Clinical trial NCT03287869
Conditions: Bipolar I Disorder Acute Mania
Keywords: Bipolar Mania Brexpiprazole
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2017-10-24; Completion date: 2019-07-31
Enrollment: 381 participants; Allocation: ; Intervention model: PARALLEL

Brief summary:
This study evaluated the safety and evaluate the safety and tolerability of open-label brexpiprazole (2 - 4 mg/day, with a starting dose of 2 mg/day) for the treatment of adult subjects with bipolar I disorder. All participants received a starting dose of brexpiprazole.

Detailed description:
While the availability of atypical antipsychotics had increased the therapeutic options available, there remains a need for safer and more effective therapies in the treatment of manic and depressive episodes of bipolar I disorder. Brexpiprazole's specific receptor activity profile likely correlates with its established efficacy in schizophrenia and major depressive disorder, and may prove to be an effective target for the treatment of acute mania of bipolar I disorder.

Arms: arm 1: Brexpiprazole was administered in participants orally with flexible dosing from 2 mg/day from Days 1 to 3 regardless of treatment assignment in the previous double-blind trial, followed by titration to 3 mg/day on Day 4. Participants may have been titrated (or re-titrated) to a higher dose of brexpiprazole, up to a maximum of 4 mg/day, based on treatment response and at the investigator's discretion anytime at Day 7 or thereafter. Participants who were unable to tolerate their current dose could have been titrated down to a minimum of 2 mg/day any time after Day 4.
Interventions: intervention 1: Brexpiprazole
Intervention descriptions: intervention 1: Brexpiprazole tablets

Protocol documents:
Prot_002.pdf: 
Protocol 331-201-00083 
Confidential - Proprietary Information 
Protocol number: 331-201-00083
Document title: A Multicenter, Open-label Trial to Evaluate the 
Safety and Tolerability of Brexpiprazole in the Treatment of 
Subjects with Bipolar I Disorder
Version number: 2.0
Date of the document: 23 October 2017
NCT number:    NCT03287869




Protocol 331-201-00083
Confidential - Proprietary Information
2
Version 2.0, 20 Oct 2017
Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  
Brexpiprazole (OPC-34712)
Protocol No.:  
331-201-00083
IND No.:  134115
EudraCT No.:  
2017-002225-38
Protocol Title:
A Multicenter, Open-label Trial to Evaluate the Safety and 
Tolerability of Brexpiprazole in the Treatment of Subjects with 
Bipolar I Disorder
Clinical Phase/Trial 
Type:
Phase 3/Therapeutic use
Treatment Indication: Bipolar I disorder
Objective(s):
Primary: To assess the safety and tolerability of brexpiprazole
(OPC-34712) in the treatment of subjects with bipolar I 
disorder.  
Trial Design:
Multicenter, open-label
Subject Population:
Men and women 18 to 65 years of age with a Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
diagnosis of bipolar I disorder will be enrolled in the trial and 
will include eligible rollover subjects who completed one of 
the double-blind, phase 3 efficacy trials (ie, 
Trials 331-201-00080 or 331-201-00081) and could, in the 
opinion of the investigator, potentially benefit from treatment 
with brexpiprazole (OPC-34712).  In the event the sponsor 
determines that the enrollment rate of rollover subjects will not 
be sufficient to meet the target completion of approximately 
175 subjects at 6 months, de novo subjects may be enrolled at 
select sites.  The enrollment of de novo subjects at any site will 
not be permitted until initiation and notification by the 
sponsor.  Approximately 60% of subjects will be enrolled from 
North America and 40% of subjects will be enrolled from the 
rest of the world (ROW).
Inclusion/Exclusion 
Criteria:
Diagnosis of bipolar I disorder, as confirmed by the Mini 
International Neuropsychiatric Interview (MINI), and a history 
of at least 1 previous manic episode, with or without mixed 
features, and manic symptoms of sufficient severity to require 
one of the following interventions:  hospitalization or 
treatment with a mood stabilizer, or treatment with an 
antipsychotic agent.  Eligible subjects must not currently have 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
2






Protocol 331-201-00083
Confidential - Proprietary Information
5
Version 2.0, 20 Oct 2017
be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term.  The incidence of 
treatment-emergent adverse events (TEAEs) will include the 
following summaries:

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 
investigational medicinal product (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.
Descriptive statistics will be provided for each endpoint, and 
will be summarized at each trial visit using the observed cases 
(OC) dataset and at the last visit using the last observation 
carried forward (LOCF) dataset.  Baseline is defined as the last 
available measurement prior to the first dose of open-label 
IMP in the open-label treatment phase.
Trial Duration:
The duration of this trial for an individual subject who 
completes the trial without ET early withdrawal is 
approximately 29 to 35 weeks.  This is inclusive of a 
maximum 14-day screening period, a 4 week conversion phase
(if applicable), a 26-week open-label treatment period, and a 
safety follow-up period via telephone contact or clinic visit 21 
(± 2) days after the last dose of IMP.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
5


Protocol 331-201-00083
Confidential - Proprietary Information
6
Version 2.0, 20 Oct 2017
Table of Contents 
Protocol Synopsis...........................................................................................2
Table of Contents...........................................................................................6
List of In-text Tables ...................................................................................11
List of In-text Figures..................................................................................12
List of Appendices........................................................................................13
List of Abbreviations and Definitions of Terms .......................................14
1
Introduction ........................................................................................16
1.1
Nonclinical Data................................................................................................17
1.2
Clinical Data......................................................................................................17
1.3
Known and Potential Risks and Benefits ..........................................................17
2
Trial Rationale and Objectives..........................................................18
2.1
Trial Rationale...................................................................................................18
2.2
Dosing Rationale...............................................................................................18
2.3
Trial Objectives.................................................................................................19
3
Trial Design.........................................................................................19
3.1
Type/Design of Trial .........................................................................................19
3.2
Trial Treatments ................................................................................................24
3.2.1
De Novo Subjects ...........................................................................................24
3.2.1.1
Conversion Phase (Phase A).......................................................................24
3.2.2
Rollover and De Novo Subjects .....................................................................25
3.2.2.1
Open-label Treatment Phase (Phase B).......................................................25
3.3
Trial Population.................................................................................................26
3.3.1
Number of Subjects and Description of Population .......................................26
3.3.2
Subject Selection and Numbering ..................................................................27
3.4
Eligibility Criteria..............................................................................................27
3.4.1
Informed Consent ...........................................................................................27
3.4.2
Inclusion Criteria ............................................................................................28
3.4.3
Exclusion Criteria...........................................................................................28
3.5
Endpoints...........................................................................................................33
3.5.1
Primary Endpoint............................................................................................33
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
6


Protocol 331-201-00083
Confidential - Proprietary Information
7
Version 2.0, 20 Oct 2017
3.5.2
Secondary Endpoints ......................................................................................33
3.5.3
33
3.5.4
Additional Safety Endpoints...........................................................................34
3.6
Measures to Minimize/Avoid Bias....................................................................34
3.7
Trial Procedures ................................................................................................34
3.7.1
Schedule of Assessments................................................................................43
3.7.1.1
Screening and Baseline ...............................................................................43
3.7.1.1.1
Rollover Subjects.....................................................................................43
3.7.1.1.2
De Novo Subjects....................................................................................43
3.7.1.1.2.1
Screening..............................................................................................43
3.7.1.1.2.2
Baseline (Phase B)...............................................................................45
3.7.1.1.2.3
Baseline (Phase A)...............................................................................46
3.7.1.1.2.4
Conversion to Oral Brexpiprazole (Conversion Weeks 1, 2, 3, 
and 4 of Phase A).................................................................................47
3.7.1.2
Open-Label Treatment (Phase B - All Subjects).........................................48
3.7.1.2.1
Week 1.....................................................................................................48
3.7.1.2.2
Week 2.....................................................................................................49
3.7.1.2.3
Week 4.....................................................................................................49
3.7.1.2.4
Week 8.....................................................................................................50
3.7.1.2.5
Week 12...................................................................................................50
3.7.1.2.6
Week 18...................................................................................................51
3.7.1.2.7
End of Treatment - Week 26/Early Termination.....................................52
3.7.1.3
Post-treatment Follow-up Period ................................................................52
3.7.2
53
3.7.2.4
Other Assessments ......................................................................................54
3.7.3
Safety Assessments.........................................................................................54
3.7.3.1
Adverse Events............................................................................................54
3.7.3.2
Clinical Laboratory Assessments................................................................54
3.7.3.3
Physical Examination and Vital Signs........................................................56
3.7.3.3.1
Physical Examination..............................................................................56
3.7.3.3.2
Measurement of Vital Signs ....................................................................57
3.7.3.4
Electrocardiogram Assessments..................................................................58
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
7
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
8
Version 2.0, 20 Oct 2017
3.7.3.5
Other Safety Assessments...........................................................................59
3.7.4
Prior and Concomitant Medications...............................................................61
3.7.5
Pharmacokinetic Assessments........................................................................61
3.7.6
End of Trial.....................................................................................................61
3.7.7
Independent Data Monitoring Committee......................................................61
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................61
3.8.1
Entire Trial......................................................................................................61
3.8.2
Individual Site.................................................................................................61
3.8.3
Individual Subject Discontinuation ................................................................62
3.8.3.1
Treatment Interruption ................................................................................62
3.8.3.2
Treatment Discontinuation..........................................................................62
3.8.3.3
Documenting Reasons for Treatment Interruption/Discontinuation...........62
3.8.3.4
Withdrawal of Consent ...............................................................................63
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................64
3.9
Screen Failures ..................................................................................................64
3.10
Definition of Completed Subjects.....................................................................64
3.11
Definition of Subjects Lost to Follow-up..........................................................64
3.12
Subject Compliance...........................................................................................65
3.13
Protocol Deviations...........................................................................................65
4
Restrictions..........................................................................................65
4.1
Prohibited Medications......................................................................................65
4.1.1
Use of Benzodiazepines During the Trial.......................................................67
4.2
Other Restrictions..............................................................................................68
5
Reporting of Adverse Events.............................................................69
5.1
Definitions.........................................................................................................69
5.2
Eliciting and Reporting Adverse Events ...........................................................71
5.3
Immediately Reportable Events ........................................................................71
5.4
Potential Serious Hepatotoxicity.......................................................................72
5.5
Pregnancy..........................................................................................................72
5.6
Procedure for Breaking the Blind......................................................................73
5.7
Follow-up of Adverse Events............................................................................73
5.7.1
Follow-up of Nonserious Adverse Events......................................................74
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
8


Protocol 331-201-00083
Confidential - Proprietary Information
9
Version 2.0, 20 Oct 2017
5.7.2
Follow-up of Serious Adverse Events ............................................................74
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact ..................................................................................74
6
Pharmacokinetic Analysis..................................................................75
7
Statistical Analysis..............................................................................75
7.1
Sample Size.......................................................................................................75
7.2
Datasets for Analysis.........................................................................................75
7.3
75
7.4
Primary and Secondary Endpoint Analyses ......................................................76
7.4.1
Primary Endpoint Analysis.............................................................................76
7.4.2
Secondary Endpoint Analysis.........................................................................76
7.4.3
76
7.4.4
Interim Analysis..............................................................................................77
7.5
Analysis of Demographic and Baseline Characteristics....................................77
7.6
Additional Safety Analysis................................................................................77
7.6.1
Clinical Laboratory Data ................................................................................77
7.6.2
Physical Examination and Vital Signs Data ...................................................78
7.6.3
Electrocardiogram Data..................................................................................78
7.6.4
Other Safety Data ...........................................................................................78
8
Management of Investigational Medicinal Product........................78
8.1
Packaging and Labeling ....................................................................................79
8.2
Storage...............................................................................................................79
8.3
Accountability ...................................................................................................79
8.4
Returns and Destruction....................................................................................79
8.5
Reporting of Product Quality Complaints.........................................................79
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................80
8.5.2
Information Required for Reporting Purposes ...............................................80
8.5.3
Return Process ................................................................................................81
8.5.4
Assessment/Evaluation...................................................................................81
9
Records Management.........................................................................81
9.1
Source Documents.............................................................................................81
9.2
Data Collection..................................................................................................81
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
9
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
10
Version 2.0, 20 Oct 2017
9.3
File Management at the Trial Site.....................................................................83
9.4
Records Retention at the Trial Site....................................................................83
10
Quality Control and Quality Assurance...........................................84
10.1
Monitoring.........................................................................................................84
10.2
Auditing.............................................................................................................84
11
Ethics and Responsibility...................................................................84
12
Confidentiality ....................................................................................85
13
Amendment Policy..............................................................................85
14
Publication Authorship Requirements.............................................86
15
References............................................................................................86
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
10


Protocol 331-201-00083
Confidential - Proprietary Information
11
Version 2.0, 20 Oct 2017
List of In-text Tables
Table 3.2.1.1-1
Recommendation for Switching from Other Antipsychotics 
to Oral Brexpiprazole Monotherapy..............................................24
Table 3.2.2.1-1
Dosing Schedule - Open-label Treatment Phase ...........................26
Table 3.4.2-1
Inclusion Criteria ...........................................................................28
Table 3.4.3-1
Exclusion Criteria ..........................................................................29
Table 3.7-1
Schedule of Assessments - Open-label Treatment (Phase B)........35
Table 3.7-2
Schedule of Assessments - Screening and Conversion (Phase 
A):  De Novo Subjects...................................................................39
Table 3.7.3.2-1
Clinical Laboratory Assessments...................................................55
Table 4.1-1
List of Medications Prohibited Before the Trial............................66
Table 4.1-2
List of Medications Prohibited During the Trial............................66
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
11


Protocol 331-201-00083
Confidential - Proprietary Information
12
Version 2.0, 20 Oct 2017
List of In-text Figures
Figure 3.1-1
Trial Design Schematic - Rollover Subjects..................................22
Figure 3.1-2
Trial Design Schematic - De Novo Subjects .................................23
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
12


Protocol 331-201-00083
Confidential - Proprietary Information
13
Version 2.0, 20 Oct 2017
List of Appendices
Appendix 4
Mini International Neuropsychiatric Interview ...........................108
Appendix 5
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .......................................................................111
Appendix 6
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance .......................................................................112
Appendix 7
Criteria for Identifying Electrocardiogram Measurements of 
Potential Clinical Relevance........................................................113
Appendix 14
Protocol Amendment(s)/Administrative Change(s) ....................127
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
13
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
14
Version 2.0, 20 Oct 2017
List of Abbreviations and Definitions of Terms
Abbreviation
Definition
5-HT
Serotonin
ADHD
Attention-deficit hyperactivity disorder
AE
Adverse event
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BMI
Body mass index
CNS
Central nervous system
CPK
Creatine phosphokinase
CYP
Cytochrome P450
DBP
Diastolic blood pressure
D/C
Discontinue
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
Electrocardiogram
EPS
Extrapyramidal symptoms
ET
Early termination
EudraCT
European Clinical Trial Data Base
FDA
Food and Drug Administration
 
GCP
Good Clinical Practice
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IDDM
Insulin-dependent diabetes mellitus
IEC
Independent ethics committee
IMP
Investigational medicinal product
IND
Investigative new drug
INR
International normalized ratio
IRB
Institutional review board
IRE
Immediately reportable event
IR IM
Immediate-release intramuscular
IWRS
Interactive web response system
LOCF
Last observation carried forward
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
14
CCI
CCI
CCI
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
15
Version 2.0, 20 Oct 2017
MAOI
Monoamine oxidase inhibitor
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
OC
Observed cases
OTC
Over-the-counter
PK
Pharmacokinetics
PQC
Product quality complaint
PT
Prothrombin time
PTSD
Post-traumatic stress disorder
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
QTcN
QT interval corrected for heart rate by the FDA Neuropharm Division 
formula
RBC
Red blood cell
ROW
Rest of world
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SSRI
Selective serotonin reuptake inhibitors
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
T4
Free thyroxine
US 
United States 
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
Women of childbearing potential
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
15
CCI
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
16
Version 2.0, 20 Oct 2017
1
Introduction
Bipolar I disorder is a lifelong episodic illness characterized by manic and depressive 
episodes.  Psychotic symptoms (ie, delusions, hallucinations, thought disorders) often 
accompany the manic phase of bipolar I disorder.  The lifetime prevalence of bipolar I 
disorder is estimated to be 0.4% to 1.6% with a mean age of onset for first manic episode 
in the early 20s.1
Atypical antipsychotics are currently recommended as first-line treatment for acute mania 
across multiple United States (US) and international treatment guidelines based on 
established evidence.2,3,4,5  Although the availability of newer atypical antipsychotics has 
increased the therapeutic options in the treatment of manic and depressive episodes of 
bipolar I disorder, there still remains a need for safer and more effective therapies to 
expand the current options.6
Brexpiprazole (also referred to as OPC-34712 and Lu AF41156) is a novel atypical 
antipsychotic synthesized by Otsuka that is being codeveloped by Otsuka and Lundbeck.  
Brexpiprazole (OPC-34712) is currently approved in Canada and the US as monotherapy 
for the treatment of schizophrenia and the US for use as an adjunctive therapy to 
antidepressants for the treatment of major depressive disorder (MDD).  While the precise 
mechanism of action of brexpiprazole (OPC-34712) in treating psychiatric conditions is 
unknown, the pharmacology of brexpiprazole (OPC-34712) is believed to be mediated by 
a combination of high binding affinity and functional activities at multiple 
monoaminergic receptors.  It has modulatory activity at the serotonin (5-HT) and 
dopamine systems that combines partial agonist activity at serotonergic 5-HT1A and at 
dopaminergic D2 receptors with antagonist activity at serotonergic 5-HT2A receptors, 
with similar high affinities at all of these receptors (Ki: 0.1 - 0.5 nM).  Brexpiprazole
(OPC-34712) also shows antagonist activity at noradrenergic α1B/2C with affinity in the 
same subnanomolar Ki range (Ki: 0.2 - 0.6 nM). The 5-HT1A/D2 receptor partial agonist 
activity in combination with 5-HT2A and α1B/2C receptors antagonism of brexpiprazole
(OPC-34712) may correlate with antipsychotic and antidepressant efficacy, reduced 
impulsive behavior, and cognitive improvement.7  This receptor activity profile may also 
prove an effective target for the treatment of bipolar I disorder.  
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
16


Protocol 331-201-00083
Confidential - Proprietary Information
17
Version 2.0, 20 Oct 2017
1.1
Nonclinical Data
A complete description of the available efficacy and safety pharmacology data from 
nonclinical studies, including pharmacokinetic (PK) and toxicology studies in different 
animal species can be found in the current Investigator’s Brochure (IB).7
1.2
Clinical Data
Currently, brexpiprazole (OPC-34712) is approved in the US for use in adult patients as 
an adjunctive therapy to antidepressants for the treatment of MDD and in Canada and the 
US as monotherapy for the treatment of schizophrenia.  In addition to the proposed trial 
in the treatment of bipolar I disorder,  the current brexpiprazole clinical development 
program includes ongoing investigations in the following indications:  adjunctive 
treatment of adult attention-deficit hyperactivity disorder (ADHD) coadministered with 
marketed stimulant therapy; treatment of agitation associated with dementia of the 
Alzheimer’s type; and adjunctive treatment of adult post-traumatic stress disorder 
(PTSD) coadministered with selective serotonin reuptake inhibitors (SSRIs).7
As of 17 Apr 2016, the brexpiprazole (OPC-34712) clinical development program 
consisted of a total of 65 clinical trials conducted in North America, Latin America, 
Europe, and Asia (53 completed and 12 ongoing).  This includes 59 trials conducted 
under US Investigational New Drug Applications (INDs) (47 completed and 12 ongoing) 
for schizophrenia, adjunctive treatment of MDD, adjunctive treatment of ADHD, 
agitation associated with dementia of the Alzheimer’s type, or PTSD; and 6 non-US IND 
trials, completed in either South Korea or Japan, conducted in healthy subjects and 
subjects with schizophrenia.7
Please refer to the IB for more detailed information.7
1.3
Known and Potential Risks and Benefits
Phase 1 data indicated that brexpiprazole (OPC-34712) demonstrated good safety and 
tolerability when administered to healthy volunteers at single doses of 0.2 to 6 mg and at 
a repeated dose of 2 mg/day.  Data from completed repeated dosing trials in the US 
indicate that brexpiprazole (OPC-34712) demonstrated good tolerability when 
administered to subjects with schizophrenia or schizoaffective disorder at doses of up to 
12 mg/day; when administered to subjects with MDD at doses of up to 4 mg/day in 
combination with a marketed antidepressant; as adjunctive therapy in elderly subjects 
(70-85 years of age) with MDD up to 3 mg/day; and when administered to subjects with 
ADHD at doses of up to 4 mg/day in combination with a marketed stimulant.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
17


Protocol 331-201-00083
Confidential - Proprietary Information
18
Version 2.0, 20 Oct 2017
Please refer to the current IB for a summary of available nonclinical and clinical safety 
data.7
2
Trial Rationale and Objectives
2.1
Trial Rationale
Current guidelines for the treatment of acute mania in bipolar I disorder advocate 
first-line use of atypical antipsychotics, such as aripiprazole, as monotherapy or in 
combination with lithium or divalproex.2,3,4,5
Brexpiprazole (OPC-34712) is a novel atypical antipsychotic that is a serotonin-
dopamine activity modulator and is indicated in the US as monotherapy for the treatment 
of schizophrenia in adult patients (2-4 mg/day) and as an adjunctive therapy to 
antidepressants for the treatment of MDD (2-3 mg/day).7  Like other atypical 
antipsychotics that have demonstrated efficacy across the indications of schizophrenia, 
MDD, and bipolar I disorder, brexpiprazole’s (OPC-34712) specific receptor activity 
profile likely correlates with its established efficacy in schizophrenia and MDD, and may 
also prove to be an effective target for the treatment of the acute mania of bipolar I 
disorder.  This 26-week, multicenter, open-label trial will be conducted to evaluate the 
long-term safety and tolerability of brexpiprazole (OPC-34712) for the treatment of 
subjects with bipolar I disorder.
2.2
Dosing Rationale
The dosing paradigm of brexpiprazole (OPC-34712) to be used in Trial 331-201-00083 
has been determined based on the current approved dosing ranges and phase 3 trial results 
across related psychiatric indications (MDD and schizophrenia) and on dosing paradigms 
used in the development of other atypical antipsychotics used for bipolar I disorder.  In 
general, for most atypical antipsychotics, the recommended dosing range and maximal 
doses tend to be comparable for subjects with either schizophrenia or bipolar I acute 
mania.7  
The dosing paradigm is within the currently approved recommended dose range for 
schizophrenia, ie, 2 to 4 mg/day, but with a more rapid titration schedule.  A higher 
starting dose and faster titration for acute mania is proposed to reach the target dose 
quickly, without resulting in undesirable side effects.  This decision is consistent with 
clinical trial programs and labeling for other atypical antipsychotics, where similar 
differences are seen between schizophrenia and acute mania dosing paradigms with 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
18


Protocol 331-201-00083
Confidential - Proprietary Information
19
Version 2.0, 20 Oct 2017
respect to the starting doses and recommended dose ranges.  In addition, this is consistent 
with previously tested dosing paradigms for brexpiprazole in schizophrenia that resulted 
in similar safety and tolerability profiles as seen with the labeled dosing paradigm.  This 
includes trials with higher starting doses without titration (up to 12 mg/day), and with 
more rapid titration schedules (Trials 331-07-203, 331-08-205, and 14644A).
  
2.3
Trial Objectives
The purpose of this trial is to assess the safety and tolerability of brexpiprazole 
(OPC-34712) in the treatment of subjects with bipolar I disorder.    
3
Trial Design
3.1
Type/Design of Trial
This is a multicenter, open-label trial designed to assess the safety and tolerability of oral 
brexpiprazole (OPC-34712) (2-4 mg/day) as treatment in adults with bipolar I disorder.  
The trial will be conducted on an outpatient basis.  Enrollment into the trial will be drawn 
from eligible subjects who will include subjects who completed the 3-week treatment in 
the double-blind, phase 3 efficacy trials (ie, Trials 331-201-00080 or 331-201-00081) 
and, in the investigator’s judgment, could potentially benefit from treatment with oral 
brexpiprazole (OPC-34712) for bipolar I disorder.  In the event the sponsor determines 
that the enrollment rate of rollover subjects will not be sufficient to meet the target 
completion of approximately 175 subjects at 6 months, de novo subjects may be enrolled
at select sites. The enrollment of de novo subjects at any site will not be permitted until 
initiation and notification by the sponsor.
The trial will be organized as follows:
Rollover Subjects:
Screening/Baseline:  Subjects who completed Day 21 of the double-blind trial and had no 
major protocol deviation will be screened for eligibility at the last visit of the double-
blind trial (ie, Week 3 [Day 21] visit of Trials 331-201-00080 or 331-201-00081).  
Subjects will sign a separate informed consent form (ICF) for participation in 
Trial 331-201-00083 before any procedures specific to the open-label trial are performed.  
The assessments from the last visit of the double-blind trial will serve as the baseline 
measures for Trial 331-201-00083 for any assessment that is not unique to the open-label 
trial.  Medical history will be updated, if necessary.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
19


Protocol 331-201-00083
Confidential - Proprietary Information
20
Version 2.0, 20 Oct 2017
Open-label Treatment Phase (Phase B):  Eligible subjects from Trials 331-201-00080 or 
331-201-00081 will receive 26 weeks of daily treatment with open-label brexpiprazole
(OPC-34712) (2-4 mg/day) in Phase B of Trial 331-201-00083, as described in
Section 3.2.  Visits will occur at the end of Weeks 1, 2, 4, 8, 12, 18, and 26.  
Follow-up:  Subjects will be followed up for safety via telephone contact or clinic visit 
21 (± 2) days after the last dose of open-label investigational medicinal product (IMP).
De Novo Subjects (The enrollment of de novo subjects at any site will not be permitted 
until initiation and notification by the sponsor):
Screening:  Subjects will enter a pretreatment screening phase that will range from a 
minimum of 1 day to a maximum of 14 days to assess eligibility criteria and to washout 
from prohibited concomitant medications, if applicable.  A screening number will be 
assigned for each subject with a signed ICF.  Subjects with a lapse in antipsychotic 
treatment (“lapse” defined as > 7 consecutive days without oral antipsychotic medication) 
will proceed directly to the baseline of the open-label treatment phase (Phase B) after 
completing screening assessments, provided that all eligibility criteria are met, including 
washout of all prohibited medications.  All other subjects will undergo conversion to oral 
brexpiprazole in the conversion phase (Phase A).
Conversion Phase (Phase A):  Any subject receiving antipsychotic treatment(s) at the 
initial screening visit will undergo cross-titration to oral brexpiprazole (OPC-34712) for 
4 weeks in Phase A, as described in Section 3.2.  Those subjects on mood stabilizers and 
antipsychotics will need to be on monotherapy brexpiprazole (OPC-34712) by end of the 
conversion phase.  Visits will occur at the end of Conversion Weeks 1, 2, 3, and 4 during 
Phase A.  The goal in Phase A is for the de novo subjects to achieve a brexpiprazole
(OPC-34712) target dose of 2 mg daily by the Conversion Week 4 visit, which will also 
be the baseline visit of Phase B.  Therefore, the assessments from the Conversion Week 4 
visit of Phase A will serve as the baseline measures for Phase B.
Baseline and Open-label Treatment Phase (Phase B):  After completing baseline 
assessments (Phase B baseline visit for subjects entering Phase B directly from screening 
or Conversion Week 4 visit of Phase A for subjects who participated in Phase A), eligible 
subjects will receive daily treatment with open-label brexpiprazole (OPC-34712) in 
Phase B, as described in Section 3.2.  Subjects will receive 26 weeks of open-label 
brexpiprazole (OPC-34712) (2-4 mg/day) in Phase B.  Visits will occur at the end of 
Weeks 1, 2, 4, 8, 12, 18, and 26.  
Follow-up: Subjects will be followed up for safety via telephone contact or clinic visit 
21 (± 2) days after the last dose of open-label medication.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
20


Protocol 331-201-00083
Confidential - Proprietary Information
21
Version 2.0, 20 Oct 2017
See Figure 3.1-1 and Figure 3.1-2 for schematics of the trial design for rollover and de 
novo subjects, respectively. 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
21


Protocol 331-201-00083
Confidential - Proprietary Information
22
Version 2.0, 20 Oct 2017
Figure 3.1-1
Trial Design Schematic - Rollover Subjects
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
22


Protocol 331-201-00083
Confidential - Proprietary Information
23
Version 2.0, 20 Oct 2017
Figure 3.1-2
Trial Design Schematic - De Novo Subjects
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
23


Protocol 331-201-00083
Confidential - Proprietary Information
24
Version 2.0, 20 Oct 2017
3.2
Trial Treatments
3.2.1
De Novo Subjects
The enrollment of de novo subjects at any site will not be permitted until initiation 
and notification by the sponsor.
3.2.1.1
Conversion Phase (Phase A)
For de novo subjects, Conversion (Phase A) applies only to subjects who are receiving 
antipsychotic medication(s) when being considered for entry into Trial 331-201-00083.  
All other de novo subjects will enter the trial at Phase B (see Section 3.2.2.1) after 
completing screening assessments.  The purpose of Phase A is to cross-titrate de novo 
subjects from current antipsychotic treatment(s) to monotherapy with brexpiprazole
(OPC-34712) 2 mg/day over a 4-week period to minimize the possibility of rebound (eg, 
cholinergic or histaminergic) from abrupt changes in antipsychotic medication.  The 
procedure as it pertains to this protocol is summarized in Table 3.2.1.1-1.
Table 3.2.1.1-1
Recommendation for Switching from Other Antipsychotics to 
Oral Brexpiprazole Monotherapy
Trial Visit
Phase A 
Baselinea
Conversion 
Week 1b
Conversion 
Week 2
Conversion 
Week 3
Conversion 
Week 4/
Baseline of 
Phase Bc
Dose of 
brexpiprazole 
(OPC-34712)
1 mg/day
1 mg/day
1 or 2 mg/day
2 mg/day
2 mg/day
Dose of other 
antipsychotic(s)
No change
No change
Decrease
Decrease
D/C
D/C = discontinue.
aAdd short-term concomitant medications as needed to control symptoms (eg, agitation and insomnia).
bGradually withdraw concomitant medications.
cMonotherapy with brexpiprazole 2 mg/day will begin at the Conversion Week 4 visit/baseline of 
Phase B which will occur the day after discontinuation of all other antipsychotic treatment(s).
The scheme in Table 3.2.1.1-1 represents the optimal approach for conversion of subjects 
from other antipsychotic(s) to brexpiprazole and is highly recommended for use in this 
trial; however, the investigator may adjust the dose(s) of other antipsychotic(s) during the 
4-week cross-titration as deemed appropriate for individual subjects.  The dose of 
brexpiprazole (OPC-34712) can increase during cross-titration, but cannot decrease.  
Subjects must achieve a monotherapy dose of brexpiprazole (OPC-34712) 2 mg/day at 
the Conversion Week 4 visit/baseline of Phase B in order to progress to Phase B.  
Although de novo subjects must be outpatient at screening, the investigator has the option 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
24


Protocol 331-201-00083
Confidential - Proprietary Information
25
Version 2.0, 20 Oct 2017
to hospitalize subjects during the conversion phase (Phase A), if deemed medically 
necessary.  The need for hospitalization should be discussed with the medical monitor in 
advance.  However, de novo subjects must be outpatient at baseline of Phase B.
3.2.2
Rollover and De Novo Subjects
3.2.2.1
Open-label Treatment Phase (Phase B)
The only antipsychotic treatment permitted during Phase B will be open-label 
brexpiprazole (OPC-34712).  Any subject who requires additional antipsychotic 
treatment must be withdrawn from the trial.  Timing of the first dose of brexpiprazole 
(OPC-34712) in Phase B will be as follows:
De Novo Subjects (The enrollment of de novo subjects at any site will not be 
permitted until initiation and notification by the sponsor.)

For de novo subjects who undergo conversion in Phase A, open-label dosing of 
brexpiprazole (OPC-34712) in Phase B will begin the day after discontinuation of all 
other antipsychotic treatment(s), which is the Conversion Week 4 visit/baseline of 
Phase B.

De novo subjects with a lapse in oral antipsychotic treatment of > 7 consecutive days 
at screening will receive the first dose of open-label brexpiprazole (OPC-34712) in 
Phase B as soon as all screening and baseline evaluations are completed, including 
washout of all other prohibited medications.
Rollover Subjects

The first dose of open-label brexpiprazole (OPC-34712) will be taken one day after 
the last dose of double-blind IMP is taken in Trials 331-201-00080 or 331-201-00081 
so that treatment continues without interruption.  It is anticipated that the last dose of 
the double-blind, phase 3 efficacy trial will be taken the day of the Day 21 (Week 3) 
visit of Trial 331-201-00080 or 331-201-00081 (ie, the day of the screening/baseline 
visit for the open-label trial).

All subjects will start on 2 mg/day of brexpiprazole (OPC- 34712) regardless of 
treatment assignment in the double-blind trial.
All subjects will receive a starting dose of 2 mg/day of brexpiprazole from Days 1 to 3, 
followed by titration to 3 mg/day brexpiprazole on Day 4.  Subjects may be titrated (or 
re-titrated) to a higher dose of brexpiprazole, up to a maximum of 4 mg/day, based on 
treatment response and at the investigator’s discretion anytime at Day 7 or thereafter.  
Subjects who are unable to tolerate their current dose can be titrated down at any time to 
a minimum of 2 mg/day.  Dose adjustments must be made in increments of 1 mg/day.  
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
25


Protocol 331-201-00083
Confidential - Proprietary Information
26
Version 2.0, 20 Oct 2017
Subjects who are unable to tolerate 2 mg/day brexpiprazole will be discontinued from the 
trial.
The dosing strategy is summarized in Table 3.2.2.1-1.  Subjects must return to the clinic 
for unscheduled visits if dose adjustments for brexpiprazole are required between 
scheduled visits.  Dose adjustments must ultimately be made based upon the clinical 
judgment of the investigator as it relates to tolerability and therapeutic response.  All 
doses of brexpiprazole should be taken orally once daily and can be administered without 
regard to meals.  Subjects are to take IMP at approximately the same time each day.
Table 3.2.2.1-1
Dosing Schedule - Open-label Treatment Phase
IMP
Trial Visit
Days 1-3
Day 4a
Day 7-Week 26
Brexpiprazole
(OPC-34712)
2 mg/day
3 mg/day
2-4 mg/dayb
aDown titration can occur at any time due to tolerability after Day 4. The minimum dose allowed is 
2 mg/day.
bOption to titrate to 2 to 4 mg  (ie, 2 mg, 3 mg, or 4 mg) based on clinical response and tolerability; 
changes must occur in 1 mg/day increments.  Increases up to 4 mg/day may occur no earlier than 
Day 7.  
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
It is estimated that approximately 384 rollover subjects may be enrolled into Trial 331-
201-00083 to achieve a target completion of approximately 175 subjects at 6 months at 
approximately 90 trial sites in North America and the rest of world (ROW).  Men and 
women 18 to 65 years of age with a Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) diagnosis of bipolar I disorder will be enrolled in the 
trial and will include rollover subjects from the double-blind, phase 3 efficacy trials (ie, 
Trials 331-201-00080 or 331-201-00081).  In the event the sponsor determines that the
enrollment rate of rollover subjects will not be sufficient to meet the target completion of 
approximately 175 subjects at 6 months, de novo subjects may be enrolled at select sites. 
The enrollment of de novo subjects at any site will not be permitted until initiation and 
notification by the sponsor.
Diagnosis will be confirmed by the Mini International Neuropsychiatric Interview 
(MINI)8,9 and a history of at least 1 previous manic episode with or without mixed 
features and manic symptoms of sufficient severity to require one of the following 
interventions:  hospitalization or treatment with a mood stabilizer, or treatment with an 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
26


Protocol 331-201-00083
Confidential - Proprietary Information
27
Version 2.0, 20 Oct 2017
antipsychotic agent.  Eligible subjects must not currently have severity of bipolar 
symptoms that, in the opinion of the investigator, would require hospitalization. 
Approximately 60% of subjects will be enrolled from North America and 40% of 
subjects will be enrolled from the rest of world (ROW).
3.3.2
Subject Selection and Numbering
At screening, subjects will be assigned a unique subject identification (ID) number upon 
completion of the consent process.  
3.4
Eligibility Criteria
3.4.1
Informed Consent
Informed consent will be freely obtained from all subjects.  The ICF will be approved by 
the same institutional review board or independent ethics committee (IRB/IEC) that 
approves this protocol.
Each ICF will comply with the International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline10 and local regulatory requirements.  The investigator 
will ensure that the sponsor reviews and authorizes any written site-specific ICF used in 
the trial before submission to the IRB/IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent.  However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).  
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Prospective trial participants will be provided with controlled access to the electronic 
informed consent application by site staff.  When the site staff and the participant agree 
that the participant has enough information to make an informed decision to participate, 
the participant will electronically sign the electronic ICF application and an electronic 
date and time stamp will be applied to the signature.  The participant will be given a 
printed, signed copy of the consent form.  Any other parties required by the IRB/IEC 
(trial site staff, witnesses, or legally authorized representative) are also required to sign 
electronically and these signatures will be stored with the electronic ICF in accordance 
with the ICH GCP Guideline and local regulatory requirements/guidelines.  These 
signatures cannot be altered, removed, or copied.  In the event electronic ICFs are not 
allowed per local or country regulations, a paper consent will be utilized.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
27


Protocol 331-201-00083
Confidential - Proprietary Information
28
Version 2.0, 20 Oct 2017
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol results in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on trial participation.
3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
De Novo Subjectsa
1.
Male or female subjects, ages 18 to 65 years, inclusive, at the time of informed consent.
2.
Subjects who are able to complete the consent process and/or consent obtained from a legally 
acceptable representative (as required by IRB/IEC) prior to the initiation of any protocol-required 
procedures.
3.
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 ingestion, and 
discontinuation of prohibited medication; to read and understand written word in order to be 
reliably rated on assessment scales.
4.
Subjects with a DSM-5 diagnosis of bipolar I disorder who do not have severity of bipolar 
symptoms that, in the opinion of the investigator, would require hospitalization. Diagnosis 
confirmed by the MINI and a history of at least one previous manic episode, with or without mixed
features, with manic symptoms of sufficient severity to require one of the following interventions:  
hospitalization or treatment with a mood stabilizer, or treatment with an antipsychotic agent.  
“Require” is defined as an intervention that occurred rather than one that was recommended.  
5.
Subjects who, in the investigator’s judgment, require treatment with an antipsychotic medication 
for their bipolar I disorder.
6.
Subjects willing to discontinue all prohibited medications to meet protocol-required washouts prior 
to and during the trial period.
7.
Outpatient status.  Subjects hospitalized at the investigator’s discretion during conversion to oral 
brexpiprazole (OPC-34712) in Phase A and hospitalization for psychosocial reasons (eg, 
homelessness or need for shelter that is unrelated to the subject’s underlying psychiatric condition) 
will be considered outpatient status for the purpose of enrollment in Trial 331-201-00083.  Subjects 
hospitalized during the conversion phase (Phase A) must be outpatient at the baseline of Phase B.  
Rollover Subjects from Trial 331-201-00080 or 331-201-00081
8.
Subjects remaining in hospital at the Day 21 (Week 3) visit of Trial 331-201-00080  or Trial 331-
201-00081 (for other than psychosocial reasons) will be permitted to enroll in Trial 331-201-00083 
at the Week 3 visit of the double-blind trial if they are planned to be discharged from the hospital 
before the Week 1 visit of Trial 331-201-00083.  Subjects not discharged by the Week 1 visit of 
Trial 331-201-00083 must be withdrawn.
9.
Subjects who, in the opinion of the investigator, could potentially benefit from administration of 
oral brexpiprazole for the treatment of bipolar I disorder and who completed 3 weeks of 
post-randomization treatment in Trial 331-201-00080 or Trial 331-201-00081.
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; IEC = independent 
ethics committee; IRB = institutional review board.
aThe enrollment of de novo subjects at any site will not be permitted until initiation and notification by 
the sponsor.
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
28


Protocol 331-201-00083
Confidential - Proprietary Information
29
Version 2.0, 20 Oct 2017
Table 3.4.3-1
Exclusion Criteria
De Novo Subjectsa
Sex and Reproductive Status
1.
Sexually active males or WOCBP who do not agree to practice 2 different methods of birth control 
or remain abstinent during the trial and for 30 days after the last dose of IMP.  If employing birth 
control, 2 of the following precautions must be used:  vasectomy, tubal ligation, vaginal diaphragm, 
intrauterine device, birth control pill, birth control implant, birth control depot injection, condom 
with spermicide, or sponge with spermicide.
2.
Females who are breastfeeding and/or who have a positive pregnancy test result prior to receiving 
IMP in Trial 331-201-00083.
Target Disease
3.
Subjects with a history of DSM-5 diagnosis other than bipolar I disorder, including schizophrenia, 
schizoaffective disorder, major depressive disorder, attention-deficit/hyperactivity disorder, 
delirium, dementia, amnestic, or other cognitive disorders.  Also, subjects with borderline, 
paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.  All other current 
diagnoses must be discussed with the medical monitor.
4.
Subjects with manic symptoms that are better accounted for by another general medical condition 
or direct physiological effects of a substance (eg, medications).
5.
Subjects considered unresponsive to clozapine or who are only responsive to clozapine.
6.
Subjects with bipolar I disorder who are considered resistant or refractory to treatment for manic 
symptoms by history.
7.
Electroconvulsive treatment within the past 2 months of the screening/baseline visit for 
Trial 331-201-00083.
8.
Use of psychotropic medications (other than benzodiazepines) within 7 days of the baseline 
YMRS.
9.
Rapid cyclers with more than 6 episodes in the previous year.
10.
Subjects whose current manic episode has lasted for more than 4 weeks overall, or who require 
hospitalization for the current acute episode at the time of the screening visit, excluding 
hospitalization for psychosocial reasons.
Medical History and Concurrent Diseases
11.
Subjects who have a current diagnosis or history of substance or alcohol use disorder (excluding 
nicotine) (DSM-5 criteria) 120 days prior to the screening visit.
12.
Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal Ideation with 
Some Intent to Act, Without Specific Plan) and whose most recent episode meeting criteria for this 
C-SSRS Item 4 occurred within the last 6 months, OR
Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation with 
Specific Plan and Intent) and whose most recent episode meeting criteria for this C-SSRS Item 5 
occurred within the last 6 months OR
Subjects who answer “Yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, 
interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent episode 
meeting criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred within the last 
2 years, OR
Subjects who, in the opinion of the investigator, present a serious risk of suicide or homicide.
13.
Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with 
medications for at least the past 90 days) or an abnormal result for free T4 at screening.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
29


Protocol 331-201-00083
Confidential - Proprietary Information
30
Version 2.0, 20 Oct 2017
Table 3.4.3-1
Exclusion Criteria
14.
Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, 
hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders such as the 
following:

any history of myocardial infarction or congestive heart failure (whether controlled or 
uncontrolled),  

HIV seropositive status or acquired immunodeficiency syndrome, chronic hepatitis B or C 
(defined as positive serology and AST or ALT elevated to > 2 × ULN).  
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 AE 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.  Subjects who are 
severely obese, as confirmed by a correspondingly high BMI, need to be reviewed and discussed 
with the medical monitor.
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:

HbA1c < 7.0%, AND

Screening glucose must be ≤ 125 mg/dL (fasting) or < 200 mg/dL (nonfasting).  If the 
nonfasting screening glucose is ≥ 200 mg/dL, subjects must be retested in a fasted state and the 
retested value must be ≤ 125 mg/dL, AND

Subject has been maintained on a stable regimen of oral anti-diabetic medication(s) for at least 
28 days prior to screening or diabetes has been well-controlled by diet for at least 28 days prior 
to screening, AND

Subject has not had any hospitalizations within the 12 months prior to screening due to 
diabetes or complications related to diabetes, AND

Subject’s diabetes is not newly diagnosed during screening for the trial.
16.
Subjects with uncontrolled hypertension (DBP > 95 mmHg in any position) 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.
NOTE:  Blood pressure measurements may be repeated once to ensure reproducibility of the 
exclusionary result(s) before excluding a subject based on the criteria noted above.
17.
Subjects with epilepsy or a history of seizures, except for a single seizure episode; for instance 
childhood febrile, post traumatic, or alcohol withdrawal seizure.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
30


Protocol 331-201-00083
Confidential - Proprietary Information
31
Version 2.0, 20 Oct 2017
Table 3.4.3-1
Exclusion Criteria
Physical and Laboratory Results
18.
Subjects with abnormal laboratory tests results, vital signs results, or ECG findings, unless, based 
on the investigator’s judgment, the findings are not medically significant and would not impact the 
safety of the subject or the interpretation of the trial results.  The medical monitor should be 
contacted to discuss individual cases, as needed.  Criteria are provided in Section 3.7.3.2.  In 
addition, subjects with the following laboratory test and ECG results at screening must be excluded 
from the trial:

Platelets ≤ 75000/mm3

Hemoglobin ≤ 9 g/dL

Neutrophils, absolute ≤ 1000/mm3

AST > 2 × ULN

ALT > 2 × ULN

CPK > 3 × ULN, unless discussed with and approved by the medical monitor

Creatinine ≥ 2 mg/dL

QTcF ≥ 450 msec in men and ≥ 470 msec in women, unless due to ventricular pacing.
Tests with exclusionary results should be repeated to ensure reproducibility of the abnormality 
before excluding a subject based on the criteria noted above. For ECG, perform 3 consecutive 
recordings.  If 2 of the 3 remain exclusionary then the subject must be excluded.
19.
Subjects with a positive drug screen for cocaine or other drugs of abuse (excluding stimulants and 
other prescribed medications and marijuana) 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.
Subjects with a history of a gastric bypass surgery that creates a malabsorptive state, including 
Roux-en-Y gastric bypass and biliopancreatic bypass with duodenal switch.  This does not include 
gastric banding, gastric stapling, and sleeve gastrectomy procedures.
Disallowed and Concomitant Medication
21.
Recent treatment with a long acting or depot antipsychotic in which the last dose was less than one 
full cycle plus 1/2 cycle from baseline visit.
22.
Subjects who would be likely to require prohibited concomitant therapy during the trial.
23.
Subjects who received brexpiprazole (OPC-34712) in any prior clinical trial or currently taking 
commercially available brexpiprazole (Rexulti®).
Allergies and Adverse Drug Reactions
24.
Subjects with a history of neuroleptic malignant syndrome, serotonin syndrome, or clinically 
significant tardive dyskinesia.
25.
Subjects with a history of true allergic response (ie, not intolerance) to more than 1 class of 
medications.
26.
Subjects who are known to be allergic or hypersensitive to brexpiprazole (OPC-34712) or other 
quinolinones.
Other
27.
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.
28.
Any subject who, in the opinion of the sponsor, investigator, or medical monitor, should not 
participate in the trial.
29.
Subjects who participated in a clinical trial within the last 60 days or who participated in more than 
2 clinical trials within the past year.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
31


Protocol 331-201-00083
Confidential - Proprietary Information
32
Version 2.0, 20 Oct 2017
Table 3.4.3-1
Exclusion Criteria
Rollover Subjects from Trial 331-201-00080 or 331-201-00081
30.
Subjects with a major protocol violation during the course of their participation in the double-blind 
phase 3 trial (ie, Trial 331-201-00080 or 331-201-00081).  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 331-201-00083; however, continual lack of compliance with the visit 
schedule, trial assessments, or treatment regimen in the prior double-blind trial would be 
considered a major violation that would result in exclusion from Trial 331-201-00083.  The 
medical monitor should be contacted if the investigator is unsure of a subject’s eligibility.
AE = adverse event;  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI  =  body 
mass index; CPK = creatine phosphokinase; C-SSRS = Columbia-Suicide Severity Rating Scale; 
DBP  = diastolic blood pressure; ECG = electrocardiogram; HbA1c = glycosylated hemoglobin; HIV 
= human immunodeficiency virus; IDDM = insulin dependent diabetes mellitus; OTC = over-the-
counter; QTcF = QT interval as corrected by Fridericia’s formula; SBP = systolic blood pressure; T4
= free thyroxine; ULN = upper limit of normal; WOCBP = women of childbearing potential.
aThe enrollment of de novo subjects at any site will not be permitted until initiation and notification by 
the sponsor.
Nonchildbearing potential is defined as male and female subjects who are surgically 
sterile (ie, male subjects who have undergone bilateral orchidectomy and female subjects 
who have undergone bilateral oophorectomy and/or hysterectomy) and female subjects 
who have been postmenopausal for at least 12 consecutive months.
Subjects must agree to restrictions to medications and lifestyle as described in Section 4.
Subjects with a positive blood alcohol screen should be reassessed for alcohol abuse and 
dependence before consultation with medical monitor about approval for inclusion.  
Subjects with a positive drug screen that, in the judgment of the investigator with 
concurrence of the medical monitor, could compromise the subject’s safety or ability to 
comply with the trial procedures that could interfere with the interpretation of trial results 
should be excluded from the trial.  Subjects with a positive drug screen for cocaine or 
other illicit drugs are excluded and may not be retested or rescreened.  Subjects with a 
positive urine drug screen resulting from use of marijuana, prescription, or over-
the-counter (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 or the subject does not meet DSM-5 criteria for substance 
abuse or dependence, may continue evaluation for the trial following consultation and 
approval by the medical monitor.
Screen failures may be rescreened at any time if the exclusion characteristic has changed.  
Subjects who sign an ICF but who are not started on treatment are permitted to be 
rescreened. If a subject is rescreened for trial participation, and the rescreening is not 
completed within the original screening window, a new ICF must be signed.  
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
32




Protocol 331-201-00083
Confidential - Proprietary Information
34
Version 2.0, 20 Oct 2017
3.5.4
Additional Safety Endpoints
Standard safety variables will include clinical laboratory tests (hematology, serum 
chemistry [including prolactin and glycosylated hemoglobin (HbA1c)], coagulation 
parameters, and urinalysis), physical examinations, vital sign measurements, and 
electrocardiograms (ECGs).  Body weight, height, and waist circumference will also be 
measured.
 
 
 
  
 
3.6
Measures to Minimize/Avoid Bias
This trial is open-label.
3.7
Trial Procedures
This is a multicenter, open-label trial designed to assess the safety and tolerability of oral 
brexpiprazole (OPC-34712) (2-4 mg/day) as treatment in adults with bipolar I disorder.  
The trial will be conducted on an outpatient basis.  The trial comprises a 26-week open-
label treatment period with a 21 (± 2) day follow-up.
Trial assessment time points are summarized in Table 3.7-1 (open-label treatment phase 
[Phase B]) and Table 3.7-2 (conversion phase [Phase A]).
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
34
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
35
Version 2.0, 20 Oct 2017
Table 3.7-1
Schedule of Assessments - Open-label Treatment (Phase B) 
Assessment
Screening
/ 
Baselinea
(Rollover)
Phase B 
Baselinea
(De 
Novo)
Open-Label Treatment Phase Trial Week Visit (2 days)
Follow-up
21 (± 2) daysc
1
2
4
8
12
18
26/ ETb
ENTRANCE CRITERIA
Informed consent
Xd
Inclusion/exclusion 
criteria
X
X
Medical history
Xe
SAFETY
Physical examination
Xf
Xg
X
Waist circumference
Xf
Xg
X
Vital signsi
Xf
Xg
X
X
X
X
X
X
X
12-lead ECGj
Xf
Xg
X
X
Clinical laboratory 
testsk
Xf,l
Xg,l
Xm
Xm
HbA1c
Xf,l
Xg,l
Xm
Xm
Drug screen/blood 
alcoholn
Xf
Xg
X
X
X
Urine pregnancy test 
(WOCBP only)o
Xf
Xg
X
X
X
X
X
X
X
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
35
CCI
CCI




Protocol 331-201-00083
Confidential - Proprietary Information
37
Version 2.0, 20 Oct 2017
cConsists of telephone contact or clinic visit (investigator’s discretion) for evaluation of safety and applies to all subjects (completers and premature 
withdrawals).
dInformed consent for Trial 331-201-00083 will occur at screening/baseline for rollover subjects and must be obtained before any trial-related procedures 
specific to the open-label trial are performed.
eUpdate, if necessary, for rollover subjects.
fScreening/baseline value will be obtained from the Day 21 (Week 3) visit of Trial 331-201-00080 or Trial 331-201-00081.
gBaseline assessment will be performed at baseline of Phase B for de novo subjects who enter Phase B directly after screening, but will be obtained from the 
Conversion Week 4 visit of Phase A for subjects who participate in Phase A.
 
iVital 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 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.
jStandard 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.  However, ECG results will also be evaluated at the investigational 
site to monitor safety during the trial.  Rollover subjects will be enrolled in Trial 331-201-00083 based on the screening/baseline ECG results from the trial 
site.  If the screening/baseline ECG results from the central reader, when available, indicate a QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) 450 msec in men and ≥ 470 msec in women, unless due to ventricular pacing.at screening/baseline, the investigator must contact the medical 
monitor to discuss the subject’s continued participation in the trial.  For de novo subjects, ECG results from the central reader must be reviewed for 
exclusion criteria prior to the first dose of open-label brexpiprazole in Phase B.  Any ECGs scheduled for the same visit as blood samples are to be 
completed before blood is drawn.
kIncludes hematology (including prothrombin time [PT], activated partial thromboplastin time [aPTT], and international normalized ratio [INR]), serum 
chemistry (including prolactin, HbA1c, and thyroid-stimulating hormone [TSH], with reflex to free thyroxine [T4] if the result for TSH is abnormal), and 
urinalysis.
lRollover subjects must be fasting for a minimum of 8 hours prior to blood draws for screening/baseline laboratory assessments, if at all possible.  If fasting 
blood samples are not feasible at screening, nonfasting blood samples may be obtained initially for determining eligibility for the trial. A fasting blood 
sample is required at baseline prior to dosing.  De novo subjects must fast for a minimum of 8 hours prior to blood draws for baseline laboratory 
assessments.
mBlood samples for clinical laboratory tests must be drawn after a minimum 8-hour fast at Week 26/ET and should be drawn after a minimum 8-hour fast at 
all other visits, if possible.  Vital sign and ECG assessments should be completed before any blood samples are collected.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
37
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
38
Version 2.0, 20 Oct 2017
nA 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.  If results of either or both are positive, the investigator must contact the medical monitor to discuss the subject’s eligibility 
for continued participation in the trial.
oAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with positive urine and serum pregnancy test results at screening, 
baseline, or screening/baseline must not be enrolled in Trial 331-201-00083.  Subjects with 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.
 
qAE recording will begin with the signing of the ICF for Trial 331-201-00083.
rAdjustments to the dose of brexpiprazole can be made at scheduled and unscheduled visits during the 26-week open-label treatment phase (ie, Phase B) to 
optimize efficacy and tolerability as described in the protocol.  Subjects must return to the clinic for unscheduled visits if dose adjustments for 
brexpiprazole are required between scheduled visits.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
38
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
39
Version 2.0, 20 Oct 2017
Table 3.7-2
Schedule of Assessments - Screening and Conversion (Phase A):  De Novo Subjects 
The enrollment of de novo subjects at any site will not be permitted until initiation and notification by the sponsor.
Assessment
Screening 
(Days -14 to -1)a
Phase A 
Baseline
Conversion 
Week 1 
(2 days)
Conversion 
Week 2
(2 days)
Conversion 
Week 3
(2 days)
Conversion 
Week 4/ 
Phase B 
Baselineb
(2 days)
ENTRANCE CRITERIA
Informed consentc
X
Inclusion/exclusion criteria
X
X
Medical history
X
Demography
X
Psychiatric history
X
MINI 
X
Prior medication washoutd
X
HIV, HBsAg, and anti-HCV
X
SAFETY
Physical examinatione
X
X
Waist circumference
X
X
Vital signsf
X
X
X
X
X
X
12-lead ECGg
X
X
Clinical laboratory tests (hematology, 
serum chemistry [including prolactin], 
and urinalysis)h
Xi
X
TSH with reflex to free T4 if abnormalh
Xi
X
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
39
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
40
Version 2.0, 20 Oct 2017
Table 3.7-2
Schedule of Assessments - Screening and Conversion (Phase A):  De Novo Subjects 
The enrollment of de novo subjects at any site will not be permitted until initiation and notification by the sponsor.
Assessment
Screening 
(Days -14 to -1)a
Phase A 
Baseline
Conversion 
Week 1 
(2 days)
Conversion 
Week 2
(2 days)
Conversion 
Week 3
(2 days)
Conversion 
Week 4/ 
Phase B 
Baselineb
(2 days)
HbA1ch
Xi
X
X
PT, aPTT, and INRh
X
X
X
Drug screen/blood alcoholj
X
X
Urine pregnancy test (WOCBP only)k
X
X
Adverse events
Xm
X
X
X
X
X
Concomitant medicationsn
X
X
X
X
X
X
OTHER
 
Register visit in IWRS
X
X
X
X
X
X
Cross-titrationo
X
X
X
X
X
IMP dispensing
X
X
X
X
X
IMP accountability
X
X
X
X
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus.
aAll de novo subjects (ie, subjects who did not participate in one of the double-blind phase 3 trials) will enter a screening period to determine eligibility for the 
open-label trial.  Screening begins when the ICF is signed and will take place between Day −14 and Day −1; however, screening procedures should be initiated 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
40
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
41
Version 2.0, 20 Oct 2017
with a sufficient amount of time allotted in order to obtain laboratory results prior to baseline.  Review of inclusion/exclusion criteria at baseline will be based on 
some assessments performed during screening.
bIf a subject discontinues early before Week 4, procedures noted for Week 26/ ET must be completed at the ET visit.  Attempts should be made to complete 
ALL evaluations, particularly efficacy assessments for the Week 26/ET visit prior to the administration of any new psychotropic medications.  However, if 
the subject receives a new antipsychotic prior to ET procedures, no efficacy assessments should be done.  Any prohibited medications started before the 
end of the trial assessments should be documented as a protocol deviation in the source notes.
cInformed consent must be obtained before any trial-related procedures are performed.
dWashout of prohibited medications begins after signing the ICF.  Details of medications requiring washout are provided in Section 4.1.  Prohibited and 
restricted medications are also provided in Section 4.1.  In addition, all antipsychotic medications used within 30 days of the first dose of IMP will be 
recorded.
eTo include measurement of height at screening only.
fVital signs include body weight, body temperature, SBP, DBP, and heart rate.  Blood pressure and heart rate will be measured in the following order:  supine 
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.
gStandard 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.  However, ECGs will also be evaluated at the investigational site 
to monitor safety during the trial.  Any screening 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.  ECGs scheduled for the same visit as blood samples are to be completed before blood is drawn.
hBlood samples for clinical laboratory tests must be drawn after a minimum 8-hour fast at screening and Conversion Week 4, if at all possible.  If fasting 
blood samples are not feasible at screening, nonfasting blood samples may be obtained initially for determining eligibility for the trial.  Vital sign and ECG 
assessments should be completed before any blood samples are collected.
iSee Section 3.4.3 for exclusions based on screening laboratory results.
jA 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.  If results of either or both are positive, the investigator must contact the medical monitor to discuss the subject’s eligibility 
for continued participation in the trial.
kAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with positive urine and serum pregnancy test results at screening must 
not be enrolled.  Subjects with 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.
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
41
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
42
Version 2.0, 20 Oct 2017
mAE recording will begin with the signing of the ICF.
nAll 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 4.1.
oCross-titration will occur over a 4-week period in order to bring about a stable transition from previous antipsychotic treatment(s) to oral brexpiprazole.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
42


Protocol 331-201-00083
Confidential - Proprietary Information
43
Version 2.0, 20 Oct 2017
3.7.1
Schedule of Assessments
3.7.1.1
Screening and Baseline
3.7.1.1.1
Rollover Subjects
Subjects who completed Day 21 of the double-blind trial and had no major protocol 
deviation will be screened for eligibility at the last visit of the double-blind trial (ie, 
Week 3 [Day 21] visit of Trials 331-201-00080 or Trial 331-201-00081).  Subjects will 
sign a separate ICF for participation in Trial 331-201-00083 before any procedures 
specific to the open-label trial are performed.  The assessments from the last visit of the 
double-blind trial will serve as the baseline measures for Trial 331-201-00083 for the 
following assessments:  
 
physical examination, waist circumference, vital signs, ECG, clinical laboratory tests, 
urine drug screen, blood alcohol, and urine pregnancy test.  
Additional procedures to be performed for rollover subjects at screening/baseline of the 
open-label trial are as follows:

Inclusion/exclusion criteria for Trial 331-201-00083 will be reviewed to ensure the 
subject’s eligibility.

Trial personnel will register the visit in the interactive web response system (IWRS).

Medical history will be updated, if necessary.

Concomitant medications will be reviewed to assure that the subject is not receiving 
any prohibited medications.


Open-label brexpiprazole (OPC-34712) will be dispensed to the subject.

Recording of AEs will begin with the signing of the ICF for Trial 331-201-00083.
3.7.1.1.2
De Novo Subjects
The enrollment of de novo subjects at any site will not be permitted until initiation 
and notification by the sponsor.  
3.7.1.1.2.1
Screening
Screening procedures for de novo subjects are shown in Table 3.7-2 and begin after 
written informed consent has been obtained.  These procedures can be performed at any 
time from Day −14 to Day −1.  Although the screening period continues up to 
administration of the first dose of IMP, screening procedures should be initiated with a 
sufficient amount of time allotted in order to obtain laboratory results and ECG results 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
43
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
44
Version 2.0, 20 Oct 2017
from the central reader prior to enrollment/baseline.  The sponsor reserves the right to 
utilize external quality oversight methods to ensure the validity of diagnosis, severity of 
illness, and other factors determining appropriateness of subject selection.  After a subject 
has signed the ICF, sites will access the IWRS and enter a screening number.  
Completion of screening activities may require more than 1 visit; however, only the 
initial visit will be registered in the IWRS.  Screening evaluations for de novo subjects 
will include the following:

An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial.

Demographic data will be recorded.

A general clinical evaluation will be performed, including concurrent medical 
conditions, medical history over the past 2 years, and medical history beyond 2 years 
which is considered to be clinically relevant per the investigator’s judgment.

Psychiatric history will be recorded, including the DSM-5 diagnosis of bipolar I 
disorder that will be made by an adequately trained and experienced clinician and will 
be confirmed by the administration of the MINI.

Medications (including those that were taken within 30 days of the first dose of IMP) 
will be recorded.  In addition, all prescription and non-prescription medications taken 
during the trial will be recorded as concomitant medications.  Details of 
prohibited/restricted medications are provided in Table 4.1-1 and Table 4.1-2.

Washout from prohibited concomitant medications, if applicable (Table 4.1-1).


A complete physical examination (including height) 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 and standing after the subject has been in each position at 
least 3 minutes.  See Section 3.4.3 for exclusions based on outcome of screening vital 
sign measurements.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes.  See Table 3.4.3-1 for exclusions based on ECG results.

Blood samples for clinical laboratory tests (hematology, coagulation parameters, and 
serum chemistry, including prolactin, HbA1c, and thyroid-stimulating hormone 
[TSH] with reflex to free thyroxine [T4] if the result for TSH is abnormal) should be 
drawn after a minimum 8-hour fast at screening.  See Table 3.4.3-1 for exclusions 
based on outcome of screening clinical laboratory tests.

Blood samples will be drawn for human immunodeficiency virus (HIV) serology and 
the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C
virus (anti-HCV).  Subjects with a positive result for any of these tests will be 
excluded from the trial.  Vital sign and ECG assessments should be completed before 
any blood samples are collected.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
44
CCI


















Protocol 331-201-00083
Confidential - Proprietary Information
53
Version 2.0, 20 Oct 2017
events and concomitant medications will be recorded.  This contact also applies to 
subjects withdrawn prematurely from the trial.
3.7.2
Efficacy Assessments
It is required that trained and experienced clinicians administer all rating scales.  
 
 
  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, 
certification, and materials for rating will be provided by Otsuka Pharmaceutical 
Development & Commercialization, Inc. or a designee.
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
53
C
CI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
54
Version 2.0, 20 Oct 2017
 
 
3.7.2.4
Other Assessments
The MINI8,9,14 will be conducted at the screening visit (where applicable) to confirm the 
subject’s diagnosis of bipolar I disorder and to rule out exclusionary comorbid psychiatric 
diagnoses.  Detailed instructions for administration of this structured interview will be 
provided.  A copy of the score sheet is provided in Appendix 4.
 
 
 
 
 
 
 
3.7.3
Safety Assessments
Refer to Section 5, Reporting of Adverse Events.
3.7.3.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
3.7.3.2
Clinical Laboratory Assessments
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, 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.  Subjects should 
be fasting for a minimum of 8 hours prior to the blood draws, if possible.  If fasting blood 
samples are not feasible at screening, nonfasting blood samples may be obtained initially 
for determining eligibility for the trial.  The results of these tests at screening must be 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
54
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
55
Version 2.0, 20 Oct 2017
reviewed by the investigator prior to initiation of the administration of the IMP.  
Additional urine and blood samples may be collected for further evaluation of safety as 
warranted by the investigator’s judgment. 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.
Table 3.7.3.2-1
Clinical Laboratory Assessments
Hematology:
White Blood Cell (WBC) count with differential
Red Blood Cell (RBC) count
Hematocrit
Hemoglobin
Platelet count
Urinalysis:
pH
Specific Gravity
Protein
Ketones
Glucose
Blood
Microscopic analysis (performed only if any part of
the urinalysis is not negative)
Urine Drug Screen:
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Marijuana
Methadone
Opiates
Phencyclidine
Propoxyphene
Other:
Blood Alcohol
Serum Chemistry:
Alkaline Phosphatase (ALP)
Alanine Aminotransferase (ALT)
Albumin
Aspartate Aminotransferase (AST)
Bicarbonate
Bilirubin, total 
Blood Urea Nitrogen (BUN)
Creatine phosphokinase (CPK)
Calcium
Chloride
Cholesterol (total, low density lipoprotein, and high 
density lipoprotein)
Creatinine
Gamma Glutamyl Transferase (GGT)
Glucose
HbA1c
Inorganic phosphorus
Insulin
Lactic Dehydrogenase (LDH)
Magnesium
Potassium
Prolactin
Protein, total 
Sodium
Thyroid Stimulating Hormone (TSH)
Thyroxine, Free (T4) (if needed)
Uric acid
Triglycerides
Additional Tests:
Urine or serum pregnancy for WOCBP
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
International normalized ratio (INR)
HbA1c
Additional Tests (screening only);
HIV
HbsAg
anti-HCV
ALP = alkaline phosphatase; BUN = blood urea nitrogen; GGT = gamma glutamyl transferase; LDH = 
lactic dehydrogenase; MCHC = mean corpuscular hemoglobin concentration; RBC = red blood cell; 
WBC = white blood cell.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
55


Protocol 331-201-00083
Confidential - Proprietary Information
56
Version 2.0, 20 Oct 2017
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.  If the result of any test (or 
repeat test, if done) is indicated as clinically significant in the samples taken during the 
screening period, the subject will NOT be enrolled into the trial without the permission of 
the medical monitor.  In addition, follow-up unscheduled laboratory tests should be 
performed if clinically significant abnormalities are observed.  Unscheduled laboratory 
tests may be repeated at any time at the discretion of the investigator for appropriate 
medical care.  Refer to Appendix 5 for criteria for identifying values of potential clinical 
relevance.
The following laboratory test results at screening are exclusionary:

Platelets ≤ 75000/mm3

Hemoglobin ≤ 9 g/dL

Neutrophils, absolute ≤ 1000/mm3

Aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN)

Alanine aminotransferase (ALT) > 2 × ULN

Creatine phosphokinase (CPK) > 3 × ULN, unless discussed with and approved by 
the medical monitor

Creatinine ≥ 2 mg/dL
The total volume of blood to be collected during the trial is expected to be approximately 
50 mL.
A pregnancy test will be conducted in WOCBP prior to trial intervention; results must be 
available prior to the administration of the IMP.  Pregnancy tests can be performed at any 
point during the trial if pregnancy is suspected.
3.7.3.3
Physical Examination and Vital Signs
3.7.3.3.1
Physical Examination
A complete physical examination will consist of measurement of height and waist 
circumference and a review of the following body systems: head, eyes, ears, nose, and 
throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosae.  
Height will be measured with a stadiometer, measuring stick, or tape.  Waist 
circumference will be measured with each physical examination.  The following 
procedures will aid in the standardization of these measurements:

The subject should be minimally clothed (ie, lightweight clothing; no heavy 
overgarments).
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
56


Protocol 331-201-00083
Confidential - Proprietary Information
57
Version 2.0, 20 Oct 2017

Waist circumference should be recorded before a subject’s meal and at approximately 
the same time at each visit.

The waist circumference 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.16
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 Food and Drug Administration (FDA) Form 1572.  Whenever possible, 
the same individual should perform all physical examinations.  Any condition present at 
the post-treatment physical examination that was not present at the baseline examination 
should be documented as an AE and followed to a satisfactory conclusion.
3.7.3.3.2
Measurement of Vital Signs
The measurement of vital signs 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 and standing 
positions after the subject has been in each position for at least 3 minutes.  The supine 
measurements will be performed first followed by standing.
Subjects with uncontrolled hypertension (screening DBP > 95 mmHg in any position) 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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
57


Protocol 331-201-00083
Confidential - Proprietary Information
58
Version 2.0, 20 Oct 2017
should be excluded if they have any other vital sign measurement at screening that, in the 
investigator’s judgment, is medically significant in that it would impact the safety of the 
subject or the interpretation of the trial results.  However, any abnormal screening vital 
sign result(s) considered to be clinically significant should be repeated to confirm the 
finding(s) before excluding the subject from the trial.  Appendix 6 is included to assist 
investigators in their assessments of results that may be potentially medically significant, 
depending on the subject’s medical history and clinical presentation.
3.7.3.4
Electrocardiogram Assessments
All ECG recordings will be obtained after the subject has been supine and at rest for at 
least 5 minutes.  Additional 12-lead ECGs may be obtained at the investigator’s 
discretion and should always be obtained in the event of an ET.  Electrocardiogram 
results will be evaluated at the investigational site to determine the subject’s eligibility 
and to monitor safety during the trial.  The principal investigator or qualified designee 
will review, sign, and date each ECG reading, noting whether or not any abnormal results 
are of clinical significance.  The ECG will be repeated if any results are considered to be 
clinically significant.  A central ECG service will be utilized for reading all ECGs in
order to standardize interpretations for the safety analysis.
If, according to the investigator's judgment, any abnormal ECG finding is deemed 
medically significant (impacting the safety of the subject and/or the interpretation of the 
trial results) or meets an exclusion criterion (see Table 3.4.3-1), the subject should be 
excluded from the trial.  Abnormal results for ECGs should be repeated once at screening 
with 3 consecutive ECG recordings to ensure reproducibility of the abnormality before 
excluding a subject based on the criteria noted above.  Each ECG recording should be 
taken approximately 5 minutes apart (the ECG result reported will be evaluated at each 
time point).  The central ECG service will provide the corrections for the 3 ECGs 
performed.  Based on the QT interval corrected for heart rate by Fridericia’s formula 
(QTcF) reported by the central service, a subject will be excluded if the corrections are ≥ 
450 msec in men and ≥ 470 msec in women for 2 of the 3 time points of the ECGs done, 
unless due to ventricular pacing.  If only 1 ECG time point has a QTcF of ≥ 450 msec in 
men and ≥ 470 msec in women, and this is not reproduced at either of the other 2 time
points, the subject can be included in the trial.
Refer to Appendix 7 for a list of potentially clinically relevant ECG abnormalities to 
guide investigators for the assessment of potential ECG abnormalities for clinical 
significance.  Exclusion criteria for screening do not apply as mandatory discontinuation 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
58


Protocol 331-201-00083
Confidential - Proprietary Information
59
Version 2.0, 20 Oct 2017
criteria for subjects who are already enrolled in the trial.  Please consult the medical 
monitor in case of questions.
3.7.3.5
Other Safety Assessments
It is required that a trained and experienced clinician administer the safety assessments, 
  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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
59
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
60
Version 2.0, 20 Oct 2017
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
60
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
61
Version 2.0, 20 Oct 2017
 
3.7.4
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject from 30 
days prior to the first dose of IMP through the end of the evaluation period (defined as 
the time period during which subjects are evaluated for primary and/or secondary 
objectives) on the case report form.  The investigator will record all medications and 
therapies taken by the subject for treatment of an AE or which caused an AE until the end 
of the trial (defined as the last date of contact or date of final contact attempt) on the case 
report form.
3.7.5
Pharmacokinetic Assessments
None.
3.7.6
End of Trial
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up ePlatform page for the last subject completing 
or withdrawing from the trial.
3.7.7
Independent Data Monitoring Committee
Not applicable.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs/IECs, and regulatory authorities in accordance with 
regulatory requirements.
3.8.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC if judged to be necessary for medical, safety, regulatory, ethical or other 
reasons consistent with applicable laws, regulations, and GCP.  The investigator will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB/IEC at 
the site.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
61
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
62
Version 2.0, 20 Oct 2017
3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Interruption
All attempts should be made to avoid treatment interruption during the trial.  For subjects 
who have an interruption of treatment, investigator or designee will contact the sponsor at 
the earliest possible time by telephone.  The investigator and sponsor will come as 
quickly as possible to a joint decision regarding the subject’s continuation in the trial.  
This decision will be documented by the investigator and the sponsor, and reviewed by 
the site monitor.  The treatment interruption will be recorded in the ePlatform and also 
recorded as a protocol deviation (Section 3.13).
3.8.3.2
Treatment Discontinuation
After starting open-label IMP, a subject may stop treatment permanently for a variety of 
reasons.  Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator.  
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 3.8.3.5.
3.8.3.3
Documenting Reasons for Treatment 
Interruption/Discontinuation
A subject may temporarily interrupt or discontinue IMP for a number of reasons 
including those listed below:

Reasons related to AE:

Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard

Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP)

Serious adverse event (SAE) 

Other potentially IMP-related safety concerns or AEs

Death

Reasons unrelated to medical condition (provide detail and review AE history with 
subject)

Withdrawal of informed consent (complete written withdrawal of consent form)

Lost to follow-up

Pregnancy (see Section 5.5)

Termination of all or part of the trial by the sponsor
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
62


Protocol 331-201-00083
Confidential - Proprietary Information
63
Version 2.0, 20 Oct 2017
If the subject temporarily interrupts or discontinues IMP due to an AE, the investigator, 
or other trial personnel, will make every effort to follow the event until it has resolved or 
stabilized.  Follow up procedures in Section 3.8.3.1 and Section 3.8.3.2 must be followed.
3.8.3.4
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice.  Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation.  The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary.  
Unless the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial ICF):

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).

Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail,
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent.  
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial.  
A subject may initially express their desire to interrupt or discontinue IMP 
administration, which is not equivalent to a complete withdrawal of consent for further 
participation (see Section 3.8.3.1 and Section 3.8.3.2).  A subject may, however, indicate 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
63


Protocol 331-201-00083
Confidential - Proprietary Information
64
Version 2.0, 20 Oct 2017
that further trial participation is creating a burden on their work or social schedule.  
Therefore, the investigator should follow the procedures outlined in Section 3.8.3.3 to 
determine if the subject can continue participation in the trial if modifications to his/her 
treatment and/or schedule of assessments can be accommodated.  Only subjects who 
withdraw their permission for all of the above degrees of follow-up are considered to 
have completely withdrawn their consent to participate in the trial.
3.8.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be given instructions to meet and discuss with the subject their options of continuing in 
the trial, preferably on therapy.  The investigator should ensure understanding and 
documentation of the reasons for the subject’s desire to withdraw consent.  
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on treatment, 
whether through randomization or open assignment.
Subjects who sign an ICF but who are not started on treatment are permitted to be 
rescreened.  In the event that the subject is rescreened for trial participation, and the 
rescreening is not completed within the original screening window, a new ICF must be 
signed.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP.  Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers.  For purposes of this 
trial, subjects who complete the Week 26 visit will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the Week 26 visit during the treatment 
period, who do not have a known reason for discontinuation (eg, withdrew consent or 
AE), and for whom a survival status at the end of the trial cannot be determined will be 
classified as “lost to follow-up” as the reason for discontinuation. Survival status can be 
determined from a variety of sources, either by obtaining acceptable documentation for 
death (ie, death certificate, medical records, public records, statement by a family 
member or primary care physician) or acceptable documentation for life (ie, direct 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
64


Protocol 331-201-00083
Confidential - Proprietary Information
65
Version 2.0, 20 Oct 2017
contact with the subject, medical records, successful telephone contact with the subject, 
statement by a family member or primary care physician, or public records).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.12
Subject Compliance 
Responsible trial personnel will dispense the IMP (ie, brexpiprazole).  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.
3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor at 
the earliest possible time by telephone.  The investigator and sponsor will come as 
quickly as possible to a joint decision regarding the subject’s continuation in the trial.  
This decision will be documented by the investigator and the sponsor, and reviewed by 
the site monitor.
4
Restrictions
4.1
Prohibited Medications
All subjects must agree to discontinue all prohibited medications during the screening 
period in order to meet the protocol-specified washout periods.  Table 4.1-1 provides the 
required duration of washout for selected prohibited medications.  All other prohibited 
medications must be discontinued at least 24 hours before the first dose of IMP.  Subjects 
who are receiving prohibited medications that would require a washout of more than 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
65


Protocol 331-201-00083
Confidential - Proprietary Information
66
Version 2.0, 20 Oct 2017
14 days (eg, current use of depot or long-acting injectable antipsychotics) are excluded 
from the trial.  However, subjects whose last injection of antipsychotic occurred at least 
one full cycle (based on the prescribing label) before the initial screening visit are eligible 
to enter the 14-day screening period if at least one full cycle plus 1/2 cycle (length of 
1 cycle based on the prescribing label) will have elapsed before enrollment.  Other 
therapies restricted or prohibited prior to enrollment and during the trial are presented in
Section 4.2.
Table 4.1-1
List of Medications Prohibited Before the Trial
Medication
Required Washout Prior to 
Dosing
Antipsychotics
Oral (or IR IM) aripiprazole
Other oral (or IR IM) antipsychotics
Depot or long-acting injectable antipsychotics
14 days
7 days
One full cycle plus 1/2 cyclea
(length of 1 cycle based on the 
prescribing label)
Antidepressants
Fluoxetine or Symbyax
MAOIs
Citalopram and escitalopram
Venlafaxine and desvenlafaxine
All other antidepressants
28 daysa
14 days
8 days
3 days
14 days
Mood stabilizers (ie, lithium and/or anticonvulsants)
7 days
Varenicline
5 days
Benzodiazepines
Refer to Section 4.1.1 for 
details on benzodiazepine use 
during the trial
CYP2D6 inhibitors and CYP3A4 inhibitors and inducersb
14 days
CYP = cytochrome P450; IR IM = immediate-release intramuscular; MAOIs = monoamine oxidase 
inhibitors.
aSubjects must satisfy the washout restriction within the 14-day screening period.  Therefore, subjects 
currently receiving depot or long-acting injectable antipsychotics, fluoxetine, or Symbyax at 
screening are excluded from the trial.  However, if these medications were recently discontinued prior 
to the initial screening visit for reasons unrelated to this trial and the required washout will be met 
within 14 days of the initial screening visit, the subject may be screened for the trial.
bConcomitant use of CYP3A4 inducers or CYP2D6/CYP3A4 inhibitors may be allowed with prior 
approval from the medical monitor, including a discussion with the medical monitor for potential 
dose adjustments of the IMP prior to initiation of therapy.
Table 4.1-2
List of Medications Prohibited During the Trial
1.
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including depot or long-acting injectable formulations
b)   Anticonvulsants
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
66


Protocol 331-201-00083
Confidential - Proprietary Information
67
Version 2.0, 20 Oct 2017
Table 4.1-2
List of Medications Prohibited During the Trial
c) Antidepressants (including MAOIs)
d) Mood stabilizers (ie, lithium and/or anticonvulsants)
e) Benzodiazepines, except specific benzodiazepines when used as rescue therapya
f)   Prescription stimulants (including appetite suppressants and treatments for ADHD or 
narcolepsy)
g)  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).
h)  Nutritional supplements and non-prescription herbal preparations with CNS effects (eg, St.
John’s Wort, omega-3 fatty acids, kava extracts, gamma-aminobutyric acid supplements, etc)
2.
Hypnotics, including ramelteon and other non-benzodiazepine sleep aids, except for specific 
medications when used to manage treatment-emergent AEs related to insomniab
3.
Antihistamines (except for loratadine and cetirizine)
4.
Varenicline
5.
Vitamins, other nutritional supplements, and non-prescription herbal preparations, unless approved 
in advance by the medical monitor
6.
Investigational agents.
7.
CYP2D6 inhibitors or CYP3A4 inhibitors and inducers. Selected CYP2D6 inhibitors 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.)
ADHD = attention-deficit hyperactivity disorder; CNS = central nervous system; CYP = cytochrome 
p450; MAOIs = monoamine oxidase inhibitors.
aRefer to Section 4.1.1 for details on benzodiazepine use during the trial.
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 8 hours prior 
to scheduled efficacy and safety assessments, including EPS scales.  Investigators are encouraged to 
delay scale administration until 8 hours have elapsed, if at all possible.  However, if delaying 
administration of efficacy and safety scales is not feasible, the scales should still be administered and 
the use of the sleep aid documented, including a notation of the drug name, dose, and time of 
administration on the eSource.
4.1.1
Use of Benzodiazepines During the Trial
The use of intramuscular benzodiazepines and continual use of oral benzodiazepines is 
prohibited during this trial.  However, limited use of oral lorazepam (up to 4 mg/day) as a 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
67


Protocol 331-201-00083
Confidential - Proprietary Information
68
Version 2.0, 20 Oct 2017
rescue medication for the short-term management of treatment-emergent AEs (TEAEs) of 
anxiety, agitation, and insomnia will be allowed during the trial.  Lorazepam equivalents 
are prohibited unless explicitly authorized by the medical monitor.  During the washout 
period, the prior use of other benzodiazepines must be discontinued in favor of oral 
lorazepam.  In countries where lorazepam is not commercially available, the use of oral 
oxazepam, alprazolam, diazepam, or clonazepam is only acceptable with prior 
authorization 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.  
Benzodiazepines must not be administered within 8 hours prior to and scheduled 
efficacy or safety scale assessments.  Investigators are encouraged to delay scale 
administration until a full 8 hours have elapsed since the last benzodiazepine dose, if at 
all possible, including at screening and baseline assessments.  However, if delaying 
administration of efficacy and safety scales is not feasible, the scales should still be 
administered and the use of benzodiazepine documented, including a notation of the drug 
name, dose, and time of administration on the eSource.
4.2
Other Restrictions 
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.20

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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
68


Protocol 331-201-00083
Confidential - Proprietary Information
69
Version 2.0, 20 Oct 2017
diarrhea) following the concomitant use of SSRIs or serotonin-norepinephrine 
reuptake inhibitors and these drugs.
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 3 times daily (total of 60 mg/day).  Sites should only utilize 
medications that are approved for these indications in their respective countries.
All trial personnel should be familiar with the content of the IB for brexpiprazole in order 
to manage the subject’s condition adequately and select appropriate concomitant 
medications, if needed.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as medical 
history at screening for preplanned procedures for which the underlying condition was 
known and no worsening occurred.  An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the IMP and the AE.  
Suspected adverse reaction implies a lesser degree of certainty about causality.
An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions.

Requires in-patient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
69


Protocol 331-201-00083
Confidential - Proprietary Information
70
Version 2.0, 20 Oct 2017

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious adverse events are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event (IRE):  

Any SAE.

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.4).

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on the clinical trial 
pregnancy and breastfeeding form, or other designated form, to the sponsor. 
Pregnancy will only be documented on the AE ePlatform if there is an 
abnormality or complication.
Clinical Laboratory Test Value Changes:  It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available.  This review will be 
documented by the investigator’s dated signature on the laboratory report.  For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed.  The investigator may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests.  If this laboratory value is 
considered medically relevant by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the ePlatform.  The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
70


Protocol 331-201-00083
Confidential - Proprietary Information
71
Version 2.0, 20 Oct 2017
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related: 
There is no temporal or causal relationship between the IMP and 
the AE.
5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  To avoid 
bias in eliciting AEs, subjects should be asked the non-leading question: “How have you 
felt since your last visit?”  All AEs (serious and nonserious) reported by the subject must 
be recorded on the eSource platform provided by the sponsor.  Serious AE collection is to 
begin after a subject has signed the ICF.  
Use medical terminology in AE reporting.  Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms.  Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3.  Special attention should 
be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, potential serious hepatotoxicity, or confirmed pregnancy, by 
telephone, fax, or e-mail to the sponsor using the contact information on the cover page 
of this protocol.  An IRE form must be completed and sent by e-mail, fax, or overnight 
courier to the sponsor.  (Please note that the IRE form is NOT the AE ePlatform.)
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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
71


Protocol 331-201-00083
Confidential - Proprietary Information
72
Version 2.0, 20 Oct 2017
supportive care for the subject and will provide prompt updates on the subject’s status to 
the sponsor.
5.4
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is 3 times the upper 
limit of normal (ULN), a total bilirubin level should also be evaluated. If the total 
bilirubin is 2 times the ULN, complete an IRE form with all values listed and also 
report as an AE on the ePlatform.
5.5
Pregnancy
Women of child-bearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 
12 months).
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures 
(ie, double-barrier method) to prevent pregnancy during the course of the trial and for 
30 days after the last dose of IMP.  Unless the subject is sterile (ie, women who have had 
a bilateral oophorectomy and/or hysterectomy or who have been postmenopausal for at 
least 12 consecutive months; or men who have had a bilateral orchidectomy) or remains 
abstinent, 2 of the following precautions must be used: vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth control pills, birth control depot injection, birth 
control implant, condom with spermicide, or sponge with spermicide.  Any single method 
of birth control, including vasectomy and tubal ligation, may fail, leading to pregnancy.  
The contraceptive method will be documented at each trial visit.
Before enrolling WOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all 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
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
72


Protocol 331-201-00083
Confidential - Proprietary Information
73
Version 2.0, 20 Oct 2017
Before 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 informed consent form stating that the above-
mentioned risk factors and the consequences were discussed with her.
A urine and/or serum pregnancy test for human chorionic gonadotropin will be performed 
at screening on all WOCBP.  If a urine test is performed and is positive, the investigator 
will follow up with a confirmatory serum test.
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 is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available.  If the 
pregnancy is confirmed, the subject must not receive the IMP and must not be enrolled in 
the trial.  If pregnancy is suspected while the subject is taking IMP, the IMP must be 
withheld immediately (if reasonable, taking into consideration any potential withdrawal 
risks) until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for subject safety) and the subject will be withdrawn from the trial.  
The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure during the trial and for 30 days after the last dose of IMP, and record the 
event on the IRE form and forward it to the sponsor.  The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy. 
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered, if indicated.  In addition, the 
investigator must report to the sponsor, on appropriate Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome.  Infants will be followed for a minimum of 6 months from the date of 
birth.  
5.6
Procedure for Breaking the Blind 
Not applicable.  This is an open-label trial.
5.7
Follow-up of Adverse Events 
For this trial, information on AEs will be followed for up to 21 days after the last dose of 
IMP has been administered.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
73


Protocol 331-201-00083
Confidential - Proprietary Information
74
Version 2.0, 20 Oct 2017
5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE ePlatform with the current status noted.  If a subject has an AE or has not recovered 
from an AE at the last scheduled contact, follow-up contacts will be scheduled at least 
every 4 weeks until resolution of the AE is confirmed or the condition is considered 
clinically stable.  All nonserious events that are ongoing at the last scheduled contact will 
be recorded as ongoing on the ePlatform.  For any AE having been identified throughout 
the trial, during analysis, additional relevant medical history information may be 
requested to further ascertain causality (including, but not limited to, information such as 
risk-related behavior, family history and occupation).
5.7.2
Follow-up of Serious Adverse Events
This trial requires that subjects be actively monitored for SAEs up to 21days after the last 
dose of IMP is administered.
Serious AEs that are identified or ongoing at the last scheduled contact must be 
recorded on the AE ePlatform and reported to the sponsor according to the reporting 
procedures outlined in Section 5.3.  This may include unresolved previously reported
SAEs, or new SAEs.  The investigator will follow SAEs until the events are resolved, 
stabilized, or the subject is lost to follow-up.  Resolution means that the subject has 
returned to the baseline state of health and stabilized means that the investigator does not 
expect any further improvement or worsening of the subject’s condition.  The 
investigator will continue to report any significant follow-up information to the sponsor 
up to the point the event has been resolved.
5.7.3
Follow-up and Reporting of Serious Adverse Events Occurring 
after Last Scheduled Contact
Any new SAEs reported by the subject to the investigator that occur after the last 
scheduled contact, and are determined by the investigator to be reasonably associated 
with the use of the IMP, should be reported to the sponsor.  This may include SAEs that 
are captured on follow-up telephone contact or at any other time point after the defined 
trial period (ie, up to last scheduled contact). The investigator should follow SAEs
identified after the last scheduled contact until the events are resolved, stabilized, or the 
subject is lost to follow-up.  The investigator should continue to report any significant 
follow-up information to the sponsor up to the point the event has been resolved or 
stabilized.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
74








Protocol 331-201-00083
Confidential - Proprietary Information
78
Version 2.0, 20 Oct 2017
7.6.2
Physical Examination and Vital Signs Data
Physical examination findings will be listed by subject.  Potentially clinically relevant 
results in vital signs and body weight will also be summarized.
Summary statistics for change from baseline in vital signs, body weight, and waist 
circumference will be provided.
7.6.3
Electrocardiogram Data 
Mean change from baseline will be summarized by visit.
The incidence of clinically relevant changes will be calculated for ECG parameters and 
summarized by visit.
For the analysis of QT and QTc data from 3 consecutive complexes (representing 3 
consecutive heart beats) will be measured to determine average values.  The following 
QT corrections will be used:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett’s formula:  
QTcB=QT/(RR)0.5, and
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
Results will be summarized by visit.
7.6.4
 
 
  
8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the brexpiprazole (OPC-34712) IB.7
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
78
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
79
Version 2.0, 20 Oct 2017
8.1
Packaging and Labeling
The IMP will be provided to the investigators and the persons designated by the 
investigator(s) or institution(s) by the sponsor or designated agent as 1-mg, 2-mg, 3-mg, 
and 4-mg tablets.  The IMP will be supplied as blister cards.  Each blister card used in the 
dosing period will be labeled to include a section for the sites to indicate the subject 
initials and ID, as well as compound ID, trial number, sponsor’s name and address, 
instructions for use, route of administration, and appropriate precautionary statements.
8.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure.  Access will be limited 
to investigators and their designees.  Neither investigators nor any designees may provide 
IMP to any subject not participating in this protocol.
The IMP will be stored according to the storage conditions indicated on the clinical 
label(s).  The clinical site staff will maintain a temperature log in the IMP storage area 
recording the temperature at least once each working day.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially used IMP must be returned to the sponsor or a designated agent, or destroyed at 
the trial site(s) (if applicable). The IMP may only be destroyed by the trial site(s), if 
approved by the sponsor and if the IMP destruction meets all local regulations.
All IMP returned to the sponsor must be accompanied by appropriate documentation and 
be clearly identified by protocol number with trial site number on the outermost shipping 
container.  Returned supplies should be in the original containers (eg, subject kits).  The 
assigned trial monitor will facilitate the return or destruction (if applicable) of used IMP 
containers, unused IMP, and partially-used IMP.
8.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
79


Protocol 331-201-00083
Confidential - Proprietary Information
80
Version 2.0, 20 Oct 2017
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution.  Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor, or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing.  The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail or telephone within 
24 hours of becoming aware of the PQC according to the procedure outlined below.

Online – Send information required for reporting purposes (listed below) to 

Phone 
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
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
80
PPD
PPD


Protocol 331-201-00083
Confidential - Proprietary Information
81
Version 2.0, 20 Oct 2017
8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return.  If 
complaint sample is available for return, return it in the product retrieval package, which
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF.  In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
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;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings.  The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
81


Protocol 331-201-00083
Confidential - Proprietary Information
82
Version 2.0, 20 Oct 2017

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes.
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.
Source documents and source data will be captured electronically in this trial, and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records.  These data will be collected 
into a system that is fully validated.  Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms.  Designated trial site staff will not be given access to 
the system until they have been appropriately trained.  Information to be originally 
captured and reviewed electronically shall include details of the subject visit and the 
protocol-required assessments performed as a part of these visits, medical history, AEs, 
and concomitant medications.  Because this trial is using an electronic source record as 
the original point of data capture, there is no additional data entry step for the trial site for 
data collected directly into the application - rather, the electronic source record directly 
populates the trial database.
Some data may be captured via paper and then entered into the eSource system.  These 
and any other data treated in this manner will be source data verified by the trial clinical 
research associate, and the location of the source data (ie, eSource, paper, or a local 
electronic system) will be documented before the trial start.  Any changes to information 
in paper source documents will be initialed and dated on the day the change is made by a 
trial site staff member authorized to make the change.  Changes will be made by striking 
a single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (eg, wrong data right data).  If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation 
by the clinician.
Another exception will be safety laboratory data, where the official source documentation 
will be considered the report issued by the analyzing laboratory.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
82


Protocol 331-201-00083
Confidential - Proprietary Information
83
Version 2.0, 20 Oct 2017
Remote monitoring of the original electronic source record will take place, however 
on-site monitoring inspections will continue to take place in order to review data entry of 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess trial site operational capabilities and to perform 
other monitoring activities that cannot be performed remotely.
At the end of the trial, the investigator must certify that the data entered into the eSource 
application are complete and accurate.  After database lock, the investigator will receive 
an electronic copy of the subject data.
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline E6 and as required by applicable local regulations. 
The investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods:

A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if IMP development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.

Longer, region-specific storage requirements, if applicable.  
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for sponsor to 
collect such records.  The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities.  
If the investigator withdraws from the trial (eg, due to relocation or retirement), all trial-
related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe.  Notice of such transfer will be given to the sponsor in 
writing.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
83


Protocol 331-201-00083
Confidential - Proprietary Information
84
Version 2.0, 20 Oct 2017
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws.  As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications.  In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented.
10.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of ePlatform with source documents.  The 
investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science guidelines, and applicable local laws and 
regulations. Each trial site will seek approval/favorable opinion by an IRB or IEC
according to regional requirements, and the investigator will provide that documentation 
to the sponsor. The IRB/IEC will evaluate the ethical, scientific and medical 
appropriateness of the trial. Further, in preparing and handling eSource, the investigator, 
sub-investigator and their staff will take measures to ensure adequate care in protecting 
subject privacy. To this end, a subject number and subject identification code will be
used to identify each subject.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
84


Protocol 331-201-00083
Confidential - Proprietary Information
85
Version 2.0, 20 Oct 2017
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region(s) where the trial 
is conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  All IMPs, subject bodily fluids, and/or other 
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the sponsor.
Subjects will be identified only by unique subject numbers in ePlatform.  If further 
subject identification is required, subjects’ full names may be made known to a 
regulatory agency or other authorized officials if necessary, subject to local regulations.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB/IEC. Any 
permanent change to the protocol, whether an overall change or a change for specific trial 
site(s), must be handled as a protocol amendment.  Any amendment will be written by the 
sponsor.  Each amendment will be submitted to the IRB/IEC, as required by local 
regulations.  Except for “administrative” or “non-substantial” amendments, investigators 
will wait for IRB/IEC approval/favorable opinion of the amended protocol before 
implementing the change(s).  Administrative amendments are defined as having no effect 
on the safety of subjects, conduct or management of the trial, trial design, or the quality 
or safety of IMP(s) used in the trial.  A protocol change intended to eliminate an apparent 
immediate hazard to subjects should be implemented immediately after agreement by the 
sponsor and investigator, followed by IRB/IEC notification within local applicable 
timelines.  The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
85


Protocol 331-201-00083
Confidential - Proprietary Information
86
Version 2.0, 20 Oct 2017
subject, the currently approved written ICF will require similar modification.  In such 
cases, after approval/favorable opinion of the new ICF by the IRB/IEC, repeat written 
informed consent will be obtained from subjects enrolled in the trial before expecting 
continued participation and before the amendment-specified changes in the trial are 
implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
15
References
1
American Psychiatric Association. Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition. Washington, DC, American Psychiatric Association, 2013.
2
Fountoulakis KN, Grunze H, Vieta E, Young A, Yatham L, Blier P, et al.  The 
International College of Neuro-Psychopharmacology (CINP) treatment guidelines for 
Bipolar disorder in adults (CINP-BD-2017), part 3: The clinical guidelines. Int J 
Neuropsychopharmacol. 2017;20(2):180-95.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
86






Protocol 331-201-00083
Confidential - Proprietary Information
89
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
89
CCI




Protocol 331-201-00083
Confidential - Proprietary Information
91
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
91
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
92
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
92
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
93
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
93
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
94
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
94
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
95
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
95
CCI




Protocol 331-201-00083
Confidential - Proprietary Information
97
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
97
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
98
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
98
CCI






Protocol 331-201-00083
Confidential - Proprietary Information
101
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
101
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
102
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
102
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
103
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
103
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
104
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
104
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
105
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
105
CCI


Confidential - Proprietary Information
106
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
106
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
107
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
107
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
108
Version 2.0, 20 Oct 2017
Appendix 4
Mini International Neuropsychiatric Interview
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
108


Protocol 331-201-00083
Confidential - Proprietary Information
109
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
109


Protocol 331-201-00083
Confidential - Proprietary Information
110
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
110


Protocol 331-201-00083
Confidential - Proprietary Information
111
Version 2.0, 20 Oct 2017
Appendix 5
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
111


Protocol 331-201-00083
Confidential - Proprietary Information
112
Version 2.0, 20 Oct 2017
Appendix 6
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
112


Protocol 331-201-00083
Confidential - Proprietary Information
113
Version 2.0, 20 Oct 2017
Appendix 7
Criteria for Identifying Electrocardiogram Measurements of 
Potential Clinical Relevance
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
113




Protocol 331-201-00083
Confidential - Proprietary Information
115
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
115
CCI




Protocol 331-201-00083
Confidential - Proprietary Information
117
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
117
CCI




Protocol 331-201-00083
Confidential - Proprietary Information
119
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
119
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
120
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
120
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
121
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
121
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
122
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
122
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
123
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
123
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
124
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
124
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
125
Version 2.0, 20 Oct 2017
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
125
CCI










Protocol 331-201-00083
Confidential - Proprietary Information
130
Version 2.0, 20 Oct 2017
Table 3.7-1
Schedule of Assessments - Open-label Treatment (Phase B) 
Assessment
Screening
/ 
Baselinea
(Rollover)
Phase B 
Baselinea
(De 
Novo)
Open-Label Treatment Phase Trial Week Visit (2 days)
Follow-up
21 (± 2) daysc
1
2
4
8
12
18
26/ ETb
ENTRANCE CRITERIA
Informed consent
Xd
Inclusion/exclusion 
criteria
X
X
Medical history
Xe
SAFETY
Physical examination
Xf
Xg
X
Waist circumference
Xf
Xg
X
Vital signsi
Xf
Xg
X
X
X
X
X
X
X
12-lead ECGj
Xf
Xg
X
X
Clinical laboratory 
testsk
Xf,l
Xg,l
Xm
Xm
HbA1c
Xf,l
Xg,l
Xm
Xm
Drug screen/blood 
alcoholn
Xf
Xg
X
X
X
Urine pregnancy test 
(WOCBP only)o
Xf
Xg
X
X
X
X
X
X
X
SAS 
Xf
Xg
X
X
X
X
X
X
X
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
130
CCI






Protocol 331-201-00083
Confidential - Proprietary Information
133
Version 2.0, 20 Oct 2017
mBlood samples for clinical laboratory tests must be drawn after a minimum 8-hour fast at Week 26/ET and should be drawn after a minimum 8-hour fast at 
all other visits, if possible.  Vital sign and ECG assessments should be completed before any blood samples are collected.
nA 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.  If results of either or both are positive, the investigator must contact the medical monitor to discuss the subject’s eligibility 
for continued participation in the trial.
oAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with positive urine and serum pregnancy test results at screening, 
baseline, or screening/baseline must not be enrolled in Trial 331-201-00083.  Subjects with 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.
 
qAE recording will begin with the signing of the ICF for Trial 331-201-00083.
rAdjustments to the dose of brexpiprazole can be made at scheduled and unscheduled visits during the 26-week open-label treatment phase (ie, Phase B) to 
optimize efficacy and tolerability as described in the protocol.  Subjects must return to the clinic for unscheduled visits if dose adjustments for 
brexpiprazole are required between scheduled visits.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
133
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
134
Version 2.0, 20 Oct 2017
Table 3.7-2
Schedule of Assessments - Screening and Conversion (Phase A):  De Novo Subjects 
The enrollment of de novo subjects at any site will not be permitted until initiation and notification by the sponsor.
Assessment
Screening 
(Days -14 to -1)a
Phase A 
Baseline
Conversion 
Week 1 
(2 days)
Conversion 
Week 2
(2 days)
Conversion 
Week 3
(2 days)
Conversion 
Week 4/ 
Phase B 
Baselineb
(2 days)
ENTRANCE CRITERIA
Informed consentc
X
Inclusion/exclusion criteria
X
X
Medical history
X
Demography
X
Psychiatric history
X
MINI 
X
Prior medication washoutd
X
HIV, HBsAg, and anti-HCV
X
SAFETY
Physical examinatione
X
X
Waist circumference
X
X
Vital signsf
X
X
X
X
X
X
12-lead ECGg
X
X
Clinical laboratory tests (hematology, 
serum chemistry [including prolactin], 
and urinalysis)h
Xi
X
TSH with reflex to free T4 if abnormalh
Xi
X
HbA1ch
Xi
X
X
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
134
CCI




Protocol 331-201-00083
Confidential - Proprietary Information
136
Version 2.0, 20 Oct 2017
with a sufficient amount of time allotted in order to obtain laboratory results prior to baseline.  Review of inclusion/exclusion criteria at baseline will be based on 
some assessments performed during screening.
bIf a subject discontinues early before Week 4, procedures noted for Week 26/ ET must be completed at the ET visit.  Attempts should be made to complete 
ALL evaluations, particularly efficacy assessments for the Week 26/ET visit prior to the administration of any new psychotropic medications.  However, if 
the subject receives a new antipsychotic prior to ET procedures, no efficacy assessments should be done.  Any prohibited medications started before the 
end of the trial assessments should be documented as a protocol deviation in the source notes.
cInformed consent must be obtained before any trial-related procedures are performed.
dWashout of prohibited medications begins after signing the ICF.  Details of medications requiring washout are provided in Section 4.1.  Prohibited and 
restricted medications are also provided in Section 4.1.  In addition, all antipsychotic medications used within 30 days of the first dose of IMP will be 
recorded.
eTo include measurement of height at screening only.
fVital signs include body weight, body temperature, SBP, DBP, and heart rate.  Blood pressure and heart rate will be measured in the following order:  supine 
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.
gStandard 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.  However, ECGs will also be evaluated at the investigational site 
to monitor safety during the trial.  Any screening 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.  ECGs scheduled for the same visit as blood samples are to be completed before blood is drawn.
hBlood samples for clinical laboratory tests must be drawn after a minimum 8-hour fast at screening and Conversion Week 4, if at all possible.  If fasting 
blood samples are not feasible at screening, nonfasting blood samples may be obtained initially for determining eligibility for the trial.  Vital sign and ECG 
assessments should be completed before any blood samples are collected.
iSee Section 3.4.3 for exclusions based on screening laboratory results.
jA 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.  If results of either or both are positive, the investigator must contact the medical monitor to discuss the subject’s eligibility 
for continued participation in the trial.
kAll positive urine pregnancy test results must be confirmed by a serum test.  Subjects with positive urine and serum pregnancy test results at screening must 
not be enrolled.  Subjects with 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.
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
136
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
137
Version 2.0, 20 Oct 2017
mAE recording will begin with the signing of the ICF.
nAll 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 4.1.
oCross-titration will occur over a 4-week period in order to bring about a stable transition from previous antipsychotic treatment(s) to oral brexpiprazole.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
137








Protocol 331-201-00083
Confidential - Proprietary Information
141
Version 2.0, 20 Oct 2017
Section 7.5, Analysis 
of Demographic and
Baseline 
Characteristics
Baseline demographic characteristics 
including age, race, ethnicity, gender, 
weight, height, and body mass index 
(BMI) for the randomized subjects 
will be summarized by descriptive 
statistics (frequency, mean, median, 
standard deviation, maximum, 
minimum, and percentage when 
applicable).
Baseline disease severity and 
psychiatric history will also be 
summarized by descriptive statistics 
for the Safety Sample to identify any 
potential lack of balance between the 
treatment groups.
Baseline demographic characteristics 
including age, race, ethnicity, gender, 
weight, height, and body mass index 
(BMI) will be summarized by 
descriptive statistics (frequency, mean, 
median, standard deviation, maximum, 
minimum, and percentage when 
applicable).
Section 7.6.3, 
Electrocardiogram
Data
Mean change from baseline will be 
summarized by treatment group and 
by visit.
The incidence of clinically relevant 
changes will be calculated for ECG 
parameters and summarized by 
treatment group and by visit.
Mean change from baseline will be 
summarized by visit.
The incidence of clinically relevant 
changes will be calculated for ECG 
parameters and summarized by visit.
 
Appendix 5, Criteria 
for Identifying 
Laboratory Values of 
Potential Clinical 
Relevance
Laboratory test criteria updated to match text of the protocol.
 
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
141
CCI
CCI


Protocol 331-201-00083
Confidential - Proprietary Information
142
Version 2.0, 20 Oct 2017
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, OPC-34712, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) or receive a 
favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in the 
clinical trial facility where OPC-34712 will be tested prior to commencement of this trial. I agree to 
adhere strictly to the attached protocol (unless amended in the manner set forth in the sponsor's 
Clinical Trial Agreement, at which time I agree to adhere strictly to the protocol as amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways, such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor and designee monitors and 
auditors full access to all medical records at the research facility for subjects screened or enrolled 
in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.1 Protocol and Protocol Amendments
142



SAP_003.pdf: 
Protocol 331-201-00083 
Confidential - Proprietary Information 
Protocol number: 331-201-00083
Document title: A Multicenter, Open-label Trial to Evaluate the 
Safety and Tolerability of Brexpiprazole in the Treatment of 
Subjects with Bipolar I Disorder
Version number: 2.0
Date of the document: 17 July 2019
NCT number:    NCT03287869


SAP 331-201-00083
Confidential - Proprietary Information  
1
10 July 2019
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational New Drug
Brexpiprazole (OPC-34712)
A Multicenter, Open-label Trial to Evaluate the Safety and Tolerability of Brexpiprazole in 
the Treatment of Subjects with Bipolar I Disorder
Protocol No. 331-201-00083
IND No. 134115
EudraCT No. 2017-002225-38
Statistical Analysis Plan
Version: Final
Date: July 10, 2019
CONFIDENTIAL – PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
1


SAP 331-201-00083
Confidential - Proprietary Information  
2
10 July 2019
Table of Contents
Table of Contents.......................................................................................... 2
1
Introduction.......................................................................................... 4
2
Study Objectives .................................................................................. 4
3
Trial Details.......................................................................................... 4
3.1
Study Design ...................................................................................................... 4
3.2
Trial Treatments ................................................................................................. 7
4
Sample Size and Power Justification ................................................. 8
5
Data Sets for Analysis and Missing Data........................................... 8
5.1
Data Sets for Analysis ........................................................................................ 8
5.2
Handling of Missing Data................................................................................... 8
6
Study Conduct...................................................................................... 8
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation .......... 8
6.2
Treatment Compliance ....................................................................................... 9
7
Baseline Characteristics...................................................................... 9
7.1
Baseline Definition............................................................................................. 9
7.2
Demographic Characteristics.............................................................................. 9
7.3
Baseline Psychiatric Evaluation ......................................................................... 9
8
Efficacy Analysis.................................................................................. 9
9
Safety Analysis ................................................................................... 11
9.1
Adverse Events................................................................................................. 12
9.2
Clinical Laboratory Tests ................................................................................. 13
9.2.1
Drug Induced Liver Injury (DILI) ................................................................. 13
9.2.2
Metabolic Change.......................................................................................... 13
9.3
Physical Examination and Vital Signs Data..................................................... 14
9.4
12-Lead ECG.................................................................................................... 15
16
9.6
Concomitant Medications................................................................................. 16
9.7
Extent of Exposure ........................................................................................... 17
17
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
2
CCI
CCI


SAP 331-201-00083
Confidential - Proprietary Information  
3
10 July 2019
10
Conventions........................................................................................ 17
11
Potential Clinical Relevance Criteria from Protocol ..................... 22
12
Proposed List of Summary Tables................................................... 25
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
3
CCI
CCI
CCI
CCI


SAP 331-201-00083
Confidential - Proprietary Information  
4
10 July 2019
1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data analysis 
algorithms and conventions to be applied for statistical analysis and reporting of efficacy and 
safety data of study 331-201-00083.  All amendments to the protocol are taken into 
consideration in developing this SAP.
2
Study Objectives
The purpose of this trial is to assess the safety and tolerability of brexpiprazole (OPC-34712) 
in the treatment of subjects with bipolar I disorder.
3
  Trial Details
3.1
Study Design
This is a multicenter, open-label trial designed to assess the safety and tolerability of oral 
brexpiprazole (OPC-34712) (2-4 mg/day) as treatment in adults with bipolar I disorder.  The 
trial will be conducted on an outpatient basis.  Enrollment into the trial will be drawn from 
eligible subjects who will include subjects who completed the 3-week treatment in the double-
blind, phase 3 efficacy trials (ie, Trials 331-201-00080 or 331-201-00081) and, in the 
investigator’s judgment, could potentially benefit from treatment with oral brexpiprazole
(OPC-34712) for bipolar I disorder.  In the event the sponsor determines that the enrollment 
rate of rollover subjects will not be sufficient to meet the target completion of approximately 
175 subjects at 6 months, de novo subjects may be enrolled at select sites. The enrollment of 
de novo subjects at any site will not be permitted until initiation and notification by the 
sponsor.
The trial will be organized as follows:
Rollover Subjects:
Screening/Baseline:  Subjects who completed Day 21 of the double-blind trial and had no 
major protocol deviation will be screened for eligibility at the last visit of the double-blind 
trial (i.e., Week 3 [Day 21] visit of Trials 331-201-00080 or 331-201-00081).  Subjects will 
sign a separate informed consent form (ICF) for participation in Trial 331-201-00083 before 
any procedures specific to the open-label trial are performed.  The assessments from the last 
visit of the double-blind trial will serve as the baseline measures for Trial 331-201-00083 for 
any assessment that is not unique to the open-label trial.  Medical history will be updated, if 
necessary.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
4


SAP 331-201-00083
Confidential - Proprietary Information  
5
10 July 2019
Open-label Treatment Phase:  Eligible subjects from Trials 331-201-00080 or 331-201-00081 
will receive 26 weeks of daily treatment with open-label brexpiprazole (OPC-34712) (2-4 
mg/day) in open-label treatment phase of Trial 331-201-00083, as described in Section 3.2.  
Visits will occur at the end of Weeks 1, 2, 4, 8, 12, 18, and 26.  
Follow-up:  Subjects will be followed up for safety via telephone contact or clinic visit 21 (± 
2) days after the last dose of open-label investigational medicinal product (IMP).
De Novo Subjects
There are no de novo subjects enrolled in the study.
See Figure 3.1-1 for schematics of the trial design for rollover subjects.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
5


SAP 331-201-00083
Confidential - Proprietary Information
6
10 July 2019
Figure 3.1-1
Trial Design Schematic - Rollover Subjects
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
6


SAP 331-201-00083
Confidential - Proprietary Information
7
10 July 2019
3.2
Trial Treatments
Rollover Subjects

The first dose of open-label brexpiprazole (OPC-34712) will be taken one day after the 
last dose of double-blind IMP is taken in Trials 331-201-00080 or 331-201-00081 so that 
treatment continues without interruption.  It is anticipated that the last dose of the double-
blind, phase 3 efficacy trial will be taken the day of the Day 21 (Week 3) visit of Trial 
331-201-00080 or 331-201-00081 (ie, the day of the screening/baseline visit for the open-
label trial).

All subjects will start on 2 mg/day of brexpiprazole (OPC- 34712) regardless of treatment 
assignment in the double-blind trial.
All subjects will receive a starting dose of 2 mg/day of brexpiprazole from Days 1 to 3, 
followed by titration to 3 mg/day brexpiprazole on Day 4.  Subjects may be titrated (or re-
titrated) to a higher dose of brexpiprazole, up to a maximum of 4 mg/day, based on treatment 
response and at the investigator’s discretion anytime at Day 7 or thereafter.  Subjects who are 
unable to tolerate their current dose can be titrated down at any time to a minimum of 2 
mg/day.  Dose adjustments must be made in increments of 1 mg/day.  Subjects who are 
unable to tolerate 2 mg/day brexpiprazole will be discontinued from the trial.
The dosing strategy is summarized in Table 3.2.2.1-1.  Subjects must return to the clinic for 
unscheduled visits if dose adjustments for brexpiprazole are required between scheduled 
visits.  Dose adjustments must ultimately be made based upon the clinical judgment of the 
investigator as it relates to tolerability and therapeutic response.  All doses of brexpiprazole 
should be taken orally once daily and can be administered without regard to meals.  Subjects 
are to take IMP at approximately the same time each day.
Table 3.2.2.1-1
Dosing Schedule - Open-label Treatment Phase
IMP
Trial Visit
Days 1-3
Day 4a
Day 7-Week 26
Brexpiprazole 
(OPC-34712)
2 mg/day
3 mg/day
2-4 mg/dayb
aDown titration can occur at any time due to tolerability after Day 4.  The minimum dose allowed is 
2 mg/day.
bOption to titrate to 2 to 4 mg  (ie, 2 mg, 3 mg, or 4 mg) based on clinical response and 
tolerability; changes must occur in 1 mg/day increments.  Increases up to 4 mg/day may occur 
no earlier than Day 7.  
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
7


SAP 331-201-00083
Confidential - Proprietary Information
8
10 July 2019
4
Sample Size and Power Justification
The sample size is not based on statistical power considerations but on ICH/GCP 
requirements.  The trial population will be derived from eligible subjects from the double-
blind, phase 3 trials (ie, Trials 331-201-00080 and 331-201-00081). In the event the sponsor 
determines that the enrollment rate of rollover subjects will not be sufficient to meet the target 
completion of approximately 175 subjects at 6 months, de novo subjects may be enrolled at 
selected sites. The enrollment of de novo subjects at any site will not be permitted until 
initiation and notification by the sponsor.
5
Data Sets for Analysis and Missing Data 
5.1
Data Sets for Analysis
The following datasets are defined for this trial:  

Enrolled Sample, which comprises all subjects who sign an ICF for the trial.

Safety Sample, which comprises all subjects who will receive at least 1 dose of IMP.
 
 
 
 
 
 
 
 
6
Study Conduct
There are no de novo subjects enrolled in the study.
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation
Subject disposition will be summarized for the Enrolled Sample by parent study treatment 
group for rollover subjects and overall. 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
8
C
C
I
CCI






SAP 331-201-00083
Confidential - Proprietary Information
11
10 July 2019
 
 
 
 
 
 
 
 
 
 
 
 
9
Safety Analysis
The primary safety endpoint analysis is the frequency and severity of AEs in the open-label 
treatment phase (see Section 9.1). Other standard safety variables to be analyzed include 
clinical laboratory tests, vital signs, body weight, waist circumference, BMI, 12-lead 
electrocardiograms (ECGs), and physical examinations.  
 
 
Safety analyses will be conducted based on the Safety Sample, and summary statistics will be 
provided by parent study treatment group for rollover subjects and overall, unless otherwise 
indicated. 
Unless otherwise specified, in general, analysis of safety data will be performed on observed 
case and for last visit.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
11
C
C
I
CCI


SAP 331-201-00083
Confidential - Proprietary Information
12
10 July 2019
9.1
Adverse Events
All adverse events will be coded by System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs that are sex-
specific, e.g., ovarian cancer, will have their incidence rates evaluated for the specific sex.
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the first 
dose of IMP. In more detail, TEAEs are all adverse events which started after start of IMP; or 
if the event was continuous from baseline and was worsening, serious, study drug related, or 
resulted in death, discontinuation, interruption or reduction of study therapy. Adverse events 
occurring up to 21 days after the last day of IMP will be included in the summary tables.
The incidence of the following events in the open-label treatment phase will be summarized
using the Safety Sample:
a) TEAEs
b) TEAEs by severity
c) TEAEs potentially causally related to the IMP
d) TEAEs with an outcome of death
e) Serious TEAEs
f)
TEAEs leading to discontinuations of the IMP
The above summaries (b), (e) and (f) will also be prepared for TEAEs potentially causally 
related to the IMP.
In addition, incidence of TEAE during the open-label 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, age and region
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 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
12


SAP 331-201-00083
Confidential - Proprietary Information
13
10 July 2019
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.
9.2
Clinical Laboratory Tests
Summary statistics for mean and mean change from baseline in the routine clinical laboratory 
measurements, prolactin concentrations, and HbA1c will be provided. Potentially clinically 
relevant results in laboratory tests will also be summarized.
Potentially clinically relevant laboratory measurement test results in the open-label treatment 
phase will be identified, summarized, and listed. Criteria for identifying laboratory values of 
potential clinical relevance are provided in  Appendix 2.
9.2.1
Drug Induced Liver Injury (DILI)
Total bilirubin level should be checked for any subject with increased ALT or AST levels 
three times the upper normal limits (ULN) or baseline. 

Reporting all DILI as SAE to the FDA based on Hy's Law: 
AST or ALT > 3 x ULN or baseline and 
T_Bili > 2 x ULN or baseline
A separate incidence table will be provided for DILI cases, and the corresponding listing will 
be provided for Safety Sample during the open-label treatment phase.
9.2.2
Metabolic Change
In addition to mean change from baseline, incidence of treatment emergent significant 
changes in fasting lipids, fasting glucose, and metabolic syndrome will be summarized by 
parent study treatment group for rollover subjects and overall using the following criteria.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
13


SAP 331-201-00083
Confidential - Proprietary Information
14
10 July 2019
Criteria for Treatment-Emergent Significant Change in Lipids and Glucose
LAB PARAMETER
BASELINE¹
ANYTIME POST BASELINE     
LDL Direct, Fasting  
(MG/DL)
Borderline 100-<160   
Normal/Borderline <160
Normal <100           
Any Value             
High >=160            
High >=160            
Borderline/High >=100 
Increased >=30        
HDL Cholesterol, Fasting 
(MG/DL)
Normal >=40  
Any Value    
Low <40            
Decreased >=20     
Triglycerides, Fasting  
(MG/DL)   
Normal <150           
Borderline 150-<200   
Normal/Borderline <200
Normal <150           
Any Value    
High 200-<500             
High 200-<500             
High 200-<500             
Borderline/High/Very High >=150       
Increased >=50            
Glucose Fasting, Serum  
(MG/DL)   
Normal <100           
Impaired 100-<126     
Normal/Impaired <126  
Any Value             
High >=126       
High >=126       
High >=126       
Increased >=10   
    ¹ BASELINE IS DEFINED AS THE LAST AVAILABLE MEASUREMENT PRIOR TO THE FIRST DOSE OF OPEN-LABEL IMP IN THE OPEN-
LABEL TREATMENT PHASE       
Criteria for Treatment-Emergent Metabolic Syndrome
DESCRIPTION
ANYTIME POST BASELINE¹     
Central Obesity        
                       
Dyslipidemia           
                       
Dyslipidemia           
                       
Supine Blood Pressure  
                       
Glucose Fasting, Serum
Waist Circumference >=102cm(MALE), >=88cm (FEMALE)    
                                                     
Triglycerides >= 150mg/dl                            
                                                     
HDL < 40mg/dl (MALE), <50mg/dl (FEMALE)              
                                                     
Systolic>=130mmHg and Diastolic>=85mmHg              
                                                     
>=100mg/dl                                           
Metabolic Syndrome             
Met 3 Or More of the Above Criteria at a Visit
    ¹ BASELINE IS DEFINED AS THE LAST AVAILABLE MEASUREMENT PRIOR TO THE FIRST DOSE OF OPEN-LABEL IMP IN THE OPEN-
LABEL TREATMENT PHASE
9.3
Physical Examination and Vital Signs Data
Summary statistics for changes from baseline in vital signs will be provided for the Safety 
Sample. By-patient listings will be provided for physical examination.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
14


SAP 331-201-00083
Confidential - Proprietary Information
15
10 July 2019
Potentially clinically relevant vital signs measurements identified in the open-label treatment 
phase for the Safety Sample will be listed and summarized. Criteria for identifying vital signs 
of potential clinical relevance are provided in Appendix 1.
In addition, the change from baseline in weight, BMI, and waist circumference, and 
potentially clinically relevant abnormalities in weight, will also be summarized.
9.4
12-Lead ECG
Summary statistics and incidence of potentially clinically relevant changes will be provided 
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 and
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
Potentially clinically relevant changes in the 12-lead ECG identified in the open-label 
treatment phase for the Safety Sample will be listed and summarized. Criteria for identifying 
ECG measurements of potential clinical relevance are provided in Appendix 3.
Categorical changes in ECG parameters during the open-label treatment phase will be 
summarized based on the following criteria:
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
for men and ≥470 Msec
for women)
New onset (≥450 Msec for men and (≥470 Msec
for women) in QTc means a subject who attains a 
value ≥450 Msec for men or ≥470 Msec for 
women during treatment period but not at baseline.
New Onset (≥450 Msec
for men and ≥470 Msec
for women) 
And > 10% Increase
New onset (≥450 Msec for men and ≥470 Msec for 
women) and 
> 10% increase in QTc means a subject who attains 
a value ≥450 Msec for men or  ≥470 Msec for 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
15


SAP 331-201-00083
Confidential - Proprietary Information
16
10 July 2019
Categorical Change Criteria in QT/QTc Parameters
Classification
Category
Criteria 
women, 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.
 
 
 
 
 
 
 
 
 
 
                                                  
 
9.6
Concomitant Medications
Number and proportion of patients taking concomitant medications prior to the open-label 
treatment phase, during the open-label treatment phase, and after study therapy are tabulated by 
drug classification using the WHO drug dictionary.    
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
16
CCI


SAP 331-201-00083
Confidential - Proprietary Information
17
10 July 2019
9.7
Extent of Exposure
The start date of the open-label study therapy - brexpiprazole - will be the first day of dosing
during the open-label treatment phase. The number and percentage of patients who receive
study medication during the open-label treatment phase, will be presented by week. Each 
dosing week will be based on the actual week; i.e., Day 1-7 in Week 1, Day 8-14 in Week 2, 
etc. This summary will be performed on the Safety Sample. 
The mean daily dosage will be summarized by week using descriptive statistics. The mean 
daily dosage per patient per week will be determined for each week of the study. This will be 
calculated by dividing the sum of individual total doses by the number of days in the week 
interval. The summary will contain the number of patients receiving study medication during 
the open-label treatment phase, and the mean and range of the mean daily dose for each week.
 
 
 
 
 
10 Conventions
 
 
 
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
17
CCI
CCI




SAP 331-201-00083
Confidential - Proprietary Information
19
10 July 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
19
CCI


SAP 331-201-00083
Confidential - Proprietary Information
20
10 July 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
20
CCI


SAP 331-201-00083
Confidential - Proprietary Information
21
10 July 2019
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
21
CCI


SAP 331-201-00083
Confidential - Proprietary Information
22
10 July 2019
11 Potential Clinical Relevance Criteria from Protocol
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).
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
22


SAP 331-201-00083
Confidential - Proprietary Information
23
10 July 2019
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
Lactate dehydrogenase (LDH)
3 x ULN
Blood urea nitrogen (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
Creatine phosphokinase (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
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
23


SAP 331-201-00083
Confidential - Proprietary Information
24
10 July 2019
Appendix 3
Criteria for Identifying ECG Measurements of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rate
Tachycardia
120 bpm
increase of  15 bpm
Bradycardia
50 bpm
decrease of 15 bpm
Rhythm
Sinus tachycardiab
120 bpm
increase of 15 bpm
Sinus bradycardiac
50 bpm
decrease of 15 bpm
Supraventricular premature beat
all
not present present
Ventricular premature beat
all
not present present
Supraventricular tachycardia
all
not present present
Ventricular tachycardia
all
not present present
Atrial fibrillation
all
not present present
Atrial flutter
all
not present present
Conduction
1atrioventricular block
PR 200 msec
increase of  50 msec
2atrioventricular block
all
not present present
3atrioventricular block
all
not present present
Left bundle-branch block
all
not present present
Right bundle-branch block
all
not present present
Pre-excitation syndrome
all
not present present
Other intraventricular conduction blockd
QRS 120 msec
increase of 20 msec
Infarction
Acute or subacute
all
not present present
Old
all
not present present
12 weeks post 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
(men)
QTcF 470 msec
(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.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
24






SAP 331-201-00083
Confidential - Proprietary Information
27
10 July 2019
 
 
 
 
 
 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
27
CCI


SAP 331-201-00083
Confidential - Proprietary Information
28
10 July 2019
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
28
CCI


This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 331-201-00083_Statistical_Analysis_Plan
Document Number: 1000042182
Document Version: 2.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Biostatistics Approval
11-Jul-2019
02:41:29
Clinical Approval
17-Jul-2019
00:06:42
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 331-201-00083
16.1.9 Documentation of Statistical Methods
29
PPD
PPD