trial), when available, indicate a QTcF 450 msec at screening/baseline, the investigator must contact the medical monitor to discuss 
the subject’s continued participation in the trial.  ECGs scheduled for the same visit as blood samples are to be completed before blood is drawn.
jiIncludes hematology (including PT, aPTT, and INR), serum chemistry (including prolactin and TSH, with reflex to free thyroxine [T4] if the result for TSH 
is abnormal), and urinalysis.
kkjSubjects must be fasting for a minimum of 8 hours prior to blood draws for screening/baseline laboratory assessments (ie, Week 14 visit of Trial 331-10-
227 and Trial 331-10-228the last scheduled visit of the prior double-blind phase 3 trial).
lkClinical laboratory tests should be drawn fasting, if possible, but must be drawn after a minimum 8-hour fast at Week 52/ET.  Vital sign and ECG 
assessments should be completed before any blood samples are collected.
mA fasting blood sample for analysis of ACTH, cortisol, and HbA1c must be drawn at Screening/Baseline from subjects entering Trial 331-10-238 
after completing Phase A+ of Trial 331-10-227 or Trial 331-10-228.  This is not required for subjects entering Trial 331-10-238 from Phase B of 
Trial 331-10-227 or Trial 331-10-228 because the screening/baseline values will be obtained from the last visit of the double-blind protocols.  
nlA urine drug screen and a blood alcohol test are required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator.
omAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with a positive serum pregnancy test result at Screening/Baseline 
must not be enrolled in Trial 331-10-238 and subjects with a positive serum pregnancy test result during the trial must discontinue treatment and be 
withdrawn from the trial.  Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.
pn“Since Last Visit” C-SSRS form.
qroAE recording will begin with the signing of the ICF for Trial 331-10-238.
rpAll prescription and non-prescription medications taken during the trial will be recorded as concomitant medications.  Details of prohibited and restricted 
medications are provided in Section 4.
qsAdjustments to the dose of brexpiprazole or ADT are permitted to optimize efficacy and tolerability as described in Section 3.2.  It is recommended that the 
dose of ADT not be changed while the dose of brexpiprazole is being optimized (ie, no change to ADT up to and including the Week 4 visit).  At least 5 
days must elapse between dose increases for brexpiprazole and ADT.  An interval of at least 5 days between dose adjustments is also recommended for 
dose decreases; however, the investigator may decrease the dose of brexpiprazole or ADT as needed for tolerability according to the rules described in 
Section 3.2.2.  Subjects must return to the clinic for unscheduled visits if changes to the dose of brexpiprazole or ADT (increases or decreases) are required 
between scheduled visits.  All eligible subjects entering from prior double-blind phase 3 brexpiprazole MDD trials must be able to continue therapy 
without interruption between the double-blind and open label trials.
rtBaseline RUF is completed at Screening/Baseline for all subjects.  The Follow-up RUF is completed at all other visits.
suThe IVRS/IWRS will be accessed at unscheduled visits if new blister cards are dispensed for dose adjustment of brexpiprazole.


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Section 3.6.1.1, Screening/Baseline, Paragraph 1 and bulleted list:
Subjects entering Trial 331-10-238 must sign the ICF for the open-label trial before any procedures specific to Trial 331-10-238 can 
be performed.  Subjects will retain the same subject identification (Subject ID) number assigned in the prior double-blind phase 3 trial
(ie, Trial 331-10-227 or Trial 331-10-228).  Screening/baseline values will be derived from the last visit of the double-blind 
phase 3 trial (ie, Week 14 visit of Trial 331-10-227 or Trial 331-10-228) for the following assessments:  CGI-S, SDS, IDS-SR, 
MSFQ, SAS, AIMS, BARS, C-SSRS, physical examination, waist circumference, vital signs, ECG, clinical laboratory tests 
(except for ACTH, cortisol, and HbA1c for some subjects), urine drug screen, blood alcohol, and urine pregnancy test.  The 
only additionalfollowing procedures need to be performed at Screening/Baseline of Trial 331-10-238the open-label trial are as 
follows:; if any of these assessments were conducted at the last scheduled visit of the prior double-blind phase 3 trial, then 
Screening/Baseline values for those assessments will be derived from that visit and those assessments will not need to be repeated 
at Screening/Baseline of Trial 331-10-238.

Inclusion/exclusion criteria for Trial 331-10-238 will be reviewed to assure the subject’s eligibility.

Medical history will be updated, if necessary, using information from the prior double-blind phase 3 trial.

Subjects will submit to a physical examination and assessments of waist circumference, vital signs, and ECG.

The investigator (or qualified designee) will administer any scale (ie, CGI-I and CGI-S).

Subjects will complete any Baseline instrument (ie, SDS, IDS-SR, and MSFQ).

An adequately trained and experienced clinician will administer any EPS scale (ie, SAS, AIMS, and BARS).

The investigator (or qualified designee) will complete the “Since Last Visit” C-SSRS form.

Concomitant medications will be reviewed to assure that the subject is not receiving any prohibited medications.

Subjects will complete the Baseline RUF.

For subjects entering Trial 331-10-238 after completing the last scheduled visit of the prior double-blind phase 3 trialPhase A+ 
of Trial 331-10-227 or Trial 331-10-228, a fasting blood sample will be drawn for analysis of any clinical laboratory parameter 
(ie, the clinical laboratory parameters specified in Table 3.6.2.1-1) that was not analyzed at the last scheduled visit of the prior 
double-blind phase 3 trialACTH, cortisol, and HbA1c to obtain screening/baseline values for these parameters.  For all other, the 
screening/baseline values for these parameters will be obtained from the last visit of the double-blind trial.


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
AE recording will begin with the signing of the ICF for Trial 331-10-238.

Trial personnel will call the interactive voice response system (IVRS) or access the interactive web response system (IWRS) to 
register the visit and to obtain blister card and ADT bottle number assignments.  The assigned open-label brexpiprazole and ADT 
will be dispensed.  Treatment will begin with brexpiprazole 0.5 mg/day for 1 week.  The ADT will be the same as the one taken 
during the prior double-blind phase 3 trial (ie, Trial 331-10-227 or Trial 331-10-228).  The dose of ADT should not be changed 
at this time.
Section 3.6.2.1, Clinical Laboratory Tests, Paragraph 1, Sentences 1 and 3:
As it is unlikely that the final laboratory test results from the last scheduled visit of the prior double-blind phase 3 trial (ie, Week 14 
of Trial 331-10-227 and Trial 331-10-228) will be available at the time of enrollment in Trial 331-10-238, the investigator is to 
review the subject’s most recent laboratory test results from the prior double-blind phase 3 trial (ie, Trial 331-10-227 or Trial 331-
10-228) for compliance with the exclusion criteria and the presence of abnormal laboratory test results that, in the investigator’s 
judgment, are medically significant and would impact the safety of the subject or the interpretation of the trial results.  Subjects 
meeting any of these criteria will be excluded from Trial 331-10-238.  Appendix 4 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.  If one or more results from the screening/baseline sample are clinically significant and/or exclusionary when the results 
from the last scheduled visit of the prior double-blind phase 3 trial become available, the test(s) should be repeated.
Section 3.6.2.2.1, Physical Examination, Paragraph 1, Sentences 1 and 3:
The complete physical examination at the last scheduled visit of the prior double-blind phase 3 trial (ie, Week 14 visit of Trial 331-
10-227 or Trial 331-10-228) will serve as the screening/baseline physical examination for the current protocol.  A complete physical 
examination will consist of a review of the following body systems:  HEENT, thorax, abdomen, urogenital, extremities, neurological, 
and skin and mucosae.  Repeat measurement of height is not required during Trial 331-10-238 if a Sscreening/Bbaseline value is 
available from the last scheduled visit of the prior double-blind phase 3 trial.
Section 3.6.2.2.1, Physical Examination, Paragraph 5, Sentences 1, 3, and 4:


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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 screening/baseline examination should be documented 
as an AE and followed to a satisfactory conclusion.
Section 3.6.2.4.4
Suicidality will be monitored during the trial using the C-SSRS.  Subjects completed the “Baseline/Screening” C-SSRS form at the 
beginning of the prior double-blind phase 3 trial (ie, Trial 331-10-227 or Trial 331-10-228); therefore, only the “Since Last Visit” C-
SSRS form will be used in Trial 331-10-238.  A copy of the “Since Last Visit” C-SSRS form is provided in Appendix 13.
Section 3.6.3.2, Clinical Global Impression - Improvement Scale (CGI-I), Sentence 2
The efficacy of trial treatment will be rated for each subject using the CGI-I.26  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 
Screening/Baseline (ie, Week 14 last scheduled visit of the prior double-blind phase 3 trialTrial 331-10-227 or Trial 331-10-228).  
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 7.
Section 3.6.3.3.3, Resource Utilization Form (RUF), Sentences 2 and 3:
The RUF is a self-report tool designed to collect information regarding the extent of medical care sought by subjects while 
participating in the trial (Appendix 15).  The number of hospitalizations and days of hospitalization within the past 12 months will be 
collected on the Baseline Form at Screening/Baseline, including any hospitalizations that may have occurred during the subject’s 
participation in the prior double-blind phase 3 trialTrial 331-10-227 or Trial 331-10-228.  The number of visits to various 
practitioners for mental health and other reasons within the 3 months prior to Screening/Baseline (excluding any visits from the prior 


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double-blind phase 3 trialTrial 331-10-227 or Trial 331-10-228) will be collected on the Baseline Form and the number of such 
visits occurring during the trial (excluding visits related to the trial) will be collected on the Follow-up Form at Weeks 8, 26, and 
52/ET.
Section 3.8, Screen Failures, Sentence 3:
A screen failure subject is one from whom informed consent is obtained and is documented in writing (ie, subject signs an ICF), but 
who is not started on treatment, whether through randomization or open assignment.  For the purposes of Trial 331-10-238, treatment 
begins with the first dose of open-label brexpiprazole in the Treatment Phase.  Subjects who do not qualify for Trial 331-10-238 at the 
last scheduled visit of the prior double-blind phase 3 trial (ie, Week 14 of Trial 331-10-227 or Trial 331-10-228) may not be 
rescreened.
Section 4.1, Prohibited Medications, Sentence 1:
Concomitant medications taken by subjects who are rolling over into Trial 331-10-238 from one of thea prior double-blind phase 3 
trials (ie, Trial 331-10-227 or Trial 331-10-228) should be reviewed for the prohibited medications listed in Table 4.1-1.
Section 4.2.1, Restricted Therapies and Precautions, Paragraph 4, Sentence 1:
ECT was prohibited during the prior double-blind phase 3 trials (ie, Trial 331-10-227 and Trial 331-10-228) and is also prohibited 
for the duration of Trial 331-10-238.
Section 4.2.2.2, Restrictions, Paragraph 1:
Subjects may only receive psychotherapy (eg, individual, group, marriage, or family therapy) if they initiated the therapy at least 42 
days before enrollment in one of the prior double-blind phase 3 trials (ie, Trial 331-10-227 or Trial 331-10-228), participated in the 
therapy regularly during the prior double-blind phase 3 trial, and commit to maintain their participation during the course of Trial 331-
10-238, or unless permission is obtained from the medical monitor.
Section 5.4, Potential Hy’s Law Cases:


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For a subject that experiences an elevation in AST or ALT that is 3 times the upper normal limit or whose levels increase 3 times 
their initial screening value, a total bilirubin level should also be evaluated.  If the total bilirubin is 2 times the upper normal limit
or 2 times their screening value, confirmatory repeat laboratory samples should be drawn within 48 to 72 hours of the initial 
draw.  If these values are confirmed, trial personnel will complete an IRE form with all values listed and also report as an AE on the 
eCRFs.  Please note: If the subject was enrolled into the trial with non-exclusionary elevated transaminase levels at baseline, 
please discuss any potential drug-induced liver injury events with the Medical Monitor.
Section 5.5, Pregnancy:
WOCBP and men who are sexually active must use an effective method of birth control during the course of the trial and for at least 
30 days after the last dose in a manner such that risk of failure is minimized.  Unless the subject is sterile (ie, women who have had an 
oophorectomy and/or hysterectomy or have been postmenopausal for at least 12 consecutive months; or men who have had 
orchidectomy) or remains abstinent, two of the following precautions must be used:  vasectomy or, tubal ligation (subject and 
partner), vaginal diaphragm, intrauterine device, birth control pills, birth control depot injection, birth control implant, condom or 
sponge with spermicide.  Any single method of birth control, including vasectomy and tubal ligation, may fail, leading to pregnancy.
Section 7.2, Sample Size:
The sample size is not based on statistical power considerations.  The trial population will be derived from eligible subjects from the 
prior double-blind phase 3 brexpiprazole MDD trials (ie, Trial 331-10-227 and Trial 331-10-228).  Therefore, the number of eligible 
subjects will be limited by the number of subjects enrolled into these protocols.  Based on the projected enrollment estimates for the 
prior double-blind phase 3 trials (ie, Trial 331-10-227 and Trial 331-10-228), up to approximatelyup to 3,0001280 subjects may 
enroll into Trial 331-10-238.
Section 8.1, Packaging and Labeling, Paragraph 3, Sentence 2:


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ADTs will be supplied as bulk drug in commercial packaging (eg, bottles) with an ancillary trial-specific label that will be positioned 
such that it will not obscure the original commercial label.  The sponsor reserves the right to use a generic equivalent, should any 
marketed antidepressant become unavailable during the course of the trial.
Appendix 1, Names of Sponsor Personnel:
Primary Medical Contact:
Phone 
Fax 
Backup Medical Contact:
, 
Phone 
Fax 
Backup Medical Contact:
Phone 


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Fax 
Appendix 2, Institutions Concerned with the Trial, Safety Reporting:
Country
Safety Fax Line
United States
Canada
Czech Republic
France
Germany
Hungary
Poland
Romania
Russia
Slovakia
Ukraine
All other countries
Appendix 7, Clinical Global Impression - Improvement Scale (CGI-I), Sentence 2:
Rate total improvement whether or not in your judgment it is due entirely to drug treatment.  Compared to his/her condition at the last 
scheduled visit of the prior double-blind phase 3 trialTrial 331-10-227 or Trial 331-10-228 (ie, prior to enrollment into Trial 331-
10-238), how much has patient changed?
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects as a result of this protocol amendment.


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Amendment Number:
3
Issue Date:
11 Apr 2014
PURPOSE:
The sponsor has determined the need for a third formal amendment to the original 
protocol.  Due to a well-established safety profile in the completed double-blind and 
long-term Phase 2 and Phase 3 trials the study duration has been reduced from 52 weeks 
to 26 weeks and the number of assessments has been decreased.  In addition, 
administrative clarifications were made, including changes to text to enhance readability 
and consistency and correct typographical errors.  The purpose of amending Protocol 
331-10-238, issued on 16 Nov 2012 (amendment 2), was to:

reduce the trial duration from 52 weeks to 26 weeks.

reduce the number of visits to match the reduction in trial duration.

minimize safety assessments performed at each visit.

reduce the safety scale administration performed at each visit.

reduce the efficacy scale administration performed at each visit.

make administrative changes.


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BACKGROUND:
Due to a well-established safety profile in the completed double-blind and long-term 
Phase 2 and Phase 3 trials the study duration has been reduced from 52 weeks to 26 
weeks and the number of assessments has been decreased.  In addition, administrative 
clarifications were made, including changes to text to enhance readability and 
consistency and correct typographical errors.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Changes made to Protocol 331-10-238 in this third amendment are as outlined above.  

All the references to Week 52 were changed to Week 26. The word “study” was 
replaced by “trial” throughout the document.  

All visits and assessments from Week 26 to Week 52 were removed.

Reference to Trial 331-13-214 was added wherever Trial 331-10-227 and Trial 331-
10-228 were referred. .

Sections 8.5 to 8.5.4 (Reporting of Product Quality Complaints) were added.


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General Revisions:
Changes made to Protocol 331-10-238 in this third amendment are as outlined above.  Changes by section are provided below.


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Revisions by Protocol Section:
Location
Current Text
Revised Text
Title Page
 
Phone 
Fax 
E-mail 
 
Phone 
Fax 
E-mail: 
 
Synopsis: Trial Design
This is a multicenter, 52-week, 
open-label trial designed to assess 
the long-term safety, tolerability, 
and efficacy of adjunctive 
brexpiprazole in depressed adults 
on concurrent antidepressant 
therapy (ADT).
Visits will occur at the end of 
This is a multicenter, 26-week, 
open-label trial designed to assess 
the long-term safety, tolerability, 
and efficacy of adjunctive 
brexpiprazole in depressed adults 
on concurrent antidepressant 
therapy (ADT).  The trial will be 
conducted on an outpatient basis.  
Enrollment into the trial will be 


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Weeks 1, 2, 4, 8, 14, 20, 26, 32, 
38, 44, and 52.  All subjects will 
receive up to 52 weeks of open-
label treatment in Trial 331-10-
238.
drawn from eligible subjects who 
have completed the last scheduled 
visit of a double-blind, phase 3 
brexpiprazole MDD trial and 
who, in the investigator’s 
judgment, could potentially 
benefit from adjunctive treatment 
with oral brexpiprazole for MDD.
The original 52 week open-label 
trial design has been modified in 
this Amendment 3 to shorten the 
duration of the trial to 26 weeks; 
ongoing subjects who have not 
reached their Week 26 visit will 
be re-consented and will follow 
Amendment 3 schedule of 
assessments.  Ongoing subjects 
who have already completed their 
Week 26 visit at the time of 
Amendment 3 will follow 
Amendment 3 week 26/ET 
schedule of assessments at their 
next scheduled visit
Visits will occur at the end of 
Weeks 1, 2, 4, 8, 14, 20 and 26. 
All subjects will receive up to 26 
weeks of open-label treatment in 
Trial 331-10-238.


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Synopsis: Trial Duration
The duration of this trial from 
first subject enrolled to last 
subject completed is estimated to 
be approximately 63 months, of 
which approximately 51 months 
are allotted for rollover of 
subjects from the prior double-
blind phase 3 brexpiprazole MDD 
trials.  Individual participation for 
subjects who complete the trial 
without early withdrawal will be 
approximately 56 weeks (52 
weeks of treatment and 30-day 
follow-up).
The duration of this trial from 
first subject enrolled to last 
subject completed is estimated to 
be approximately 57 months, of 
which approximately 51 months 
are allotted for rollover of 
subjects from the prior double-
blind phase 3 brexpiprazole MDD 
trials.  Individual participation for 
subjects who complete the trial 
without early withdrawal will be 
approximately 30 weeks (26 
weeks of treatment and 30-day 
follow-up).
Section 3.1:  
Type/Design of Trial
Visits will occur at the end of 
Weeks 1, 2, 4, 8, 14, 20, 26, 32, 
38, 44, and 52.  All subjects will 
receive up to 52 weeks of open-
label treatment in Trial 331-10-
238 and follow the schedule of 
assessments described in Table 
3.6-1.
See Current Figure at the end of 
the table. 
Figure 3.1-1 Trial Design 
Visits will occur at the end of 
Weeks 1, 2, 4, 8, 14, 20, and 26. 
All subjects will receive up to 26 
weeks of open-label treatment in 
Trial 331-10-238 and follow the 
schedule of assessments 
described in Table 3.6-1. 
See Revised Figure at the end of 
the table.
Figure 3.1-1 Trial Design 
Schematic


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Schematic
See current Table 3.2.1.1-1 
Dosing Schedule for 
Brexpiprazole at the end of this 
table.
See revised  Table 3.2.1.1-1  
Dosing Schedule for 
Brexpiprazole at the end of this 
table. 
See curent Table 10.2-1 Schedule
of Assessments at the end of this 
table
See revised Table 10.2-1
Schedule of Assessments at 
the end of this table.
Section 3.3: Trial 
Population
The trial population will consist 
of eligible subjects who, in the 
investigator’s judgment, could 
potentially benefit from 
adjunctive treatment with 
brexpiprazole for MDD 
according to the following 
criteria:
•
Subjects who 
participated in Trial 331-10-227, 
Trial 331-10-228 or Trial 331 13 
214 will be eligible for Trial 331-
10-238 if they meet one of the 
following conditions:
Subjects who completed 
participation in the double-blind 
randomization phase (ie, Week 
14 visit of phase B) in Trial 331-
10-227,  Trial 331-10-228 or 
The trial population will consist 
of eligible subjects who, in the 
investigator’s judgment, could 
potentially benefit from 
adjunctive treatment with 
brexpiprazole for MDD 
according to the following 
criteria:
•
Subjects who 
participated in Trial 331-10-227,  
Trial 331-10-228 or Trial 331 13 
214 will be eligible for Trial 331-
10-238 if they meet one of the 
following conditions:
Subjects who completed 
participation in the double-blind 
randomization phase (ie, Week 
14 visit of phase B) in Trial 331-
10-227,  Trial 331-10-228 or 


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Trial 331 13 214 or
Subjects who continued 
into Phase A+ (were not 
randomized into Phase B) at the 
end of prospective treatment (ie, 
Week 8 visit of Phase A) in Trial 
331-10-227, Trial 331-10-228 or 
Trial 331-13-214, BUT DID 
NOT meet criteria for remission 
(defined as a MADRS Total 
Score of 10) at the Week 14 
visit of Phase A+ in Trial 331 10 
227, Trial 331-10-228 or Trial 
331-13-214.
•
Subjects who 
participated in a double-blind 
phase 3 brexpiprazole MDD trial 
will be eligible for the 331-10-
238 trial if they have completed 
the last scheduled visit of the 
double-blind phase 3 trial.
•
Subjects must qualify 
for Trial 331-10-238 at the last 
scheduled visit of the prior 
double-blind phase 3 trial and 
must be able to continue therapy 
without interruption between the 
double-blind and open label 
Trial 331 13 214 or
Subjects who continued 
into Phase A+ (were not 
randomized into Phase B) at the 
end of prospective treatment (ie, 
Week 8 visit of Phase A) in Trial 
331-10-227,  Trial 331-10-228 or 
Trial 331-13-214, BUT DID 
NOT meet criteria for remission 
(defined as a MADRS Total 
Score of 10) at the Week 14 
visit of Phase A+ in Trial 331 10 
227,  Trial 331-10-228 or Trial 
331-13-214.
•
Subjects who 
participated in a double-blind 
phase 3 brexpiprazole MDD trial 
will be eligible for the 331-10-
238 trial if they have completed 
the last scheduled visit of the 
double-blind phase 3 trial.
•
Subjects must qualify 
for Trial 331-10-238 at the last 
scheduled visit of the prior 
double-blind phase 3 trial and 
must be able to continue therapy 
without interruption between the 
double-blind and open label 


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trials.  Based on the projected 
enrollment estimates for the prior 
double-blind phase 3 
brexpiprazole MDD trials, up to 
approximately 3,000 subjects 
may enroll into Trial 331-10-238.
trials.  Based on the projected 
enrollment estimates for the prior 
double-blind phase 3 
brexpiprazole MDD trials, up to 
approximately 3,000 subjects 
may enroll into Trial 331-10-238.
Section 3.4.2: Inclusion 
Criteria
Subjects willing to discontinue all 
prohibited psychotropic
medications starting from the 
time of signing the ICF and 
during the trial period (refer to 
Section 4).
331-10-227 331-10-228 Subjects 
Only.
Subjects willing to discontinue all 
prohibited psychotropic 
medications starting from the 
time of signing the ICF and 
during the trial period (refer to 
Section 4).
331-10-227 331-10-228 and 331-
13-214 Subjects Only.
Section 3.4.3:  Exclusion 
Criteria. 
5. Subjects who have had an 
inadequate response to ECT at 
any time in the past or who have 
had a vagus nerve stimulation or 
deep brain stimulation device 
implanted for management of 
treatment-resistant depression. 
5. Subjects who have had an 
inadequate response to ECT at 
any time in the past or who have 
had a vagus nerve stimulation or 
deep brain stimulation device 
implanted at any time for 
management of treatment-
resistant depression.  Subjects 
who have had Transcranial 
Magnetic Stimulation during the 
current major depressive episode. 
15. Continuation of subjects 
excluded based on abnormal test 
results from the 


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20. Eligibility should be based on 
the last available measurement 
during the prior double-blind 
phase 3 trial.  The medical 
monitor should be contacted if 
the investigator is unsure of a 
subject’s eligibility.
screening/baseline visit should be 
discussed with the medical 
monitor, if in the investigator's 
judgement, the subject is a 
suitable candidate for the trial.
20. Eligibility should be based on 
the Screening/baseline laboratory 
test and ECG results.  The 
medical monitor should be 
contacted if the investigator is 
unsure of a subject’s eligibility.  
Continuation of subjects excluded 
based on abnormal test and ECG 
results should be discussed with 
the medical monitor, if in the 
investigator's judgement, the 
subject is a suitable candidate for 
the trial. 
Section 3.5.2.2: Safety 
Variables
Mean change from baseline will 
be calculated for coagulation 
parameters (prothrombin time 
[PT], activated partial 
thromboplastin time [aPTT], and 
International Normalized Ratio 
[INR]), glycosylated hemoglobin 
Mean change from baseline will 
be calculated for coagulation 
parameters (prothrombin time 
[PT], activated partial 
thromboplastin time [aPTT], and 
International Normalized Ratio 
[INR]), glycosylated hemoglobin 


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(HbA1c), cortisol, 
adrenocorticotropic hormone 
(ACTH), thyroid-stimulating 
hormone (TSH), waist 
circumference, and body mass 
index (BMI; derived 
programmatically from body 
weight and height 
measurements).
(HbA1c), thyroid-stimulating 
hormone (TSH), waist 
circumference, and body mass 
index (BMI; derived 
programmatically from body 
weight and height 
measurements).
Section 3.6: Trial 
Procedures
The duration of this trial from 
first subject enrolled to last 
subject completed is estimated to 
be approximately 63 months, of 
which approximately 51 months 
are allotted for rollover of 
subjects from prior double-blind 
phase 3 brexpiprazole MDD 
trials.  Individual participation for 
subjects who complete the trial 
without early withdrawal will be 
approximately 56 weeks (52 
weeks of treatment and 30-day 
follow-up).
The duration of this trial from 
first subject enrolled to last 
subject completed is estimated to 
be approximately 57 months, of 
which approximately 51 months 
are allotted for rollover of 
subjects from prior double-blind 
phase 3 brexpiprazole MDD 
trials.  Individual participation for 
subjects who complete the trial 
without early withdrawal will be 
approximately 30 weeks (26 
weeks of treatment and 30-day 
follow-up). 
Section 3.6.1:  
Screening/Baseline

The investigator (or qualified 
designee) will administer any 
scale (ie,the CGI-I and CGI 
S).

The investigator (or qualified 
designee) will administer the 
CGI-S and CGI .
Section 3.6.1.2:  Week 1

The investigator (or qualified 
designee) will administer the 

The investigator (or qualified 
designee) will administer the 


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CGI-S and CGI-I.

An adequately trained and 
experienced clinician will 
administer the SAS, AIMS, 
and BARS to assess EPS.

The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.

The subject will complete the 
MSFQ.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure 
and heart rate are to be 
measured in the following 
order:  supine, 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 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 fasting blood draw will be 
collected for clinical 
laboratory tests (hematology, 
including PT, aPTT, and 
INR; and serum chemistry, 
CGI-S.

An adequately trained and 
experienced clinician will 
administer the SAS 
AIMS,and BARS to assess 
EPS.

The investigator (or qualified 
designee) will complete the
“Since Last Visit” C-SSRS 
form.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure and 
heart rate are to be measured 
in the following order:  
supine, 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.

Samples will be obtained for 
blood alcohol testing.

Urine will be collected for 
urinalysis and urine screen(s) 
for drugs of abuse.

Women of childbearing 
potential (WOCBP) will be 
given a urine pregnancy test.  
Any positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 


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including prolactin, HbA1c, 
ACTH, cortisol, and TSH, 
with reflex to free thyroxine 
[T4] if the result for TSH is 
abnormal).  Vital sign and 
ECG assessments should be 
completed before any blood 
samples are collected.

Samples will be obtained for 
blood alcohol testing.

Urine will be collected for 
urinalysis and urine screen(s) 
for drugs of abuse.

Women of childbearing 
potential (WOCBP) will be 
given a urine pregnancy test.  
Any positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The dose of brexpiprazole 
will be increased to 1 
mg/day.  Subjects unable to 
tolerate brexpiprazole 1 
mg/day may decrease to 0.5 
mg/day at any time after the 
Week 1 visit.  It is 
recommended that the dose 
of ADT not be changed 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The dose of brexpiprazole 
will be increased to 1 
mg/day.  Subjects unable to 
tolerate brexpiprazole 1 
mg/day may decrease to 0.5 
mg/day at any time after the 
Week 1 visit.  It is 
recommended that the dose 
of ADT not be changed while 
the dose of brexpiprazole is 
being optimized.  Trial 
personnel will call the IVRS 
or access the IWRS to 
register the visit, to enter 
dose details for brexpiprazole 
and ADT, and to obtain 
blister card and bottle number 
assignments.  The assigned 
open-label brexpiprazole and 
ADT will be dispensed to the 
subject. 

AEs and concomitant 
medications will be recorded.


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while the dose of 
brexpiprazole is being 
optimized.  Trial personnel 
will call the IVRS or access 
the IWRS to register the 
visit, to enter dose details for 
brexpiprazole and ADT, and 
to obtain blister card and 
bottle number assignments.  
The assigned open-label 
brexpiprazole and ADT will 
be dispensed to the subject.

AEs and concomitant 
medications will be recorded.
Section 3.6.1.3:  Week 2

The investigator (or qualified 
designee) will administer the 
CGI-S and CGI-I.

An adequately trained and 
experienced clinician will 
administer the SAS, AIMS, 
and BARS to assess EPS.

The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.

The subject will complete the 
MSFQ.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure 
and heart rate are to be 
measured in the following 
order:  supine, sitting, and 

The investigator (or qualified 
designee) will administer the 
CGI-S.

An adequately trained and 
experienced clinician will 
administer the SAS and 
BARS to assess EPS.

The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure and 
heart rate are to be measured 
in the following order:  
supine, sitting, and standing 
after the subject has been in 
each position at least 3 


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standing after the subject has 
been in each position at least 
3 minutes.

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The investigator will adjust 
the dose of brexpiprazole as 
necessary as described in 
Section 3.2 to achieve 
optimal efficacy and 
tolerability.  It is 
recommended that the dose 
of ADT not be changed 
while the dose of 
brexpiprazole is being 
optimized.  Any subject 
unable to tolerate the 
minimum dose of 
brexpiprazole (ie, 0.5 
mg/day) must be withdrawn 
from the trial.  Trial 
personnel will call the IVRS 
or access the IWRS to 
register the visit, to enter 
dose details for brexpiprazole 
and ADT, and to obtain 
minutes.

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The investigator will adjust 
the dose of brexpiprazole as 
necessary as described in 
Section 3.2 to achieve 
optimal efficacy and 
tolerability.  It is 
recommended that the dose 
of ADT not be changed while 
the dose of brexpiprazole is 
being optimized.  Any 
subject unable to tolerate the 
minimum dose of 
brexpiprazole (ie, 0.5 
mg/day) must be withdrawn 
from the trial.  Trial 
personnel will call the IVRS 
or access the IWRS to 
register the visit, to enter 
dose details for brexpiprazole 
and ADT, and to obtain 
blister card and bottle number 
assignments.  The assigned 
open-labelbrexpiprazole and 


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blister card and bottle 
number assignments.  The 
assigned open-label 
brexpiprazole and ADT will 
be dispensed to the subject.

AEs and concomitant 
medications will be recorded.
ADT will be dispensed to the 
subject.

AEs and concomitant 
medications will be recorded.
Section 3.6.1.4:  Week 4

The investigator (or qualified 
designee) will administer the 
CGI-S and CGI-I.

An adequately trained and 
experienced clinician will 
administer the SAS, AIMS, 
and BARS to assess EPS.

The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure 
and heart rate are to be 
measured in the following 
order:  supine, 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 after the 
subject has been supine and 
at rest for at least 5 minutes.  

The investigator (or qualified 
designee) will administer the 
CGI-S.

An adequately trained and 
experienced clinician will 
administer the SAS and 
BARS to assess EPS.

The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure and 
heart rate are to be measured 
in the following order:  
supine, 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.

Samples will be obtained for 
blood alcohol testing.

Urine will be collected for 
urine screen(s) for drugs of 


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The ECG is to be completed 
before any blood is drawn.

A fasting blood draw will be 
collected for clinical 
laboratory tests (hematology, 
including PT, aPTT, and 
INR; and serum chemistry, 
including prolactin, HbA1c, 
ACTH, cortisol, and TSH, 
with reflex to free T4 if the 
result for TSH is abnormal).  
Vital sign and ECG 
assessments should be 
completed before any blood 
samples are collected.

Samples will be obtained for 
blood alcohol testing.

Urine will be collected for 
urinalysis and urine screen(s) 
for drugs of abuse. 

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The investigator will adjust 
the dose of brexpiprazole as 
necessary as described in 
abuse.

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The investigator will adjust 
the dose of brexpiprazole as 
necessary as described in 
Section 3.2 to achieve 
optimal efficacy and 
tolerability.  If necessary, the 
dose of ADT can be changed 
after the Week 4 visit, but not 
at the same visit as a change 
to the dose of brexpiprazole 
(see Section 3.2.2.2).  Any 
subject unable to tolerate the 
minimum dose of 
brexpiprazole (ie, 0.5 
mg/day) must be withdrawn 
from the trial.  Trial 
personnel will call the IVRS 
or access the IWRS to 
register the visit, to enter 
dose details for brexpiprazole 
and ADT, and to obtain 
blister card and bottle number 
assignments.  The assigned 


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Section 3.2 to achieve 
optimal efficacy and 
tolerability.  If necessary, the 
dose of ADT can be changed 
after the Week 4 visit, but 
not at the same visit as a 
change to the dose of 
brexpiprazole (see Section 
3.2.2.2).  Any subject unable 
to tolerate the minimum dose 
of brexpiprazole (ie, 0.5 
mg/day) must be withdrawn 
from the trial.  Trial 
personnel will call the IVRS 
or access the IWRS to 
register the visit, to enter 
dose details for brexpiprazole 
and ADT, and to obtain 
blister card and bottle 
number assignments.  The 
assigned open-label 
brexpiprazole and ADT will 
be dispensed to the subject.

AEs and concomitant 
medications will be recorded.
open-label brexpiprazole and 
ADT will be dispensed to the 
subject.

AEs and concomitant 
medications will be recorded.
Section 3.6.1.5:  Week 8

The investigator (or qualified 
designee) will administer the 
CGI-S and CGI-I. 

An adequately trained and 
experienced clinician will 
administer the SAS, AIMS, 
and BARS to assess EPS.

The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 

The investigator (or qualified 
designee) will administer the 
CGI-S.

An adequately trained and 
experienced clinician will 
administer the SAS and 
BARS to assess EPS.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 


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form.

The subject will complete the 
MSFQ, SDS, IDS-SR, and 
the Follow-up RUF.

A complete physical 
examination (including waist 
circumference) will be 
performed.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure 
and heart rate are to be 
measured in the following 
order:  supine, 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 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 fasting blood draw will be 
collected for clinical 
laboratory tests (hematology, 
including PT, aPTT, and 
INR; and serum chemistry, 
including prolactin, HbA1c, 
ACTH, cortisol, and TSH, 
with reflex to free T4 if TSH 
recorded.  Blood pressure and 
heart rate 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.

Samples will be obtained for 
blood alcohol testing.

Urine will be collected for 
urine screen(s) for drugs of 
abuse.

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial. 

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The investigator will adjust 
the dose of brexpiprazole as 
necessary within the range of 
0.5 to 3 mg daily as described 
in Section 3.2.  If necessary, 
the dose of ADT can also be 
adjusted (see Section 
3.2.2.2).  Trial personnel will 
call the IVRS or access the 


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is abnormal).  Vital sign and 
ECG assessments should be 
completed before any blood 
samples are collected.

Samples will be obtained for 
blood alcohol testing.

Urine will be collected for 
urinalysis and urine screen(s) 
for drugs of abuse.

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The investigator will adjust 
the dose of brexpiprazole as 
necessary within the range of 
0.5 to 3 mg daily as 
described in Section 3.2.  If 
necessary, the dose of ADT 
can also be adjusted (see 
Section 3.2.2.2).  Trial 
personnel will call the IVRS 
or access the IWRS to 
register the visit, to enter 
dose details for brexpiprazole 
and ADT, and to obtain 
blister card and bottle 
IWRS to register the visit, to 
enter dose details for 
brexpiprazole and ADT, and 
to obtain blister card and 
bottle number assignments.  
The assigned open-label 
brexpiprazole and ADT will 
be dispensed to the subject.

AEs and concomitant 
medications will be recorded.


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number assignments.  The 
assigned open-label 
brexpiprazole and ADT will 
be dispensed to the subject.

AEs and concomitant 
medications will be recorded.
Section 3.6.1.6: 
Section 3.6.1.6:  Long-term 
Treatment Visits (Weeks 14, 20, 
26, 32, 38, and 44)
All subjects will attend visits at 
Weeks 14, 20, 26, 32, 38, and 44 
(2 days).  The following 
evaluations will be performed at 
each visit, unless otherwise 
specified:

The investigator (or qualified 
designee) will administer the 
CGI-S and CGI-I.

Waist circumference will be 
measured.

An adequately trained and 
experienced clinician will 
administer the SAS, AIMS, 
and BARS to assess EPS.

The subject will complete the 
IDS-SR (except for Weeks 
32 and 44).

The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.
Section 3.6.1.6 Week 14
All subjects will attend a visit at 
Week 14 (2 days) where the 
following evaluations will be 
performed: 

The investigator (or qualified 
designee) will administer the 
CGI-S and CGI-I.

Waist circumference will be 
measured.

An adequately trained and 
experienced clinician will 
administer the SAS, AIMS, 
and BARS to assess EPS.

The subject will complete the 
IDS-SR and SDS.

The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure and 
heart rate are to be measured 


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
Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure 
and heart rate are to be 
measured in the following 
order:  supine, 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.

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The investigator will adjust 
the dose of brexpiprazole as 
necessary within the range of 
0.5 to 3 mg daily as 
described in Section 3.2.  If 
necessary, the dose of ADT
can also be adjusted (see 
Section 3.2.2.2).  Trial 
personnel will call the IVRS 
or access the IWRS to 
register the visit, to enter 
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 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 fasting blood draw will be 
collected for clinical 
laboratory tests (hematology, 
including PT, aPTT, and 
INR; and serum chemistry, 
including prolactin, HbA1c, 
and TSH, with reflex to free 
T4 if the result for TSH is 
abnormal).  Vital sign and 
ECG assessments should be 
completed before any blood 
samples are collected.

Samples will be obtained for 
blood alcohol testing.  
Additional blood alcohol 
testing may be performed at 
any other time at the 
discretion of the investigator.

Urine will be collected for 
urinalysis and urine screen(s) 
for drugs of abuse.  
Additional urine drug screens 
may be performed at any 


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dose details for brexpiprazole 
and ADT, and to obtain 
blister card and bottle 
number assignments.  The 
assigned open-label 
brexpiprazole and ADT will 
be dispensed to the subject.

AEs and concomitant 
medications will be recorded.

The following additional 
evaluations will be 
performed at Weeks 14, 26, 
and 38 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.

A fasting blood draw will be 
collected for clinical 
laboratory tests (hematology, 
including PT, aPTT, and 
INR; and serum chemistry, 
including prolactin, HbA1c, 
ACTH, cortisol, and TSH, 
with reflex to free T4 if the 
result for TSH is abnormal).  
Vital sign and ECG 
assessments should be 
completed before any blood 
samples are collected.

Samples will be obtained for 
blood alcohol testing.  
Additional blood alcohol 
other time at the discretion of 
the investigator.

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The investigator will adjust 
the dose of brexpiprazole as 
necessary within the range of 
0.5 to 3 mg daily as described 
in Section 3.2.  If necessary, 
the dose of ADT can also be 
adjusted (see Section 
3.2.2.2).  Trial personnel will 
call the IVRS or access the 
IWRS to register the visit, to 
enter dose details for 
brexpiprazole and ADT, and 
to obtain blister card and 
bottle number assignments.  
The assigned open-label 
brexpiprazole and ADT will 
be dispensed to the subject.

AEs and concomitant 
medications will be recorded.


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testing may be performed at 
any other time at the 
discretion of the investigator.

Urine will be collected for 
urinalysis and urine screen(s) 
for drugs of abuse.  
Additional urine drug screens 
may be performed at any 
other time at the discretion of 
the investigator.
The following additional 
evaluations will be performed at 
Week 26 only:

A complete physical 
examination will be 
performed.

The subject will complete the 
MSFQ, SDS, and the 
Follow-up RUF. 
Section 3.6.1.7:  Week 20
Section 3.6.1.7:  End of 
Treatment (Week 52/ET)
Section 3.6.1.7:  
All subjects will attend a visit at 
Week 20 (2 days) where the 
following evaluations will be 
performed:

The investigator (or qualified 
designee) will administer the 
CGI-S.


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
An adequately trained and 
experienced clinician will 
administer the SAS and 
BARS to assess EPS.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure and 
heart rate are to be measured 
in the following order:  
supine, 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.

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.  WOCBP 
with a positive serum 
pregnancy test result must 
discontinue the IMP and be 
withdrawn from the trial.

Drug accountability will be 
performed for brexpiprazole 
and ADT.

The investigator will adjust 
the dose of brexpiprazole as 
necessary within the range of 
0.5 to 3 mg daily as described 
in Section 3.2.  If necessary, 
the dose of ADT can also be 
adjusted (see 


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Section 3.2.2.2).  Trial
personnel will call the IVRS 
or access the IWRS to 
register the visit, to enter 
dose details for brexpiprazole 
and ADT, and to obtain 
blister card and bottle number 
assignments.  The assigned 
open-label brexpiprazole and 
ADT will be dispensed to the 
subject.

AEs and concomitant 
medications will be recorded
Section 3.6.1.8:  End of 
Treatment (Week 
26/ET)
NA

The Week 26 visit signifies 
the end of treatment.  
Therefore, all subjects will 
undergo a complete 
evaluation at Week 26 (2 
days).  In addition, Week 26 
evaluations are to be 
completed, if possible, for 
any subject withdrawn from 
the trial prematurely.  Since 
the original 52 week open-
label trial design has been 
modified as a part of 
Amendment 3 to shorten the 
duration of the trial to 26 
weeks; ongoing subjects who 
have not reached their Week 
26 visit will be re-consented 
and will follow Amendment 
3 schedule of assessments.  
Ongoing subjects who have 


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already completed their 
Week 26 visit at the time 
Amendment 3 is approved 
will follow Amendment 3 
week 26/ET schedule of 
assessments at their next 
scheduled visit.  The 
following activities and 
assessments will occur at 
Week 26 (or at the ET visit, if 
applicable):The investigator 
(or qualified designee) will 
administer the CGI-S and 
CGI-I.

An adequately trained and 
experienced clinician will 
administer the SAS, AIMS, 
and BARS to assess EPS.

The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.

The subject will complete the 
MSFQ, SDS, IDS-SR, and 
the Follow-up RUF.

A complete physical 
examination (including waist 
circumference) will be 
performed.

Vital sign measurements 
(body weight, body 
temperature, blood pressure, 
and heart rate) will be 
recorded.  Blood pressure and 
heart rate are to be measured 


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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 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 fasting blood draw will be 
collected for clinical 
laboratory tests (hematology, 
including PT, aPTT, and 
INR; and serum chemistry, 
including prolactin, HbA1c, 
ACTH,cortisol and TSH, 
with reflex to free T4 if TSH 
is abnormal).  Vital sign and 
ECG assessments should be 
completed before any blood 
samples are collected.

Samples will be obtained for 
blood alcohol testing.

Urine will be collected for 
urinalysis and urine screen(s) 
for drugs of abuse.

WOCBP will be given a 
urine pregnancy test.  Any 
positive result must be 
confirmed by a serum 
pregnancy test.


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
Final drug accountability will 
be performed.

Trial personnel will call the 
IVRS or access the IWRS to 
register completion or 
discontinuation from the trial.

AEs and concomitant 
medications will be recorded.
Section 3.6.2.1:  Clinical 
Laboratory Tests
See the current table at the end of 
this table
See the revised  table at the end of 
this table
Section 3.6.2.2.1: 
Physical Examination
Repeat measurement of height is 
not required during Trial 331-10-
238 if a Screening/Baseline value 
is available from the last 
scheduled visit of the prior 
double blind phase 3 trial.   
Waist circumference will be 
measured at each physical 
examination (ie, Weeks 8, 26, and 
52), and in addition, at Weeks 14, 
20, 32, 38, and 44.  
Repeat measurement of height is 
not required during Trial 331-10-
238 if a Screening/Baseline value 
is available from the prior double 
blind phase 3 trial.
Waist circumference will be 
measured at Screening/Baseline 
Week 14 and Week 26/ET.
Section 3.10: Definition 
of Lost to Follow-up
Subjects who cannot be contacted
on or before the Week 52 visit 
during the treatment period and 
who do not have a known reason 
for discontinuation (eg, withdrew 
consent or AE) will be classified 
as “lost to follow-up” as the 
Subjects who cannot be contacted 
on or before the Week 26 visit 
during the treatment period and 
who do not have a known reason 
for discontinuation (eg, withdrew 
consent or AE) will be classified 
as “lost to follow-up” as the 


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reason for discontinuation.
reason for discontinuation.  The 
site will make three 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.
Section 5.1:  Definitions
Examples of AEs that are 
considered extrapyramidal 
symptoms include, but are not 
limited to:  generalized rigidity, 
hyperkinesia, bradykinesia, 
akinesia, dystonia, hypertonia, 
akathisia, tremor, flexed posture, 
involuntary muscle contractions, 
athetosis, and chorea.  

Potential Hy’s Law 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. )
Examples of AEs that are 
considered extrapyramidal 
symptoms include, but are not 
limited to:  generalized rigidity, 
hyperkinesia, dyskinesia, 
bradykinesia, akinesia, dystonia, 
hypertonia, akathisia, tremor, 
flexed posture, involuntary 
muscle contractions, athetosis, 
and chorea. 

Potential Hy’s Law cases 
(Any increase of AST or 
ALT 3 times the upper 
normal limit  with an increase 
in total bilirubin 2 times the 
upper normal limit.
Section 7.1.2:  
In order to assess sensitivity of 
results due to missing data, two 
types of analyses will be 
performed for analyses by visit:  
In order to assess sensitivity of 
results due to missing data, two 
types of analyses will be 
performed for analyses by visit:  


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LOCF and OC.  The LOCF and 
OC data sets are defined in 
Section 7.1.1.  The OC data set 
will be used for analyses at each 
visit and the LOCF data set will 
be used for the last visit analyses
(ie, Week 26, LOCF).
LOCF and OC.  The LOCF and 
OC data sets are defined in 
Section 7.1.1.  The OC data set 
will be used for analyses at each 
visit and the LOCF data set will 
be used for the last visit analyses
Section 7.1.4:  Secondary 
outcome analysis
Secondary efficacy endpoints are 
as follows:
1)
Change from baseline in 
CGI-S score, by trial week and at 
the last visit (ie, Week 26/ ET); 
2)
Mean CGI-I score, by 
trial week and at the last visit (ie, 
Week 26/ET);
3)
Change from baseline in 
SDS score, by trial week and at 
the last visit (ie, Week 26/ET);
4)
Change from baseline in 
IDS-SR Total Score, by trial 
week and at the last visit (ie, 
Week 26/ET).
Descriptive statistics will be 
provided for each endpoint.  The 
analysis will be carried out on the 
Efficacy Sample.  Descriptive 
statistics will be summarized at 
Secondary efficacy endpoints are 
as follows:
1)
Change from baseline in 
CGI-S score, by trial week and at 
the last visit. 
2)
Mean CGI-I score, by 
trial week and at the last visit. 
3)
Change from baseline in 
SDS score, by trial week and at 
the last visit. 
4)
Change from baseline in 
IDS-SR Total Score, by trial week 
and at the last visit 
Descriptive statistics will be 
provided for each endpoint.  The 
analysis will be carried out on the 
Efficacy Sample.  Descriptive 
statistics will be summarized at 
each trial visit using the OC data 
set and at the last visit.


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each trial visit using the OC data 
set and at the last visit using the 
LOCF data set.
Section 7..4.5:  Other 
Safety Data
Descriptive statistics will be 
summarized at each visit using 
the OC data set and at the last 
visit (Week 26/ET) using the 
LOCF data set. Suicidality 
monitored during the trial using 
the C-SSRS
Descriptive statistics will be 
summarized at each visit using the 
OC data set and at the last visit 
using the LOCF data set. 
Suicidality monitored during the 
trial using the C-SSRS
Section 8.1:  Packaging 
and Labeling
Each blister card used in the trial 
will be given an identifying 
number and will be labeled to 
clearly disclose the blister card 
number, Subject ID (to be filled 
in by the site staff/investigator), 
subject’s initials, name of the 
investigator (to be filled in by the 
site staff/investigator), site 
number (to be filled in by the site 
staff/investigator), subject’s 
initials (to be filled in by the site 
staff/investigator), date dispensed 
(to be filled in by the site 
staff/investigator), compound ID, 
protocol number, the sponsor's 
name and address, instructions 
for use, route of administration, 
and appropriate precautionary 
Each blister card used in the trial 
will be given an identifying 
number and will be labeled to 
clearly disclose the blister card 
number, Subject ID (to be filled in 
by the site staff/investigator), 
subject’s initials or other unique 
identifier, name of the 
investigator (to be filled in by the 
site staff/investigator), site 
number (to be filled in by the site 
staff/investigator), subject’s 
initials (to be filled in by the site 
staff/investigator), date dispensed 
(to be filled in by the site 
staff/investigator), compound ID, 
protocol number, the sponsor's 
name and address, instructions for 
use, route of administration, and 


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statements.  
Subjects must remain on the same 
ADT for the duration of the trial 
(ie, Screening/Baseline through 
Week 52/ET).
appropriate precautionary 
statements.  
Subjects must remain on the same 
ADT for the duration of the trial 
(ie, Screening/Baseline through 
Week 26/ET).
Section 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


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
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
Section 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 sponsor 
through and including 
reconciliation and up to 
destruction, including subject 
dosing.  The investigator or 
designee must notify the sponsor 
(or sponsor’s designee) must be 
notified within 24 hours of 
becoming aware of the PQC by e-
mail or telephone and according 
to the procedure outlined below:

Online – Send information 


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required for reporting 
purposes (listed below) to 
OAPI-
EQCProductComplaints@Ot
suka-us.com

Phone - Rocky Mountain Call 
Center at 1-800-438-6055.
Identification of a PQC by the 
subject should be reported to the 
site investigator, who should then 
follow one of the reporting 
mechanisms above.
Section 8.5.2:  
Information Required
for Reporting Purposes

Description of compliant

Reporter identification (eg, 
subject, investigator, site, etc)

Reporter contact information 
(eg, address, phone number, 
e-mail address.)

ID of material 
(product/compound name, 
coding)

Clinical protocol reference 
(number and/or trial name)

Dosage form/strength (if 
known)

Pictures (if available)

Availability for return
Section 8.5.3:  Return 
Process
Indicate during the report of the 
PQC if the complaint sample is 
available for return.  If complaint 
sample is available for return, 


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return it in the product retrieval 
package, which will be provided 
by OAPI-EQC.  
It should be documented in the 
site accountability record that a 
complaint sample for a dispensed 
kit has been forwarded to OAPI-
EQC for complaint investigation.
Section 8.5.4:  
Assessment/Evaluation
Assessment and evaluation of 
Product Quality complaints will 
be handled by OAPI EQC QM 
group.
Section 9.4:  Records 
Retention at the Trial 
Site
FDA regulations require all 
investigators participating in 
clinical drug trials to maintain 
detailed clinical data for one of 
the following periods:

A period of at least 3 years 
following the date on which 
a New Drug Application is 
approved by the FDA.

A period of 3 years after the 
sponsor notifies the 
investigator that no further 
application is to be filed with 
the FDA.
Regulatory requirements for the 
archival of records for this trial 
necessitate that participating 
investigators maintain detailed 
clinical data for the longest of the 
following three periods

A period of at least 2 years 
following 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 


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The investigator must not dispose 
of any records relevant to this 
trial without either (1) written 
permission from the sponsor or 
(2) provision of an opportunity 
for the sponsor or designated 
agent 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 the 
eCRF data on the CD-ROM and 
any data clarification forms 
received from the sponsor (or 
sponsor’s designee).  Such 
documentation is subject to 
inspection by the sponsor, 
sponsor’s designee, and relevant 
regulatory agencies.  If the 
investigator withdraws from the 
trial (eg, due to relocation or 
retirement), all trial related 
records should be transferred to a 
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 
the sponsor or designated agent 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 the eCRF data on the 
CD ROM and any data 
clarification forms received from 
the sponsor (or sponsor’s
designee).  Such documentation is 
subject to inspection by the 
sponsor, sponsor’s designee, and 
relevant regulatory agencies.  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 


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mutually agreed upon designee.  
Notice of such transfer will be 
given to the sponsor (or designee) 
in writing.
within a sponsor-specified 
timeframe.  Notice of such 
transfer will be given to the 
sponsor (or designee) in writing.
Section 12:  
Confidentiality
Subjects will be identified only 
by initials and unique subject 
numbers in eCRFs.  Their full 
names may, however, be made 
known to a regulatory agency or 
other authorized officials if 
necessary.
Subjects will be identified only by 
initials and unique subject 
numbers in eCRFs.  Per country 
regulations, if subject initials 
cannot be collected, another 
unique identifier will be used.  
Their full names may, however, 
be made known to a regulatory 
agency or other authorized 
officials if necessary.
Appendix 1
Current Contacts 
Primary Medical Contact:
 
 
 
 
Phone 
Fax 
Primary Medical Contact:
 
Revised Contacts
 
 
 
 
 
Phone 
Mobile 
  
Backup Medical Contact:
 


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Phone 
Mobile 
Fax 
:
 
 
 
Phone 
94
Fax 
Primary Clinical Contact:
 
 
 
Phone 
Fax 
Phone 
Fax 
E-mail 
 
 
 
 
 
Phone 
Fax 
Primary Clinical Contact:
 
 
Phone: 
Fax: 
Mobile: 
email: 
 
Backup Clinical Contact:
 


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Phone 
Fax 
 
 
 
 
Phone 
Fax 


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Current Figure 3.1-1
Follow-up
30 (+ 2) days 
after last dose
Eligible subjects who 
completed the last 
scheduled visit of a 
double-blind phase 3 
brexpiprazole MDD trial 
and who could potentially 
benefit from adjunctive 
treatment with 
brexpiprazole for MDD per 
investigator
Telephone 
contact or clinic 
visit
Visits at Weeks 1, 2, 4, 8, 14, 20, 26, 32, 38, 44, and 52
(unscheduled visits as necessary for dose adjustments)
Week 52 visit of 
Trial 331-10-238
Last scheduled visit 
of a double-blind 
phase 3 brexpiprazole 
MDD trial
Screening/Baselinea
Open-label Brexpiprazole (0.5 to 3 mg/day) + ADT
Treatment Phase
aOccurs simultaneously with the last scheduled visit of a double-
blind phase 3 brexpiprazole MDD trial.


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Revised Figure 3.1-1   
Follow-up
30 (+ 2) days 
after last dose
Eligible subjects who 
completed the last 
scheduled visit of a 
double-blind phase 3 
brexpiprazole MDD trial 
and who could potentially 
benefit from adjunctive 
treatment with 
brexpiprazole for MDD per 
investigator
Telephone 
contact or clinic 
visit
Visits at Weeks 1, 2, 4, 8, 14, and 20
(unscheduled visits as necessary for dose adjustments)
Week 26 visit of 
Trial 331-10-238
Last scheduled visit 
of a double-blind 
phase 3 brexpiprazole 
MDD trial
Screening/Baselinea
Open-label Brexpiprazole (0.5 to 3 mg/day) + ADT
Treatment Phase
aOccurs simultaneously with the last scheduled visit of a double-
blind phase 3 brexpiprazole MDD trial.


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Table 4.2.2.2-2
Dosing Schedule for Brexpiprazole
IMP
Trial Visit
Screening/ 
Baseline
Week 1a
Week 2b
Week 4b
Visits at Weeks 8, 14, 20, 26, 32, 
38, and 44b
Brexpiprazole 
(mg/day)c
0.5
1
0.5, 1 or 2
0.5, 1, 2 or 3
0.5, 1, 2, or 3
ADTd
Final dose 
from double-
blind trial
No changee
No changee
No changee
Change to ADT dose is permitted as 
described in Section 3.2.2.2.
aSubjects unable to tolerate brexpiprazole 1 mg/day may decrease to 0.5 mg/day at any time after the 
Week 1 visit.
bStep-wise increases in the dose of brexpiprazole must be separated by at least 5 days.  Although step-
wise decreases in the brexpiprazole dose are permitted at any time after the Week 1 visit to a 
minimum of 0.5 mg/day, an interval of at least 5 days between dose adjustments is recommended.  
See Section 3.2.2.1 for additional information on dose adjustments.  Subjects must return to the clinic 
for unscheduled visits if changes to the dose of brexpiprazole (increases or decreases) are required 
between scheduled visits.
cSubjects unable to tolerate the minimum dose of brexpiprazole (ie, 0.5 mg/day) must be withdrawn 
from the trial.
dThroughout Trial 331-10-238, the subject must remain on the same ADT that was assigned in the prior 
double-blind phase 3 trial.
eIt is recommended that the dose of ADT not be changed while the dose of brexpiprazole is being 
optimized.


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Revised Table 4.2.2.2-3
Dosing Schedule for Brexpiprazole
IMP
Trial Visit
Screening/ 
Baseline
Week 1a
Week 2b
Week 4b
Visits at Weeks 8, 14, and 20 b
Brexpiprazole 
(mg/day)c
0.5
1
0.5, 1 or 2
0.5, 1, 2 or 3
0.5, 1, 2, or 3
ADTd
Final dose 
from double-
blind trial
No changee
No changee
No changee
Change to ADT dose is permitted as 
described in Section 3.2.2.2.
aSubjects unable to tolerate brexpiprazole 1 mg/day may decrease to 0.5 mg/day at any time after the 
Week 1 visit.
bStep-wise increases in the dose of brexpiprazole must be separated by at least 5 days.  Although step-
wise decreases in the brexpiprazole dose are permitted at any time after the Week 1 visit to a 
minimum of 0.5 mg/day, an interval of at least 5 days between dose adjustments is recommended.  
See Section 3.2.2.1 for additional information on dose adjustments.  Subjects must return to the clinic 
for unscheduled visits if changes to the dose of brexpiprazole (increases or decreases) are required 
between scheduled visits.
cSubjects unable to tolerate the minimum dose of brexpiprazole (ie, 0.5 mg/day) must be withdrawn 
from the trial.
dThroughout Trial 331-10-238, the subject must remain on the same ADT that was assigned in the prior 
double-blind phase 3 trial.
eIt is recommended that the dose of ADT not be changed while the dose of brexpiprazole is being 
optimized.


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  Current Table  3.6.1  
Schedule of Assessments
Assessment
Screening/ 
Baselinea
Open-Label Treatment Phase Visit Week (2 days)
Follow-upc
30 (+2) days
1
2
4
8
14
20
26
32
38
44
52/ETb
ENTRANCE CRITERIA
Informed consentd
X
Inclusion/exclusion criteria
X
Medical history
Xe
EFFICACY
CGI-S
X
X
X
X
X
X
X
X
X
X
X
X
CGI-If
X
X
X
X
X
X
X
X
X
X
X
SDS
X
X
X
X
IDS-SR
X
X
X
X
X
X
X
SAFETY
Physical examination
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGh
X
X
X
X
X
X
X
X
Clinical laboratory testsi
Xj
Xk
Xk
Xk
Xk
Xk
Xk
Xk
ACTH, cortisol, and HbA1c
X
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Drug screen/blood alcoholl
X
X
X
X
X
X
X
X
Urine pregnancy test 
(WOCBP only)m
X
X
X
X
X
X
X
X
X
X
X
X
SAS
X
X
X
X
X
X
X
X
X
X
X
X
AIMS
X
X
X
X
X
X
X
X
X
X
X
X
BARS
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRSn
X
X
X
X
X
X
X
X
X
X
X
X
MSFQ
X
X
X
X
X
X


Protocol 331-10-238
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203
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  Current Table  3.6.1  
Schedule of Assessments
Assessment
Screening/ 
Baselinea
Open-Label Treatment Phase Visit Week (2 days)
Follow-upc
30 (+2) days
1
2
4
8
14
20
26
32
38
44
52/ETb
Adverse events
Xo
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationsp
X
X
X
X
X
X
X
X
X
X
X
X
X
OTHER
Dose adjustmentsq
X
X
X
X
X
X
X
X
X
X
RUFr
X
X
X
X
Register visit in IVRS/IWRSs
X
X
X
X
X
X
X
X
X
X
X
X
IMP dispensing
X
X
X
X
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
X
X
X
X
IVRS = interactive voice response system; IWRS = interactive web response system; WOCBP = women of childbearing potential.
aScreening for Trial 331-10-238 occurs simultaneously with Baseline at the last scheduled visit of the prior double-blind phase 3 trial.  All assessments listed
under screening need to be performed at Screening/Baseline of Trial 331-10-238; if any of these assessments were conducted at the last scheduled visit of 
the prior double-blind phase 3 trial, then Screening/Baseline values for those assessments will be derived from that visit and those assessments will not 
need to be repeated at Screening/Baseline of Trial 331-10-238.
bIf a subject discontinues prematurely before Week 52, procedures noted for Week 52 must be completed at the early termination (ET) visit.
cConsists of telephone contact or clinic visit (investigator’s discretion) for evaluation of safety and applies to all subjects (completers and early withdrawals).
dInformed consent for Trial 331-10-238 will occur at Screening/Baseline and must be obtained before any trial-related procedures specific to the open-label 
trial are performed.
eUpdate, if necessary.
fImprovement should be based on the subject’s status at the last scheduled visit of the prior double-blind phase 3 trial.
gVital signs include body weight, body temperature, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate.  Blood pressure and heart 
rate will be measured in the following order:  supine, sitting, and standing after the subject has been in each position for at least 3 minutes.  Vital signs 
scheduled for the same visit as blood samples are to be completed before blood is drawn.
hStandard 12-lead ECGs will be performed after the subject has been supine and at rest for 5 minutes prior to the ECG.  A central ECG service will be 
utilized to review 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.  Subjects will be enrolled in Trial 331-10-238 based on the screening/baseline ECG results from the trial site.  If the 
screening/baseline ECG results from the central reader (ie, the last scheduled visit of the prior double-blind phase 3 trial), when available, indicate a QTcF 


Protocol 331-10-238
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204
13 Jun 2014
450 msec at screening/baseline, the investigator must contact the medical monitor to discuss the subject’s continued participation in the trial.  ECGs 
scheduled for the same visit as blood samples are to be completed before blood is drawn.
iIncludes hematology (including PT, aPTT, and INR), serum chemistry (including prolactin and TSH, with reflex to free thyroxine [T4] if the result for TSH is 
abnormal), and urinalysis. 
jSubjects must be fasting for a minimum of 8 hours prior to blood draws for screening/baseline laboratory assessments (ie, the last scheduled visit of the prior 
double-blind phase 3 trial).
kClinical laboratory tests should be drawn fasting, if possible, but must be drawn after a minimum 8-hour fast at Week 52/ET.  Vital sign and ECG 
assessments should be completed before any blood samples are collected.
lA urine drug screen and a blood alcohol test are required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator.
mAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with a positive serum pregnancy test result at Screening/Baseline must 
not be enrolled in Trial 331-10-238 and subjects with a positive serum pregnancy test result during the trial must discontinue treatment and be withdrawn 
from the trial.  Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.
n“Since Last Visit” C-SSRS form.
oAE recording will begin with the signing of the ICF for Trial 331-10-238.
pAll prescription and non-prescription medications taken during the trial will be recorded as concomitant medications.  Details of prohibited and restricted 
medications are provided in Section 4.
qAdjustments to the dose of brexpiprazole or ADT are permitted to optimize efficacy and tolerability as described in Section 3.2.  It is recommended that the 
dose of ADT not be changed while the dose of brexpiprazole is being optimized (ie, no change to ADT up to and including the Week 4 visit).  At least 5 
days must elapse between dose increases for brexpiprazole and ADT.  An interval of at least 5 days between dose adjustments is also recommended for 
dose decreases; however, the investigator may decrease the dose of brexpiprazole or ADT as needed for tolerability according to the rules described in 
Section 3.2.2.  Subjects must return to the clinic for unscheduled visits if changes to the dose of brexpiprazole or ADT (increases or decreases) are required 
between scheduled visits.  All eligible subjects entering from prior double-blind phase 3 brexpiprazole MDD trials must be able to continue therapy without 
interruption between the double-blind and open label trials.
rBaseline RUF is completed at Screening/Baseline for all subjects.  The Follow-up RUF is completed at all other visits.
sThe IVRS/IWRS will be accessed at unscheduled visits if new blister cards are dispensed for dose adjustment of brexpiprazole.


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205
13 Jun 2014
Revised Table 3.6-1Schedule of Assessments
Assessment
Screening/ 
Baselinea
Open-Label Treatment Phase Visit Week (2 days)
Follow-upc
30 (+2) days
1
2
4
8
14
20
26/ETb
ENTRANCE CRITERIA
Informed consentd
X
Inclusion/exclusion criteria
X
Medical history
Xe
EFFICACY
CGI-S
X
X
X
X
X
X
X
X
CGI-If
X
X
X
SDS
X
X
X
IDS-SR
X
X
X
SAFETY
Physical examination
X
X
Waist circumference
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
12-lead ECGh
X
X
X
Clinical laboratory testsi
Xj
Xk
Xk
HbA1c
Xj
Xk
Xk
Drug screen/blood alcoholl
X
X
X
X
X
X
Urine pregnancy test 
(WOCBP only)m
X
X
X
X
X
X
X
X
SAS
X
X
X
X
X
X
X
X
AIMS
X
X
X
BARS
X
X
X
X
X
X
X
X
C-SSRSn
X
X
X
X
X
X
MSFQ
X
X
Adverse events
Xo
X
X
X
X
X
X
X
X


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206
13 Jun 2014
Concomitant medicationsp
X
X
X
X
X
X
X
X
X
OTHER
Dose adjustmentsq
X
X
X
X
X
X
RUFr
X
X
Register visit in IVRS/IWRSs
X
X
X
X
X
X
X
X
IMP dispensing
X
X
X
X
X
X
X
IMP accountability
X
X
X
X
X
X
X
IVRS = interactive voice response system; IWRS = interactive web response system; WOCBP = women of childbearing potential.
aScreening for Trial 331-10-238 occurs simultaneously with Baseline at the last scheduled visit of the prior double-blind phase 3 trial.  All assessments listed 
under screening need to be performed at Screening/Baseline of Trial 331-10-238; if any of these assessments were conducted at the last scheduled visit of 
the prior double-blind phase 3 trial, then Screening/Baseline values for those assessments will be derived from that visit and those assessments will not 
need to be repeated at Screening/Baseline of Trial 331-10-238.
bIf a subject discontinues prematurely before Week 26, procedures noted for Week 26 must be completed at the early termination (ET) visit.  Subjects who 
have completed 26 weeks or more, will have the Week 26/ET procedures at their next scheduled visit.
cConsists of telephone contact or clinic visit (investigator’s discretion) for evaluation of safety and applies to all subjects (completers and early withdrawals).
dInformed consent for Trial 331-10-238 will occur at Screening/Baseline and must be obtained before any trial-related procedures specific to the open-label 
trial are performed.
eUpdate, if necessary.
fImprovement should be based on the subject’s status at the last scheduled visit of the prior double-blind phase 3 trial.
gVital signs include body weight, body temperature, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate.  Blood pressure and heart 
rate will be measured in the following order:  supine, sitting, and standing after the subject has been in each position for at least 3 minutes.  Vital signs 
scheduled for the same visit as blood samples are to be completed before blood is drawn.
hStandard 12-lead ECGs will be performed after the subject has been supine and at rest for 5 minutes prior to the ECG.  A central ECG service will be 
utilized to review 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.  Subjects will be enrolled in Trial 331-10-238 based on the screening/baseline ECG results from the trial site.  If the 
screening/baseline ECG results from the central reader (ie, the last scheduled visit of the prior double-blind phase 3 trial), when available, indicate a QTcF 
450 msec at screening/baseline, the investigator must contact the medical monitor to discuss the subject’s continued participation in the trial.  ECGs 
scheduled for the same visit as blood samples are to be completed before blood is drawn.
iIncludes hematology (including PT, aPTT, and INR), serum chemistry (including prolactin and TSH, with reflex to free thyroxine [T4] if the result for TSH is 
abnormal), and urinalysis. 


Protocol 331-10-238
Confidential - Proprietary Information
207
13 Jun 2014
jSubjects must be fasting for a minimum of 8 hours prior to blood draws for screening/baseline laboratory assessments (ie, the last scheduled visit of the prior 
double-blind phase 3 trial).
kClinical laboratory tests should be drawn fasting, if possible, but must be drawn after a minimum 8-hour fast at Week 26/ET.  Vital sign and ECG 
assessments should be completed before any blood samples are collected.
lA urine drug screen and a blood alcohol test are required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator.
mAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with a positive serum pregnancy test result at Screening/Baseline must 
not be enrolled in Trial 331-10-238 and subjects with a positive serum pregnancy test result during the trial must discontinue treatment and be withdrawn 
from the trial.  Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.
n“Since Last Visit” C-SSRS form.
oAE recording will begin with the signing of the ICF for Trial 331-10-238.
pAll prescription and non-prescription medications taken during the trial will be recorded as concomitant medications.  Details of prohibited and restricted 
medications are provided in Section 4.
qAdjustments to the dose of brexpiprazole or ADT are permitted to optimize efficacy and tolerability as described in Section 3.2.  It is recommended that the 
dose of ADT not be changed while the dose of brexpiprazole is being optimized (ie, no change to ADT up to and including the Week 4 visit).  At least 5 
days must elapse between dose increases for brexpiprazole and ADT.  An interval of at least 5 days between dose adjustments is also recommended for 
dose decreases; however, the investigator may decrease the dose of brexpiprazole or ADT as needed for tolerability according to the rules described in 
Section 3.2.2.  Subjects must return to the clinic for unscheduled visits if changes to the dose of brexpiprazole or ADT (increases or decreases) are required 
between scheduled visits.  All eligible subjects entering from prior double-blind phase 3 brexpiprazole MDD trials must be able to continue therapy without 
interruption between the double-blind and open label trials.
rBaseline RUF is completed at Screening/Baseline for all subjects.  The Follow-up RUF (as well as hospitalization questions) is completed at ET visit.
sThe IVRS/IWRS will be accessed at unscheduled visits if new blister cards are dispensed for dose adjustment of brexpiprazole.


Protocol 331-10-238
Confidential - Proprietary Information
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Section 3.6.2.1:  Clinical 
Laboratory Tests
Current Table
Table 3.6.2.1-1
Safety Clinical Laboratory Tests
Hematology:
WBC count with differential
RBC count
Hematocrit
Hemoglobin
Platelet count
Urinalysis:
pH
Specific gravity
Protein
Ketones
Glucose
Blood
Microscopic exam (performed only if any part of 
the urinalysis is not negative)
Urine Drug Screens:
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Marijuana
Methadone
Opiates
Phencyclidine
Propoxyphene
Other:
Blood alcohol
Serum Chemistry:
ALP
ALT or SGPT
AST or SGOT
BUN
CPK
Creatinine
LDH
Total bilirubin
Triglycerides 
Cholesterol (total, LDL, and HDL)
Calcium
Chloride
Glucose
Insulin
Magnesium
Bicarbonate
Inorganic phosphorous
Sodium
Potassium
Total protein
Uric acid
GGT
Prolactin
Albumin
Additional Tests:
Urine pregnancy (WOCBP)a
TSH, with reflex to free T4 if TSH is abnormal
PT, aPTT, and INR
ACTH
Cortisol
HbA1c


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Revised  Table
Table 3.6.2.1-1
Safety Clinical Laboratory Tests
Hematology:
WBC count with differential
RBC count
Hematocrit
Hemoglobin
Platelet count
Urinalysis:
pH
Specific gravity
Protein
Ketones
Glucose
Blood
Microscopic exam (performed only if any part of 
the urinalysis is not negative)
Urine Drug Screens:
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Marijuana
Methadone
Opiates
Phencyclidine
Propoxyphene
Other:
Blood alcohol
Serum Chemistry:
ALP
ALT or SGPT
AST or SGOT
BUN
CPK
Creatinine
LDH
Total bilirubin
Triglycerides 
Cholesterol (total, LDL, and HDL)
Calcium
Chloride
Glucose
Insulin
Magnesium
Bicarbonate
Inorganic phosphorous
Sodium
Potassium
Total protein
Uric acid
GGT
Prolactin
Albumin
Additional Tests:
Urine pregnancy (WOCBP)a
TSH, with reflex to free T4 if TSH is abnormal
PT, aPTT, and INR
HbA1c


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Amendment Number:
4
Issue Date:
13 Jun 2014
PURPOSE:
The sponsor has determined the need for a fourth Amendment to make the following 
administrative changes:

include C-SSRS assessment at week 8 and week 20 (removed in error from 
amendment 3 issued on 11 Apr 2014)

update sponsor contact details
General Revisions:

Changes made to Protocol 331-10-238 in this fourth amendment are as outlined 
above.  Changes by section are provided below.
Location
Current Text
Revised Text
Title Page
 
Phone 
Fax 
E-mail: 
 
 
Phone 
Fax 
E-mail: 
 
Table 3.6-1 
Schedule of 
Assessments
C-SSRS added X at week 8 
and 20
3.6.1.5 
Week 8
The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.
3.6.1.7
Week 20
The investigator (or qualified 
designee) will complete the 
“Since Last Visit” C-SSRS 
form.


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13 Jun 2014
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Research Agreement.
I will provide copies of the protocol to all physicians, nurses and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, OPC-34712, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC) responsible for such matters in the clinical trial facility where 331-10-238 
will be tested prior to commencement of this trial. I agree to adhere strictly to the attached 
protocol (unless amended in the manner set forth in Paragraph I of the sponsor's Clinical 
Research Agreement, at which time I agree to adhere strictly to the protocol as amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor monitors and auditors full access to 
all medical records at the research facility for subjects screened or enrolled in the trial.
I agree to await IRB/IEC approval before implementation of any protocol amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within 5 working days. Administrative 
changes to the protocol will be transmitted to the IRB/IEC for informational purposes only.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Research Agreement and the relevant 
regional regulation(s) and guideline(s). I further agree to provide all required information 
regarding financial certification or disclosure to the sponsor for all investigators and sub-
investigators in accordance with the terms of the relevant regional regulation(s). I understand that 
participation in the protocol involves a commitment to publish the data from this trial in a 
cooperative publication prior to publication of efficacy and safety results on an individual basis.
________________________________________________
Principal or Coordinating Investigator Signature and Date


Otsuka Pharmaceutical Development & Commercialization, Inc.
This page is a manifestation of an electronically captured signature
                                                                                                                                
SIGNATURE PAGE
Document Name:
Document Number:
Document Version:
Signed by
Meaning of Signature
Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
OPC-34712
331-10-238 Amendment 04
0001108835
3.0
Biostatistics Approval
13-Jun-2014 21:02 GMT+00
Clinical Approval
13-Jun-2014 21:04 GMT+00

SAP_001.pdf: 
SAP: 331-10-238 
Confidential - Proprietary Information 
 Protocol number: 331-10-238. 
 Document title: A Long-term, Phase 3, Multicenter, Open-label Trial to 
Evaluate the Safety and Tolerability of Oral OPC-34712 as Adjunctive 
Therapy in Adults with Major Depressive Disorder, the Orion Trial 
 Version number: 1.0. 
 Date of the document: 25 May 2017. 
 NCT number: NCT01360866. 


Protocol 331-10-238 Statistical Analysis Plan
1
Otsuka Pharmaceutical
Development & Commercialization, Inc
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
Protocol 331-10-238
IND No. 103,958
EudraCT No. 2011-001351-37
A Long-term, Phase 3, Multicenter, Open-label Trial to Evaluate the Safety and 
Tolerability of Oral OPC-34712 as Adjunctive Therapy in Adults with Major Depressive 
Disorder, the Orion Trial
Statistical Analysis Plan
Version 1.0
(Final)
Date: 25 May 2017
Protocol Version 1.0:  11 May 2011
Protocol Amendment 01:  11 Nov 2011
Protocol Amendment 02:  16 Nov2012
Protocol Amendment 03:  11 Apr 2014
Protocol Amendment 04:  13 Jun 2014
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc 


Protocol 331-10-238 Statistical Analysis Plan
2
Table of Contents
Table of Contents...........................................................................................2
List of In-text Tables......................................................................................4
List of Appendices..........................................................................................5
List of Abbreviations and Definition of Terms...........................................6
1
Introduction...........................................................................................7
2
Trial Objectives.....................................................................................7
3
Trial Design ...........................................................................................7
3.1
Type/Design of Study..........................................................................................7
3.1.1
Trial Design Before Protocol Amendment 3....................................................7
3.1.2
Trial Design After Protocol Amendment 3 ....................................................10
3.2
Study Population ...............................................................................................12
4
Sample Size and Power Justification ............................................... 12
5
Statistical Methods............................................................................. 12
5.1
Data Sets Analyzed ...........................................................................................12
5.2
Handling of Missing Data .................................................................................13
6
Study Conduct.................................................................................... 13
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation.........13
6.2
Treatment Compliance ......................................................................................13
6.3
Protocol Deviations...........................................................................................14
7
Analysis of Demographic and Baseline Characteristics ................ 14
8
Efficacy Analysis................................................................................ 14
9
Safety Analyses................................................................................... 14
9.1
Adverse Events..................................................................................................14
9.2
Clinical Laboratory Data...................................................................................16
9.2.1
Potential Hy’s Law Cases...............................................................................16
9.3
Physical Examination and Vital Signs Data......................................................16
9.4
ECG Data ..........................................................................................................16
9.5
Suicidality Data.................................................................................................17
9.6
Concomitant Medications..................................................................................18
9.7
Extent of Exposure............................................................................................18


Protocol 331-10-238 Statistical Analysis Plan
3
9.8
Other Safety Data..............................................................................................18
10
Other Outcomes................................................................................. 18
11
Conventions........................................................................................ 19
11.1
Study Visit Windows.........................................................................................19
11.2
Scales: Rules for Scoring and Handling of Missing Data.................................20
11.2.1
Clinical Global Impression (CGI) ..................................................................20
11.2.2
Sheehan Disability Scale (SDS) .....................................................................20
11.2.3
Inventory of Depressive Symptomatology (Self-Report) (IDS-SR) ..............20
11.2.4
Simpson-Angus Scale (SAS)..........................................................................21
11.2.5
Abnormal Involuntary Movement Scale (AIMS)...........................................21
11.2.6
Barnes Akathisia Rating Scale (Barnes).........................................................21
11.2.7
Massachusetts General Hospital Sexual Functioning Questionnaire 
(MSFQ)...........................................................................................................21
11.2.8
Resource Utilization Scale..............................................................................22
12
Appendices.......................................................................................... 23
13
Proposed List of Summary Tables................................................... 26


Protocol 331-10-238 Statistical Analysis Plan
4
List of In-text Tables
Table 9.4-1
Categorical Change Criteria in QT/QTc Parameters .................... 17
Table 11.1-1
Study Day and Visit Windows...................................................... 19


Protocol 331-10-238 Statistical Analysis Plan
5
List of Appendices
Appendix 1
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance...................................................................................... 23
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance ........................................................................ 24
Appendix 3
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ........................................................................ 25


Protocol 331-10-238 Statistical Analysis Plan
6
List of Abbreviations and Definition of Terms
Abbreviation
Definition
ADT
Antidepressant Therapy
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
C-SSRS
Columbia-Suicide Severity Rating Scale
CRF
Case report form
ECG
Electrocardiogram
ET
Early termination
ICF
Informed consent form
IMP
Investigational medicinal product
LOCF
Last-observation-carried-forward
MedDRA
Medical Dictionary for Regulatory Activities
OC
Observed case
SAP
Statistical analysis plan
SAS
Simpson Angus Scale
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal


Protocol 331-10-238 Statistical Analysis Plan
7
1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for statistical analysis and reporting of 
safety and tolerability data of Study 331-10-238.  All amendments to the protocol are 
taken into consideration in developing this SAP.
2
Trial Objectives
Primary:
To assess the long-term safety and tolerability of oral brexpiprazole as 
adjunctive therapy in the treatment of adults with MDD.
Secondary: 
To assess the long-term efficacy of oral brexpiprazole as adjunctive 
therapy in the treatment of adult patients with MDD.
3
Trial Design
3.1
Type/Design of Study
3.1.1
Trial Design Before Protocol Amendment 3
This is a multicenter, 52-week, open-label trial designed to assess the long-term safety, 
tolerability, and efficacy of adjunctive brexpiprazole in depressed adults on concurrent 
antidepressant therapy (ADT).  The trial will be conducted on an outpatient basis.  
Enrollment into the trial will be drawn from eligible subjects who have completed one of 
the double-blind, phase 3 brexpiprazole MDD trial and who, in the investigator’s 
judgment, could potentially benefit from adjunctive treatment with oral brexpiprazole for 
MDD. A schematic of the study design is presented in Figure 3.1-1.
The trial will be organized as follows:
Screening/Baseline:  Subjects will be screened for eligibility at the last scheduled visit of 
the prior double-blind phase 3 trial.  Subjects will sign a separate informed consent form 
(ICF) for participation in Trial 331-10-238 before any procedures specific to the open-
label trial are performed.  The assessments from the last scheduled visit of the prior 
double-blind phase 3 trial will serve as the baseline measures for Trial 331-10-238 for 
any assessment that is not unique to the open-label trial.  Medical history will be updated, 
if necessary.
Treatment Phase:  Eligible subjects will receive daily treatment with open-label 
brexpiprazole and ADT as described in the Investigational Medicinal Product (IMP), 
Dose, Formulation, Mode of Administration section.  Visits will occur at the end of 


Protocol 331-10-238 Statistical Analysis Plan
8
Weeks 1, 2, 4, 8, 14, 20, 26 32, 28, 44, and 52.  All subjects will receive up to 52 weeks 
of open-label treatment in Trial 331-10-238.
Follow-up:  Subjects will be followed up for safety via telephone contact or clinic visit 30 
(+ 2) days after the last dose of open-label medication.


Protocol 331-10-238 Statistical Analysis Plan
9
Figure 3.1-1
Trial Design Schematic 
Follow-up
30 (+ 2) days 
after last dose
Eligible subjects who 
completed the last 
scheduled visit of a 
double-blind phase 3 
brexpiprazole MDD trial 
and who could potentially 
benefit from adjunctive 
treatment with 
brexpiprazole for MDD per 
investigator
Telephone 
contact or clinic 
visit
Visits at Weeks 1, 2, 4, 8, 14, 20, 26, 32, 38, 44, and 52
(unscheduled visits as necessary for dose adjustments)
Week 52 visit of 
Trial 331-10-238
Last scheduled visit of 
a double-blind phase 3 
brexpiprazole MDD trial
Screening/Baselinea
Open-label Brexpiprazole (0.5 to 3 mg/day) + ADT
Treatment Phase
aOccurs simultaneously with the last scheduled visit of a double-blind 
phase 3 brexpiprazole MDD trial.


Protocol 331-10-238 Statistical Analysis Plan
10
3.1.2
Trial Design After Protocol Amendment 3
This is a multicenter, 26-week, open-label trial designed to assess the long-term safety, 
tolerability, and efficacy of adjunctive brexpiprazole in depressed adults on concurrent 
antidepressant therapy (ADT).  The trial will be conducted on an outpatient basis.  
Enrollment into the trial will be drawn from eligible subjects who have completed one of 
the double-blind, phase 3 brexpiprazole MDD trial and who, in the investigator’s 
judgment, could potentially benefit from adjunctive treatment with oral brexpiprazole for 
MDD. A schematic of the study design is presented in Figure 3.1-2.
The trial will be organized as follows:
Screening/Baseline:  Subjects will be screened for eligibility at the last scheduled visit of 
the prior double-blind phase 3 trial.  Subjects will sign a separate informed consent form
(ICF) for participation in Trial 331-10-238 before any procedures specific to the open-
label trial are performed.  The assessments from the last scheduled visit of the prior 
double-blind phase 3 trial will serve as the baseline measures for Trial 331-10-238 for 
any assessment that is not unique to the open-label trial.  Medical history will be updated, 
if necessary.
Treatment Phase:  Eligible subjects will receive daily treatment with open-label 
brexpiprazole and ADT as described in the Investigational Medicinal Product (IMP),
Dose, Formulation, Mode of Administration section.  Visits will occur at the end of 
Weeks 1, 2, 4, 8, 14, 20, and 26.  All subjects will receive up to 26 weeks of open-label 
treatment in Trial 331-10-238.
Follow-up:  Subjects will be followed up for safety via telephone contact or clinic visit 30 
(+ 2) days after the last dose of open-label medication.


Protocol 331-10-238 Statistical Analysis Plan
11
Figure 3.1-2
Trial Design Schematic 
Follow-up
30 (+ 2) days 
after last dose
Eligible subjects who 
completed the last 
scheduled visit of a 
double-blind phase 3 
brexpiprazole MDD trial 
and who could potentially 
benefit from adjunctive 
treatment with 
brexpiprazole for MDD per 
investigator
Telephone 
contact or clinic 
visit
Visits at Weeks 1, 2, 4, 8, 14, and 20
(unscheduled visits as necessary for dose adjustments)
Week 26 visit of 
Trial 331-10-238
Last scheduled visit of 
a double-blind phase 3 
brexpiprazole MDD trial
Screening/Baselinea
Open-label Brexpiprazole (0.5 to 3 mg/day) + ADT
Treatment Phase
aOccurs simultaneously with the last scheduled visit of a double-blind 
phase 3 brexpiprazole MDD trial.


Protocol 331-10-238 Statistical Analysis Plan
12
3.2
Study Population
The subject population will consist of eligible subjects who, in the investigator’s 
judgment, could potentially benefit from adjunctive treatment with brexpiprazole for 
MDD and who meet one of the following conditions:

Subjects who completed participation in the Double-blind Randomization Phase 
(ie, Week 14 visit of Phase B) in Trial 331-10-227 or Trial 331-10-228 or

Subjects who met criteria for a response at the end of prospective treatment (ie, 
Week 8 visit of Phase A) in Trial 331-10-227 or Trial 331-10-228, BUT DID 
NOT meet criteria for remission (defined as a MADRS Total Score of  10) at the 
Week 14 visit of Phase A+ in Trial 331-10-227 or Trial 331-10-228.
Subjects must qualify for Trial 331-10-238 at the last visit of the double-blind trial and 
must be able to continue therapy without interruption between the double-blind and open 
label trials.  Based on the projected enrollment estimates for the double-blind phase 3 
trials (ie, Trial 331-10-227 and Trial 331-10-228), up to 1280 subjects may enroll into 
Trial 331-10-238.
4
Sample Size and Power Justification
The sample size is not based on statistical power considerations.  The trial population will 
be derived from eligible subjects from the double-blind phase 3 trials (ie, Trial 331-10-
227 and Trial 331-10-228).  Therefore, the number of eligible subjects will be limited by 
the number of subjects enrolled into these protocols.  Based on the projected enrollment 
estimates for the double-blind phase 3 trials (ie, Trial 331-10-227 and Trial 331-10-228), 
up to 1280 subjects may enroll into Trial 331-10-238.
5
Statistical Methods
5.1
Data Sets Analyzed
The following datasets are defined for this study:

Enrolled Sample:  comprises all subjects who sign an ICF for the trial.

Safety Sample:  comprises those subjects who receive at least one dose of open-label 
brexpiprazole as adjunctive therapy to one of the allowed ADTs.

Efficacy Sample:  comprises those subjects in the Safety Sample who have at least 
one post-baseline efficacy evaluation of CGI-S.


Protocol 331-10-238 Statistical Analysis Plan
13
All the summaries will be done for all subjects, 52-week enrollers (before Protocol 
Amendment 3), and 26-week enrollers (after Protocol Amendment 3), and will be done 
by parent study treatment group. Selected summaries will also be done by ADT. Details 
of those summaries will be specified in the following sections.
The Safety Sample will be used for all baseline and safety summaries. The Efficacy 
Sample will be used for the efficacy summaries.
The observed case (OC) dataset will consist of the actual observations recorded at each 
visit and will be used to present summaries per trial week.
The last-observation-carried-forward (LOCF) data set will include data recorded at a 
given visit in the Treatment Phase or, if no observation is recorded at that visit, data 
carried forward from the previous visit in the Treatment Phase.  Data collected prior to or 
on the first day of Treatment Phase dosing will not be carried forward or averaged with 
Treatment Phase data to impute missing values for the LOCF data set.
5.2
Handling of Missing Data
In order to assess sensitivity of results due to missing data, 2 types of analyses will be 
performed:  LOCF and OC.  The OC dataset will consist of the actual observations 
recorded at each visit. The LOCF dataset will include data recorded at a scheduled visit, 
i.e., all OC data, or, if no observation is recorded at that visit, data carried forward from 
the previously scheduled visit.  Baseline data will not be carried forward to impute 
missing values for the LOCF dataset.   The OC data set will be used for analyses at each 
study visit and the LOCF data set will be used for analyses at the last visit.
6
Study Conduct
6.1
Subject Disposition, Completion Rate and Reasons for
Discontinuation
Subject disposition will be summarized for the Enrolled Sample.
Subject completion rate by week, and reasons for discontinuation will be summarized for 
the Enrolled Sample. In addition, these summaries will also be done by ADT
6.2
Treatment Compliance
Treatment compliance will be reported, by percentage of patients taking investigational 
medicinal product based on investigational medicinal product (IMP) panel of the case 
report form (CRF).


Protocol 331-10-238 Statistical Analysis Plan
14
6.3
Protocol Deviations
Protocol deviations data will be summarized by type of deviations (eg, deviations in entry 
criteria, dosing, concomitant medication, procedural, etc.). In addition, a patient listing 
will be provided describing the deviations for each subject.
7
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)
8
Efficacy Analysis
Efficacy is secondary objective for the study. Efficacy endpoints are as follows:
1) Change from baseline in CGI-S score, by trial week and at the last visit (ie, Week 
26/ET or Week 52/ET); 
2) Mean CGI-I score, by trial week and at the last visit (ie, Week 26/ET or Week 
52/ET);
3) Change from baseline in SDS score, by trial week and at the last visit (ie, Week 
26/ET or Week 52/ET);
4) Change from baseline in IDS-SR Total Score, by trial week and at the last visit 
(ie, Week 26/ET or Week 52/ET).
Descriptive statistics will be provided for each endpoint.  The analysis will be carried out 
on the Efficacy Sample.  Descriptive statistics will be summarized at each trial visit using 
the OC data set and at the last visit using the LOCF data set.
9
Safety Analyses
The primary safety analysis is the frequency and severity of AEs (see Section 9.1). Other 
standard safety variables to be analyzed include clinical laboratory tests, vital signs, 
ECGs, body weight, waist circumference, and BMI.  In addition, data from the following 
safety scales will be evaluated:  SAS, AIMS, BARS, C-SSRS, and MSFQ.  Analyses 
regarding safety and tolerability will be conducted based on the Safety Sample, which is 
defined in Section 5.1. In general, baseline measurements of safety variables are defined 
as their last measurements prior to the first dose of open-label brexpiprazole.
9.1
Adverse Events
All AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class and preferred term.  The incidence of the following events will be 
summarized:


Protocol 331-10-238 Statistical Analysis Plan
15

TEAEs by severity

Potentially drug-related TEAEs

TEAEs with an outcome of death

Serious TEAEs

Discontinuations due to TEAEs
A TEAE is defined as an AE that starts after the first dose of IMP or an AE that is 
reported at baseline and increases in intensity or becomes serious or trial drug-related or 
results in death, discontinuation, interruption or reduction of IMP. 
In addition, incidence of TEAE during Treatment Phase of at least 5% by SOC and PT
will be provided.
Incidence of TEAEs by SOC and PT will be summarized for sex, race and age subgroups.
EPS-related AEs will be grouped into five categories.
1) Dystonic Events, which include cervical spasm, dystonia, emprosthotonos, muscle 
contractions involuntary, muscle rigidity, muscle spasms, muscle spasticity, myotonia, 
nuchal rigidity, oculogyration, opisthotonos, pleurothotonus, risus sardonicus, torticollis, 
and trismus;
2) Parkinsonian Events, which include akinesia, asterixis, athetosis, bradykinesia, 
cogwheel rigidity, essential tremor, extrapyramidal disorder, freezing phenomenon, gait 
festinating, hypertonia, hypokinesia, hypokinesia neonatal, intention tremor, masked 
facies, parkinson’s disease, parkinsonian crisis, parkinsonian gait, parkinsonian rest 
tremor, parkinsonism, tremor, and tremor neonatal;
3) Akathisia Events, which include akathisia, hyperkinesia, and psychomotor 
hyperactivity;
4) Dyskinetic Events, which include ballismus, buccoglossal syndrome, choreoathetosis, 
clumsiness, dyskinesia, dyskinesia neonatal, dyskinesia oesophageal, fumbling, nodding 
of head, on and off phenomenon, and tardive dyskinesia;
5) Residual Events, which include chorea, huntington’s chorea, muscle twitching, and 
myoclonus.
Incidence of EPS-related TEAEs will be summarized by EPS category. This summary 
will also be provided by ADT.


Protocol 331-10-238 Statistical Analysis Plan
16
9.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements, prolactin concentrations, coagulation parameters (PT, aPTT, and INR), 
HbA1c, cortisol, ACTH, and TSH will be provided.  In addition, potentially clinically 
significant results in laboratory tests identified using prospectively defined criteria will be 
summarized.
9.2.1
Potential Hy’s Law Cases
Total bilirubin level should be checked for any subject with increased ALT or AST levels 
greater or equal to three times the upper limit of normal (or baseline). If total bilirubin 
level is greater or equal to twice upper limit of normal (or baseline), IRE form with the 
lab values will be sent to INC Research within 24 hours. The corresponding pages of the 
eCRF should be filled.
Reporting all potential cases as SAE to the FDA based on Hy's Law: 

AST or ALT 3 x ULN and  

Total Bilirubin  2 x ULN
A separate incidence table will be provided for Hy’s Law cases, and the corresponding 
listing will be provided.
9.3
Physical Examination and Vital Signs Data
By-patient listings will be provided for physical examination.  Summary statistics for 
changes from baseline in vital signs will be provided.  Potentially clinically significant 
results in vital signs will also be summarized. In addition, the change from baseline in 
weight, BMI, and waist circumference, and potentially clinically relevant abnormalities 
in weight, will also be summarized by ADT and by Gender, separately. 
9.4
ECG Data 
Mean change from baseline and incidence of clinically significant changes will be 
calculated for ECG parameters.
For the analysis of QT and QTc, data from three consecutive complexes (representing 
three consecutive heart beats) will be measured to determine average values.  The 
following QT corrections will be used for reporting purposes in the clinical study report:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett 
formula:  QTcB=QT/(RR)0.5
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula:  QTcF=QT/(RR)0.33


Protocol 331-10-238 Statistical Analysis Plan
17
3) QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula:  QTcN=QT/(RR)0.37
Categorical changes in ECG parameters will be summarized based on the following 
criteria:
Table 9.4-1
Categorical Change Criteria in QT/QTc Parameters
Classification
Category
Criteria 
QT
New Onset (> 450 Msec)
New onset (>450 msec) in QT means a subject who attains 
a value > 450 msec during treatment period but not at 
baseline.
QTc *
New Onset (> 450 Msec)
New onset (> 450 msec) in QTc means a subject who 
attains a value > 450 msec during treatment period but not 
at baseline.
New Onset (> 450 Msec) 
And > 10% Increase
New onset (> 450 msec) and 
> 10% increase in QTc means a subject who attains a value 
> 450 msec and > 10% increase during treatment period 
but not at baseline
New Onset (> 500 Msec)
New onset (> 500 msec) in QTc means a subject who 
attains a value > 500 msec during treatment period but not 
at baseline.
Increase 30 - 60 Msec
Increase from baseline value > 30 and 60 msec in QTc
Increase > 60 Msec
Increase from baseline value > 60 msec in QTc
* QTc categorical change criteria apply to QTcB, QTcF and QTcN.
9.5
Suicidality Data
Suicidality will be monitored during the study using the C-SSRS and will be summarized 
as number and percentage of subjects reporting any suicidal behavior, ideation, behavior 
by type (4 types), ideation by type (5 types) and treatment emergent suicidal behavior and 
ideation. 
Suicidality is defined as report of at least one occurrence of any type of suicidal ideation 
or at least one occurrence of any type of suicidal behavior during assessment period 
(count each person only once).
Treatment emergent suicidal behavior and ideation is summarized by four types: 
Emergence of suicidal ideation, Emergence of serious suicidal ideation, Worsening of 
suicidal ideation, Emergence of suicidal behavior. 
Emergence of suicidal behavior/ideation is defined as report of any type of suicidal 
behavior/ideation during treatment when there was no baseline suicidal behavior/ideation.
Emergence of serious suicidal ideation is defined as observation of suicidal ideation 
severity rating of 4 or 5 during treatment when there was no baseline suicidal ideation.                                    
Worsening of suicidal ideation is defined as a suicidal ideation severity rating that is 
more severe than it was at baseline.


Protocol 331-10-238 Statistical Analysis Plan
18
9.6
Concomitant Medications
Number and proportion of patients taking concomitant medications prior to Treatment 
Phase, during Treatment Phase, and after study therapy are tabulated by drug classification 
and medication preferred name using the WHO drug dictionary.
9.7
Extent of Exposure
The start date of double-blind IMP will be the first day of double-blind dosing. The 
number and percentage of patients who receive brexpiprazole will be presented by 4-
week interval. This summary will be performed on the Safety Sample, and will also be 
done by ADT.
The number and percentage of patients who receive each dose of brexpiparzole 
(0.5mg/day, 1mg/day, 2mg/day and 3mg/day) will be summarized by 4-week interval. 
This summary will also be done by ADT. 
The number and percentage of patients who receive ADT medications will also be 
summarized by ADT. 
9.8
Other Safety Data
Descriptive statistics will be provided for the SAS, AIMS, BARS, and MSFQ scales.  
Change from baseline in body weight will be summarized by descriptive statistics, as 
well as incidence of clinically significant changes in body weight.  Descriptive statistics 
will also be provided for change from baseline in waist circumference and BMI.  
Descriptive statistics will be summarized at each visit using the OC data set and at the 
last visit (Week 52/ET) using the LOCF data set.
9.8.1.1.1
Post-baseline concomitant Medications
Concomitant medications used post-baseline will be summarized in 2 categories of time 
interval - during IMP treatment period and after IMP treatment period. In each case, use 
of concomitant medication will be summarized by number and percentage of users.
10
Other Outcomes 
The percentage of subjects hospitalized for exacerbation of symptoms (including 
emergency department visits) will be tabulated as a measure of healthcare resource 
utilization.  The frequency of outpatient visits to various healthcare providers (eg, 
primary care physician, psychiatrists, other mental health practitioners, etc.) not required 
per the protocol will also be examined.


Protocol 331-10-238 Statistical Analysis Plan
19
11
Conventions
11.1
Study Visit Windows 
Study visit windows will be used to map visits using study day intervals. This visit 
window convention applies to tables and listings for all efficacy and safety scales (CGI-S, 
CGI-I, SDS, IDS-SR, SAS, AIMS, BARS and MSFQ). This derived study window 
variable will be named as WEEK and will be footnoted. In listings it will be listed along 
with the CRF study visit.
Table 11.1-1 shows classifications for study day intervals. The variable “target day” is 
defined using the number of days since the start of open-label OPC dosing in the study. 
The first day of open-label OPC dosing is defined as “Day 1”. If more than one 
observation falls within a particular study day interval, then the last observation within 
that interval is used. Evaluations occurring more than seven days after the last dosing 
date will be excluded from the analysis.
Table 11.1-1
Study Day and Visit Windows
Week
Target Day a
Study Day Interval a
1
7
2-10
2
14
11-21
4
28
22-35
6
42
36-49 
8
56
50-77
14
98
78-119
20
140
120-161
26
182
162-203
32 c
224
204-245
38 c
266
246-287
44 c
308
288-336
52 c
364
337-385 b
a Relative to the first day of open-label OPC dosing.
b Evaluations occurring more than seven days after the last OPC dosing will be excluded from summaries of 
change from baseline analyses.
c Evaluations The duration of the length of the treatment phase was reduced to 26 weeks in Protocol 
Amendment 3. Therefore, the 26-week enrollers didn’t have these visits.


Protocol 331-10-238 Statistical Analysis Plan
20
11.2
Scales: Rules for Scoring and Handling of Missing Data
11.2.1
Clinical Global Impression (CGI)
CGI consists of two scales: CGI Severity (CGI-S), and CGI Improvement (CGI-I). CGI-S 
items are: 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, 7 = among the most 
extremely ill patients. The score 0 (= not assessed) will be set to missing. The CGI-S is 
therefore a 7-point scale from 1 through 7. 
CGI-I items are: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = 
minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very 
much worse. The score of 0 (= not assessed) will be set to missing. The CGI-I is therefore 
a 7-point scale from 1 through 7. CGI improvement is judged with respect to the patient’s 
condition at baseline.
11.2.2
Sheehan Disability Scale (SDS)
The Sheehan Disability Scale (SDS) is a self-rated instrument used to measure the effect 
of the patient’s symptoms on work/school, social life, and family/home responsibilities. 
For each of the three items, scores range from 0 through 10. The number most 
representative of how much each area was disrupted by symptoms is marked along the 
line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to 
be entered if the patient did not work or go to school for reasons unrelated to the disorder 
and a response therefore not being applicable. The Mean SDS Score will be calculated 
over the three item scores. All three item scores need to be available except for the 
work/school item score when this item is not applicable.
11.2.3
Inventory of Depressive Symptomatology (Self-Report) (IDS-SR)
The IDS-SR is a 30-item self-report measure used to assess core diagnostic depressive 
symptoms as well as atypical and melancholic symptom features of major depressive 
disorders. The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the 
“best” rating and 3 being the “worst” rating. Besides item 9, two sub-items 9A and 9B 
exist, with possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for 
these two sub-items are not included in the calculation of the total score. Item 11 or item 
12 should be completed but not both, and similarly, item 13 or item 14 should be 
completed but not both. Should items 11 and 12 be rated both, then the maximum of the 
two scores will be used. The same approach will be used for handling items 13 and 14. 
The IDS-SR Total Score is the sum of ratings of 28 item scores. The possible IDS-SR 
Total Score ranges from 0 to 84. The IDS-SR Total Score will be un-evaluable if less 


Protocol 331-10-238 Statistical Analysis Plan
21
than 23 of the 28 items are recorded. If the number of items recorded is at least 23 and at 
most 27, the IDS-SR Total Score will be the mean of the recorded items multiplied by 28 
and then rounded to the first decimal place.
11.2.4
Simpson-Angus Scale (SAS)
The SAS is a rating scale used to measure EPS. The SAS is a 10-item scale, with each 
item rated from 0 to 4, with 0 being normal and 4 being the worst. The SAS Total score is 
the sum of ratings for all 10 items, with possible Total scores from 0 to 40. The SAS 
Total score will be unevaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 
10 items are recorded, the Total score will be the mean of the recorded items multiplied 
by 10 and then rounded to the first decimal place.
11.2.5
Abnormal Involuntary Movement Scale (AIMS)
The AIMS is a 12-item scale. The first 10 items are rated from 0 to 4 (0=best, 4=worst).
An item score of 0, depending on the item, either means: no abnormal involuntary
movement (AIM), or no incapacitation due to AIM, or no awareness of AIM. An item
score of 4 either means: severe AIM, or severe incapacitation due to AIM, or being aware
of, and severe distress caused by AIM. Items 11 and 12, related to dental status, have
dichotomous responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings
for the first seven items. The possible total scores are from 0 to 28. The AIMS Total
Score will be unevaluable if less than 6 of the first 7 items are recorded. If 6 of the items
are recorded, then the total score will be the mean of the recorded items multiplied by 7
and then rounded to the first decimal place.
11.2.6
Barnes Akathisia Rating Scale (Barnes)
The Barnes Akathisia Rating Scale will be used to assess the presence and severity of
akathisia. This scale consists of 4 items. Only the 4th item, the Global Clinical
Assessment of Akathisia, will be evaluated in this study. This item is rated on a 6-point
scale, with 0 being best (absent) and 5 being worst (severe akathisia).
11.2.7
Massachusetts General Hospital Sexual Functioning 
Questionnaire (MSFQ)
The MSFQ is a measure of a patient’s self-reported sexual functioning. The MSFQ 
includes 5 items, each addressing experiences over the last month: a) interest in sex, b) 
ability to get sexually aroused, c) ability to achieve orgasm, d) ability to get and maintain 
an erection, and e) overall sexual satisfaction. For items a) through e), a score of 1 
indicates ‘greater than normal’, and 6 indicates ‘totally absent’. 
All item scores are analyzed separately. No total or mean score is derived.


Protocol 331-10-238 Statistical Analysis Plan
22
11.2.8
Resource Utilization Scale
The Resource Utilization Form is a self-report tool designed to collect information 
regarding the extent of medical care sought by patients while participating in the study. 
Incidence rates (related to number of visits to a health care provider, number of times 
hospitalized, or number of days hospitalized) will be expressed through the average use 
per person-year. For each group, the number of events across all patients in that group 
will be divided by the total person year (study duration in days / 365.25) during the open-
label study across all patients.


Protocol 331-10-238 Statistical Analysis Plan
23
12
Appendices
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
a In 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.
b As 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).


Protocol 331-10-238 Statistical Analysis Plan
24
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


Protocol 331-10-238 Statistical Analysis Plan
25
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 0.20 second
increase of  0.05 second
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 0.12 second
increase of 0.02 second
Infarction
Acute or subacute
all
not present present
Old
all
not present present
12 weeks post study entry
ST/T Morphological
Myocardial Ischemia
all
not present present
Symmetrical T-wave inversion
all
not present present
Increase in QTc
QTc > 450 msec 
(men or women)
a In 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.
b No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
c No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
d No current diagnosis of left bundle branch block or right bundle branch block.


Protocol 331-10-238 Statistical Analysis Plan
26
13
Proposed List of Summary Tables
CT-1.1.1   Subject Disposition by Parent Study Treatment Group – All Subjects
CT-1.1.2   Subject Disposition by Parent Study Treatment Group – 52-Week Enrollers
CT-1.1.3   Subject Disposition by Parent Study Treatment Group – 26-Week Enrollers
CT-1.2.1.1   Subject Completion Rate by Parent Study Treatment Group – All Subjects
CT-1.2.1.2   Subject Completion Rate by Parent Study Treatment Group– 52-Week Enrollers
CT-1.2.1.3   Subject Completion Rate by Parent Study Treatment Group – 26-Week Enrollers
CT-1.2.2.1   Subject Completion Rate by ADT – All Subjects
CT-1.2.2.2   Subject Completion Rate by ADT– 52-Week Enrollers
CT-1.2.2.3   Subject Completion Rate by ADT – 26-Week Enrollers
CT-2.1.1   Reasons for Discontinuation – All Subjects
CT-2.1.2   Reasons for Discontinuation– 52-Week Enrollers
CT-2.1.3   Reasons for Discontinuation – 26-Week Enrollers
CT-2.2.1   Reasons for Discontinuation by ADT – All Subjects
CT-2.2.2   Reasons for Discontinuation by ADT– 52-Week Enrollers
CT-2.2.3   Reasons for Discontinuation by ADT – 26-Week Enrollers
CT-3.1.1   Baseline Demographic Characteristics – All Subjects
CT-3.1.2   Baseline Demographic Characteristics– 52-Week Enrollers
CT-3.1.3   Baseline Demographic Characteristics – 26-Week Enrollers
CT-4.1.1.1   Concomitant Medications: Medications Taken Prior to Start of Study Therapy – All Subjects
CT-4.1.1.2   Concomitant Medications: Medications Taken Prior to Start of Study Therapy– 52-Week 
Enrollers
CT-4.1.1.3   Concomitant Medications: Medications Taken Prior to Start of Study Therapy – 26-Week 
Enrollers
CT-4.1.2.1   Concomitant Medications: Medications Taken During Study Therapy – All Subjects
CT-4.1.2.2   Concomitant Medications: Medications Taken During Study Therapy– 52-Week Enrollers
CT-4.1.2.3   Concomitant Medications: Medications Taken During Study Therapy – 26-Week Enrollers
CT-4.1.3.1   Concomitant Medications: Medications Taken After Study Therapy – All Subjects
CT-4.1.3.2   Concomitant Medications: Medications Taken After Study Therapy– 52-Week Enrollers
CT-4.1.3.3   Concomitant Medications: Medications Taken After Study Therapy – 26-Week Enrollers
CT-5.1.1.1     Summary of Mean Change from Baseline in Clinical Global Impression - Severity of Illness 
Score (CGI-S) – All Subjects
CT-5.1.1.2     Summary of Mean Change from Baseline in Clinical Global Impression - Severity of Illness 
Score (CGI-S) – 52-Week Enrollers
CT-5.1.1.3     Summary of Mean Change from Baseline in Clinical Global Impression - Severity of Illness 
Score (CGI-S) – 26-Week Enrollers
CT-5.1.2.1   Summary of Mean Change from Baseline in Clinical Global Impression - Severity of Illness 
Score (CGI-S) by ADT – All Subjects
CT-5.1.2.2   Summary of Mean Change from Baseline in Clinical Global Impression - Severity of Illness 
Score (CGI-S) by ADT– 52-Week Enrollers


Protocol 331-10-238 Statistical Analysis Plan
27
CT-5.1.2.3   Summary of Mean Change from Baseline in Clinical Global Impression - Severity of Illness 
Score (CGI-S) by ADT – 26-Week Enrollers
CT-5.2.1.1   Summary of Clinical Global Impression - Improvement (CGI-I) – All Subjects
CT-5.2.1.2   Summary of Clinical Global Impression - Improvement (CGI-I) – 52-Week Enrollers
CT-5.2.1.3   Summary of Clinical Global Impression - Improvement (CGI-I) – 26-Week Enrollers
CT-5.2.2.1   Summary of Clinical Global Impression - Improvement (CGI-I) by ADT – All Subjects
CT-5.2.2.2   Summary of Clinical Global Impression - Improvement (CGI-I) by ADT– 52-Week Enrollers
CT-5.2.2.3   Summary of Clinical Global Impression - Improvement (CGI-I) by ADT – 26-Week Enrollers
CT-5.3.1.1   Summary of Mean Change from Baseline in Sheehan Disability Scale (SDS) Mean Score and 
Item Scores – All Subjects
CT-5.3.1.2   Summary of Mean Change from Baseline in Sheehan Disability Scale (SDS) Mean Score and 
Item Scores– 52-Week Enrollers
CT-5.3.1.3   Summary of Mean Change from Baseline in Sheehan Disability Scale (SDS) Mean Score and 
Item Scores – 26-Week Enrollers
CT-5.3.2.1   Summary of Mean Change from Baseline in Sheehan Disability Scale (SDS) Mean Score and 
Item Scores by ADT – All Subjects
CT-5.3.2.2   Summary of Mean Change from Baseline in Sheehan Disability Scale (SDS) Mean Score and 
Item Scores by ADT– 52-Week Enrollers
CT-5.3.2.3   Summary of Mean Change from Baseline in Sheehan Disability Scale (SDS) Mean Score and 
Item Scores by ADT – 26-Week Enrollers
CT-5.4.1.1   Summary of Mean Change from Baseline in Inventory of Depressive Symptomatology Self-
Report (IDS-SR) Total Score – All Subjects
CT-5.4.1.2   Summary of Mean Change from Baseline in Inventory of Depressive Symptomatology Self-
Report (IDS-SR) Total Score– 52-Week Enrollers
CT-5.4.1.3   Summary of Mean Change from Baseline in Inventory of Depressive Symptomatology Self-
Report (IDS-SR) Total Score – 26-Week Enrollers
CT-5.4.2.1   Summary of Mean Change from Baseline in Inventory of Depressive Symptomatology Self-
Report (IDS-SR) Total Score by ADT – All Subjects
CT-5.4.2.2   Summary of Mean Change from Baseline in Inventory of Depressive Symptomatology Self-
Report (IDS-SR) Total Score by ADT– 52-Week Enrollers
CT-5.4.2.3   Summary of Mean Change from Baseline in Inventory of Depressive Symptomatology Self-
Report (IDS-SR) Total Score by ADT – 26-Week Enrollers
CT-6.1.1   Summary of Mean Change from Baseline in Simpson-Angus Total Score (SAS) – All Subjects
CT-6.1.2   Summary of Mean Change from Baseline in Simpson-Angus Total Score (SAS) – 52-Week 
Enrollers
CT-6.1.3   Summary of Mean Change from Baseline in Simpson-Angus Total Score (SAS) – 26-Week 
Enrollers
CT-6.2.1   Summary of Mean Change from Baseline in Abnormal Involuntary Movement Score (AIMS) 
Total Score and Item Scores 8, 9 and 10 – All Subjects
CT-6.2.2   Summary of Mean Change from Baseline in Abnormal Involuntary Movement Score (AIMS) 
Total Score and Item Scores 8, 9 and 10– 52-Week Enrollers
CT-6.2.3   Summary of Mean Change from Baseline in Abnormal Involuntary Movement Score (AIMS) 
Total Score and Item Scores 8, 9 and 10 – 26-Week Enrollers
CT-6.3.1   Summary of Mean Change from Baseline in Barnes Akathisia Global Score (BARS) – All 
Subjects
CT-6.3.2   Summary of Mean Change from Baseline in Barnes Akathisia Global Score (BARS) – 52-Week 
Enrollers


Protocol 331-10-238 Statistical Analysis Plan
28
CT-6.3.3   Summary of Mean Change from Baseline in Barnes Akathisia Global Score (BARS) – 26-Week 
Enrollers
CT-6.4.1.1   Columbia-Suicide Severity Rating Scale (C-SSRS), Suicidality – All Subjects
CT-6.4.1.2   Columbia-Suicide Severity Rating Scale (C-SSRS), Suicidality – 52-Week Enrollers
CT-6.4.1.3   Columbia-Suicide Severity Rating Scale (C-SSRS), Suicidality – 26-Week Enrollers
CT-6.4.2.1   Columbia-Suicide Severity Rating Scale (C-SSRS), Suicidal Behavior by Type – All Subjects
CT-6.4.2.2   Columbia-Suicide Severity Rating Scale (C-SSRS), Suicidal Behavior by Type– 52-Week 
Enrollers
CT-6.4.2.3   Columbia-Suicide Severity Rating Scale (C-SSRS), Suicidal Behavior by Type – 26-Week 
Enrollers
CT-6.4.3.1   Columbia-Suicide Severity Rating Scale (C-SSRS), Suicidal Ideation by Type – All Subjects
CT-6.4.3.2   Columbia-Suicide Severity Rating Scale (C-SSRS), Suicidal Ideation by Type– 52-Week 
Enrollers
CT-6.4.3.3   Columbia-Suicide Severity Rating Scale (C-SSRS), Suicidal Ideation by Type – 26-Week 
Enrollers
CT-6.4.4.1   Columbia-Suicide Severity Rating Scale(C-SSRS) - Treatment Emergent Suicidal Behavior 
and Ideation – All Subjects
CT-6.4.4.2   Columbia-Suicide Severity Rating Scale(C-SSRS) - Treatment Emergent Suicidal Behavior 
and Ideation – 52-Week Enrollers
CT-6.4.4.3   Columbia-Suicide Severity Rating Scale(C-SSRS) - Treatment Emergent Suicidal Behavior 
and Ideation – 26-Week Enrollers
CT-6.4.5.1   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment-emergent Suicidal 
Ideation – All Subjects
CT-6.4.5.2   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment-emergent Suicidal 
Ideation – 52-Week Enrollers
CT-6.4.5.3   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment-emergent Suicidal
Ideation – 26-Week Enrollers
CT-6.4.6.1   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment-emergent Suicidal 
Behavior – All Subjects
CT-6.4.6.2   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment-emergent Suicidal 
Behavior – 52-Week Enrollers
CT-6.4.6.3   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment-emergent Suicidal 
Behavior – 26-Week Enrollers
CT-6.4.7.1   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment-emergent Serious 
Ideation – All Subjects
CT-6.4.7.2   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment-emergent Serious 
Ideation – 52-Week Enrollers
CT-6.4.7.3   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Treatment-emergent Serious 
Ideation – 26-Week Enrollers
CT-6.4.8.1   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Worsening Suicidal Ideation –
All Subjects
CT-6.4.8.2   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Worsening Suicidal Ideation –
52-Week Enrollers
CT-6.4.8.3   Columbia-Suicide Severity Rating Scale (C-SSRS) - Listing of Worsening Suicidal Ideation –
26-Week Enrollers
CT-6.5.1   Summary of Mean Change in MSFQ Item Scores – All Subjects
CT-6.5.2   Summary of Mean Change in MSFQ Item Scores – 52-Week Enrollers
CT-6.5.3   Summary of Mean Change in MSFQ Item Scores – 26-Week Enrollers
CT-6.6.1   Incidence Rates in Resource Utilization – All Subjects


Protocol 331-10-238 Statistical Analysis Plan
29
CT-6.6.2   Incidence Rates in Resource Utilization – 52-Week Enrollers
CT-6.6.3   Incidence Rates in Resource Utilization – 26-Week Enrollers
CT-7.1.1.1   Extent of Exposure – All Subjects
CT-7.1.1.2   Extent of Exposure – 52-Week Enrollers
CT-7.1.1.3   Extent of Exposure – 26-Week Enrollers
CT-7.1.2.1   Extent of Exposure by ADT– All Subjects
CT-7.1.2.2   Extent of Exposure by ADT – 52-Week Enrollers
CT-7.1.2.3   Extent of Exposure by ADT – 26-Week Enrollers
CT-7.1.3.1   Extent of Exposure to Each Dose per 4-Weekly Dosing Interval – All Subjects
CT-7.1.3.2   Extent of Exposure to Each Dose per 4-Weekly Dosing Interval – 52-Week Enrollers
CT-7.1.3.3   Extent of Exposure to Each Dose per 4-Weekly Dosing Interval – 26-Week Enrollers
CT-7.1.4.1   Extent of Exposure to Each Dose per 4-Weekly Dosing Interval by ADT – All Subjects
CT-7.1.4.2   Extent of Exposure to Each Dose per 4-Weekly Dosing Interval by ADT – 52-Week Enrollers
CT-7.1.4.3   Extent of Exposure to Each Dose per 4-Weekly Dosing Interval by ADT – 26-Week Enrollers
CT-7.2.1   Extent of Exposure to ADT Medication – All Subjects
CT-7.2.2   Extent of Exposure to ADT Medication – 52-Week Enrollers
CT-7.2.3   Extent of Exposure to ADT Medication – 26-Week Enrollers
CT-8.1.1   Adverse Events (All Causalities) – All Subjects   
CT-8.1.2   Adverse Events (All Causalities) – 52-Week Enrollers  
CT-8.1.3   Adverse Events (All Causalities) – 26-Week Enrollers   
CT-8.2.1.1   Incidence of All Treatment-emergent Adverse Events by System Organ Class – All Subjects   
CT-8.2.1.2   Incidence of All Treatment-emergent Adverse Events by System Organ Class – 52-Week 
Enrollers   
CT-8.2.1.3   Incidence of All Treatment-emergent Adverse Events by System Organ Class – 26-Week 
Enrollers   
CT-8.2.2.1.1   Incidence of All Treatment-emergent Adverse Events by System Organ Class and MedDRA 
Preferred Term – All Subjects  
CT-8.2.2.1.2   Incidence of All Treatment-emergent Adverse Events by System Organ Class and MedDRA 
Preferred Term – 52-Week Enrollers  
CT-8.2.2.1.3   Incidence of All Treatment-emergent Adverse Events by System Organ Class and MedDRA 
Preferred Term – 26-Week Enrollers  
CT-8.2.2.2.1   Incidence of All Treatment-emergent Adverse Events by System Organ Class and MedDRA 
Preferred Term by ADT – All Subjects  
CT-8.2.2.2.2   Incidence of All Treatment-emergent Adverse Events by System Organ Class and MedDRA 
Preferred Term by ADT – 52-Week Enrollers  
CT-8.2.2.2.3   Incidence of All Treatment-emergent Adverse Events by System Organ Class and MedDRA 
Preferred Term by ADT – 26-Week Enrollers
CT-8.2.2.3.1   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Gender – All 
Subjects
CT-8.2.2.3.2   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Gender – 52-
Week Enrollers
CT-8.2.2.3.3   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Gender – 26-
Week Enrollers
CT-8.2.2.4.1   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Race – All 
Subjects


Protocol 331-10-238 Statistical Analysis Plan
30
CT-8.2.2.4.2   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Race – 52-
Week Enrollers
CT-8.2.2.4.3   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Race – 26-
Week Enrollers
CT-8.2.2.5.1   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Age – All 
Subjects
CT-8.2.2.5.2   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Age – 52-
Week Enrollers
CT-8.2.2.5.3   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Age – 26-
Week Enrollers
CT-8.2.3.1   Incidence of All Treatment-emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity – All Subjects   
CT-8.2.3.2   Incidence of All Treatment-emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity – 52-Week Enrollers   
CT-8.2.3.3   Incidence of All Treatment-emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity – 26-Week Enrollers   
CT-8.3.1.1   Incidence of Potentially Drug-Related Treatment-emergent Adverse Events by System Organ 
Class – All Subjects
CT-8.3.1.2   Incidence of Potentially Drug-Related Treatment-emergent Adverse Events by System Organ 
Class – 52-Week Enrollers
CT-8.3.1.3   Incidence of Potentially Drug-Related Treatment-emergent Adverse Events by System Organ 
Class – 26-Week Enrollers
CT-8.3.2.1   Incidence of Potentially Drug-Related Treatment-emergent Adverse Events by System Organ 
Class and MedDRA Preferred Term – All Subjects
CT-8.3.2.2   Incidence of Potentially Drug-Related Treatment-emergent Adverse Events by System Organ 
Class and MedDRA Preferred Term – 52-Week Enrollers
CT-8.3.2.3   Incidence of Potentially Drug-Related Treatment-emergent Adverse Events by System Organ 
Class and MedDRA Preferred Term – 26-Week Enrollers
CT-8.3.3.1   Incidence of Potentially Drug-Related Treatment-emergent Adverse Events by System Organ 
Class, MedDRA Preferred Term and Severity – All Subjects
CT-8.3.3.2   Incidence of Potentially Drug-Related Treatment-emergent Adverse Events by System Organ 
Class, MedDRA Preferred Term and Severity – 52-Week Enrollers
CT-8.3.3.3   Incidence of Potentially Drug-Related Treatment-emergent Adverse Events by System Organ 
Class, MedDRA Preferred Term and Severity – 26-Week Enrollers
CT-8.4.1.1   Incidence of Deaths Due to Treatment-emergent Adverse Events by System Organ Class – All 
Subjects   
CT-8.4.1.2   Incidence of Deaths Due to Treatment-emergent Adverse Events by System Organ Class – 52-
Week Enrollers   
CT-8.4.1.3   Incidence of Deaths Due to Treatment-emergent Adverse Events by System Organ Class – 26-
Week Enrollers   
CT-8.4.2.1   Incidence of Deaths Due to Treatment-emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term – All Subjects
CT-8.4.2.2   Incidence of Deaths Due to Treatment-emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term – 52-Week Enrollers
CT-8.4.2.3   Incidence of Deaths Due to Treatment-emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term – 26-Week Enrollers
CT-8.5.1.1   Incidence of Serious Treatment-emergent Adverse Events by System Organ Class – All 
Subjects  
CT-8.5.1.2   Incidence of Serious Treatment-emergent Adverse Events by System Organ Class – 52-Week 
Enrollers  


Protocol 331-10-238 Statistical Analysis Plan
31
CT-8.5.1.3   Incidence of Serious Treatment-emergent Adverse Events by System Organ Class – 26-Week 
Enrollers  
CT-8.5.2.1   Incidence of Serious Treatment-emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term   – All Subjects
CT-8.5.2.2   Incidence of Serious Treatment-emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term – 52-Week Enrollers   
CT-8.5.2.3   Incidence of Serious Treatment-emergent Adverse Events by System Organ Class and 
MedDRA Preferred Term – 26-Week Enrollers   
CT-8.5.3.1   Incidence of Serious Treatment-emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity – All Subjects   
CT-8.5.3.2   Incidence of Serious Treatment-emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity – 52-Week Enrollers   
CT-8.5.3.3   Incidence of Serious Treatment-emergent Adverse Events by System Organ Class, MedDRA 
Preferred Term and Severity – 26-Week Enrollers   
CT-8.6.1.1   Incidence of Treatment-emergent Adverse Events Resulting in Discontinuation from Study 
Medication by System Organ Class – All Subjects
CT-8.6.1.2   Incidence of Treatment-emergent Adverse Events Resulting in Discontinuation from Study 
Medication by System Organ Class – 52-Week Enrollers
CT-8.6.1.3   Incidence of Treatment-emergent Adverse Events Resulting in Discontinuation from Study 
Medication by System Organ Class – 26-Week Enrollers
CT-8.6.2.1   Incidence of Treatment-emergent Adverse Events Resulting in Discontinuation from Study 
Medication by System Organ Class and MedDRA Preferred Term – All Subjects  
CT-8.6.2.2   Incidence of Treatment-emergent Adverse Events Resulting in Discontinuation from Study 
Medication by System Organ Class and MedDRA Preferred Term – 52-Week Enrollers  
CT-8.6.2.3   Incidence of Treatment-emergent Adverse Events Resulting in Discontinuation from Study 
Medication by System Organ Class and MedDRA Preferred Term – 26-Week Enrollers  
CT-8.6.3.1   Incidence of Treatment-emergent Adverse Events Resulting in Discontinuation from Study 
Medication by System Organ Class, MedDRA Preferred Term and Severity – All Subjects   
CT-8.6.3.2   Incidence of Treatment-emergent Adverse Events Resulting in Discontinuation from Study 
Medication by System Organ Class, MedDRA Preferred Term and Severity – 52-Week Enrollers   
CT-8.6.3.3   Incidence of Treatment-emergent Adverse Events Resulting in Discontinuation from Study 
Medication by System Organ Class, MedDRA Preferred Term and Severity – 26-Week Enrollers   
CT-8.7.1   Incidence of TEAE Occurring in at Least 5 Percent of Patients by System Organ Class and
MedDRA Preferred Term in the Total Group – All Subjects
CT-8.7.2   Incidence of TEAE Occurring in at Least 5 Percent of Patients by System Organ Class and
MedDRA Preferred Term in the Total Group – 52-Week Enrollers
CT-8.7.3   Incidence of TEAE Occurring in at Least 5 Percent of Patients by System Organ Class and
MedDRA Preferred Term in the Total Group – 26-Week Enrollers
CT-8.8.1.1   Incidence of TE EPS-related AEs by EPS Category and MedDRA Preferred Term – All 
Subjects
CT-8.8.1.2   Incidence of TE EPS-related AEs by EPS Category and MedDRA Preferred Term – 52-Week 
Enrollers
CT-8.8.1.3   Incidence of TE EPS-related AEs by EPS Category and MedDRA Preferred Term – 26-Week 
Enrollers
CT-8.8.2.1   Incidence of TE EPS-related AEs by EPS Category and MedDRA Preferred Term by ADT –
All Subjects
CT-8.8.2.2   Incidence of TE EPS-related AEs by EPS Category and MedDRA Preferred Term by ADT –
52-Week Enrollers
CT-8.8.2.3   Incidence of TE EPS-related AEs by EPS Category and MedDRA Preferred Term by ADT –
26-Week Enrollers


Protocol 331-10-238 Statistical Analysis Plan
32
CT-9.1   Listing of Deaths 
CT-9.2.1   Listing of Serious Adverse Events – All Subjects
CT-9.2.2   Listing of Serious Adverse Events – 52-Week Enrollers
CT-9.2.3   Listing of Serious Adverse Events – 26-Week Enrollers
CT-9.3.1   Listing of Discontinuations from Study Medication Due to Adverse Events – All Subjects
CT-9.3.2   Listing of Discontinuations from Study Medication Due to Adverse Events – 52-Week Enrollers
CT-9.3.3   Listing of Discontinuations from Study Medication Due to Adverse Events – 26-Week Enrollers
CT-10.1.1.1   Mean Change from Baseline in Clinical Laboratory Test Results - Serum Chemistry – All 
Subjects  
CT-10.1.1.2   Mean Change from Baseline in Clinical Laboratory Test Results - Serum Chemistry – 52-
Week Enrollers  
CT-10.1.1.3   Mean Change from Baseline in Clinical Laboratory Test Results - Serum Chemistry – 26-
Week Enrollers  
CT-10.1.2.1   Mean Change F from rom Baseline in Clinical Laboratory Test Results - Hematology – All 
Subjects  
CT-10.1.2.2   Mean Change from Baseline in Clinical Laboratory Test Results - Hematology – 52-Week 
Enrollers  
CT-10.1.2.3   Mean Change from Baseline in Clinical Laboratory Test Results - Hematology – 26-Week 
Enrollers  
CT-10.1.3.1   Mean Change from Baseline in Clinical Laboratory Test Results - Urinalysis – All Subjects  
CT-10.1.3.2   Mean Change from Baseline in Clinical Laboratory Test Results - Urinalysis – 52-Week 
Enrollers  
CT-10.1.3.3   Mean Change from Baseline in Clinical Laboratory Test Results - Urinalysis – 26-Week 
Enrollers  
CT-10.1.4.1   Mean Change from Baseline in Clinical Laboratory Test Results – Other Laboratory Tests –
All Subjects  
CT-10.1.4.2   Mean Change from Baseline in Clinical Laboratory Test Results – Other Laboratory Tests –
52-Week Enrollers
CT-10.1.4.3   Mean Change from Baseline in Clinical Laboratory Test Results – Other Laboratory Tests –
26-Week Enrollers  
CT-10.1.5.1   Mean Change from Baseline in Clinical Laboratory Test Results - Prolactin – All Subjects  
CT-10.1.5.2   Mean Change from Baseline in Clinical Laboratory Test Results - Prolactin – 52-Week 
Enrollers  
CT-10.1.5.3   Mean Change from Baseline in Clinical Laboratory Test Results - Prolactin – 26-Week 
Enrollers  
CT-10.2.1   Incidence of Potential Clinical Relevant of Laboratory Test Abnormalities – All Subjects
CT-10.2.2   Incidence of Potential Clinical Relevant of Laboratory Test Abnormalities – 52-Week Enrollers
CT-10.2.3   Incidence of Potential Clinical Relevant of Laboratory Test Abnormalities – 26-Week Enrollers
CT-10.3.1.1   Listing of Potential Clinical Relevant of Laboratory Test Abnormalities - by Subject  – All 
Subjects
CT-10.3.1.2  Listing of Potential Clinical Relevant of Laboratory Test Abnormalities - by Subject – 52-
Week Enrollers  
CT-10.3.1.3   Listing of Potential Clinical Relevant of Laboratory Test Abnormalities - by Subject – 26-
Week Enrollers  
CT-10.3.2.1   Listing of Potential Clinical Relevant of Laboratory Test Abnormalities - by Test – All 
Subjects


Protocol 331-10-238 Statistical Analysis Plan
33
CT-10.3.2.2   Listing of Potential Clinical Relevant of Laboratory Test Abnormalities - by Test – 52-Week 
Enrollers  
CT-10.3.2.3   Listing of Potential Clinical Relevant of Laboratory Test Abnormalities - by Test – 26-Week 
Enrollers   
CT-10.4.1.1   Incidence of Potentially Liver Injury Related Laboratory Test Abnormalities – All Subjects
CT-10.4.1.2   Incidence of Potentially Liver Injury Related Laboratory Test Abnormalities – 52-Week 
Enrollers
CT-10.4.1.3   Incidence of Potentially Liver Injury Related Laboratory Test Abnormalities – 26-Week 
Enrollers
CT-10.4.2.1   Listing of Potentially Liver Injury Related Laboratory Test Abnormalities – All Subjects
CT-10.4.2.2   Listing of Potentially Liver Injury Related Laboratory Test Abnormalities – 52-Week 
Enrollers
CT-10.4.2.3   Listing of Potentially Liver Injury Related Laboratory Test Abnormalities – 26-Week 
Enrollers
CT-10.5.1.1.1  Incidence of Treatment-Emergent Significant Change in Lipids – All Subjects
CT-10.5.1.1.2  Incidence of Treatment-Emergent Significant Change in Lipids – 52-Week Enrollers
CT-10.5.1.1.3  Incidence of Treatment-Emergent Significant Change in Lipids – 26-Week Enrollers
CT-10.5.1.2.2   Listing of Treatment-Emergent Significant Change in Lipids 
CT-10.5.2.1.1   Incidence of Treatment-Emergent Significant Change in Glucose – All Subjects
CT-10.5.2.1.2   Incidence of Treatment-Emergent Significant Change in Glucose – 52-Week Enrollers
CT-10.5.2.1.3   Incidence of Treatment-Emergent Significant Change in Glucose – 26-Week Enrollers
CT-10.5.2.2.1   Listing of Treatment-Emergent Significant Change in Glucose – All Subjects
CT-10.5.2.2.2   Listing of Treatment-Emergent Significant Change in Glucose – 52-Week Enrollers
CT-10.5.2.2.3   Listing of Treatment-Emergent Significant Change in Glucose – 26-Week Enrollers
CT-10.5.3.1.1   Incidence of Treatment-Emergent Metabolic Syndrome – All Subjects
CT-10.5.3.1.2   Incidence of Treatment-Emergent Metabolic Syndrome – 52-Week Enrollers
CT-10.5.3.1.3   Incidence of Treatment-Emergent Metabolic Syndrome – 26-Week Enrollers
CT-10.5.3.2.1   Listing of Treatment-Emergent Metabolic Syndrome – All Subjects
CT-10.5.3.2.2   Listing of Treatment-Emergent Metabolic Syndrome – 52-Week Enrollers
CT-10.5.3.2.3   Listing of Treatment-Emergent Metabolic Syndrome – 26-Week Enrollers
CT-10.6   Criteria for Potential Clinical Relevant Laboratory Test Abnormalities
CT-11.1.1.1   Mean Change from Baseline in Vital Signs – All Subjects
CT-11.1.1.2   Mean Change from Baseline in Vital Signs – 52-Week Enrollers
CT-11.1.1.3   Mean Change from Baseline in Vital Signs – 26-Week Enrollers
CT-11.1.2.1   Mean Change from Baseline in Weight, BMI and Waist Circumference – All Subjects
CT-11.1.2.2   Mean Change from Baseline in Weight, BMI and Waist Circumference – 52-Week Enrollers
CT-11.1.2.3   Mean Change from Baseline in Weight, BMI and Waist Circumference – 26-Week Enrollers
CT-11.1.3.1   Mean Change from Baseline in Weight, BMI and Waist Circumference by ADT – All 
Subjects
CT-11.1.3.2   Mean Change from Baseline in Weight, BMI and Waist Circumference by ADT – 52-Week 
Enrollers
CT-11.1.3.3   Mean Change from Baseline in Weight, BMI and Waist Circumference by ADT – 26-Week 
Enrollers


Protocol 331-10-238 Statistical Analysis Plan
34
CT-11.1.4.1   Mean Change from Baseline in Weight, BMI and Waist Circumference by Gender – All 
Subjects
CT-11.1.4.2   Mean Change from Baseline in Weight, BMI and Waist Circumference by Gender – 52-
Week Enrollers
CT-11.1.4.3   Mean Change from Baseline in Weight, BMI and Waist Circumference by Gender – 26-
Week Enrollers
CT-11.2.1.1   Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs – All Subjects
CT-11.2.1.2   Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs – 52-Week 
Enrollers
CT-11.2.1.3   Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs – 26-Week 
Enrollers
CT-11.2.2.1   Incidence of Potentially Clinically Relevant Abnormalities in Weight by Visit – All Subjects
CT-11.2.2.2   Incidence of Potentially Clinically Relevant Abnormalities in Weight by Visit – 52-Week 
Enrollers
CT-11.2.2.3   Incidence of Potentially Clinically Relevant Abnormalities in Weight by Visit – 26-Week 
Enrollers
CT-11.2.3.1   Incidence of Potentially Clinically Relevant Abnormalities in Weight by ADT – All Subjects
CT-11.2.3.2   Incidence of Potentially Clinically Relevant Abnormalities in Weight by ADT – 52-Week 
Enrollers
CT-11.2.3.3   Incidence of Potentially Clinically Relevant Abnormalities in Weight by ADT – 26-Week 
Enrollers
CT-11.2.4.1   Incidence of Potentially Clinically Relevant Abnormalities in Weight by Gender – All 
Subjects
CT-11.2.4.2   Incidence of Potentially Clinically Relevant Abnormalities in Weight by Gender – 52-Week 
Enrollers
CT-11.2.4.3   Incidence of Potentially Clinically Relevant Abnormalities in Weight by Gender – 26-Week 
Enrollers
CT-11.3.1   Listing of Potentially Clinically Relevant Abnormalities in Vital Signs – All Subjects
CT-11.3.2   Listing of Potentially Clinically Relevant Abnormalities in Vital Signs – 52-Week Enrollers
CT-11.3.3   Listing of Potentially Clinically Relevant Abnormalities in Vital Signs – 26-Week Enrollers
CT-11.4   Criteria for Potentially Clinically Relevant Abnormalities in Vital Signs
CT-12.1.1   Mean Change from Baseline in Electrocardiogram Results – All Subjects
CT-12.1.2   Mean Change from Baseline in Electrocardiogram Results – 52-Week Enrollers
CT-12.1.3   Mean Change from Baseline in Electrocardiogram Results – 26-Week Enrollers
CT-12.2.1   Incidence of Potentially Clinically Relevant Changes in ECG Evaluations – All Subjects
CT-12.2.2   Incidence of Potentially Clinically Relevant Changes in ECG Evaluations – 52-Week Enrollers
CT-12.2.3   Incidence of Potentially Clinically Relevant Changes in ECG Evaluations – 26-Week Enrollers
CT-12.3.1.1   Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations – All Subjects
CT-12.3.1.2   Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations – 52-Week 
Enrollers
CT-12.3.1.3   Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations – 26-Week 
Enrollers
CT-12.3.2.1   Criteria for Potentially Clinically Relevant Abnormalities in ECG Evaluations
CT-12.3.3.1   ECG Diagnosis Mapping for Potentially Clinically Relevant Electrocardiogram 
Abnormalities
CT-12.4.1.1   Incidence of Categorical Changes in QT Evaluations – All Subjects
CT-12.4.1.2   Incidence of Categorical Changes in QT Evaluations – 52-Week Enrollers


Protocol 331-10-238 Statistical Analysis Plan
35
CT-12.4.1.3   Incidence of Categorical Changes in QT Evaluations – 26-Week Enrollers
CT-12.4.2.1   Listing of Categorical Changes in QT Evaluations – All Subjects
CT-12.4.2.2   Listing of Categorical Changes in QT Evaluations – 52-Week Enrollers
CT-12.4.2.3   Listing of Categorical Changes in QT Evaluations – 26-Week Enrollers


Otsuka Pharmaceutical Development & Commercialization, Inc.
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OPC-34712
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0001267504
2.0
Biostatistics Approval
26-May-2017 15:06 GMT+0
Clinical Approval
30-May-2017 14:21 GMT+0