Conditions: Bipolar I Disorder Manic Episode
Keywords: Brexpiprazole Bipolar Manic episode
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 322
Healthy volunteers: no

Brief summary:
To demonstrate the efficacy of brexpiprazole for the acute treatment of manic episodes, with or without mixed features, in participants with a diagnosis of bipolar I disorder.

Detailed description:
A multicenter, randomized, double-blind trial of brexpiprazole versus placebo for the acute treatment of manic episodes, with or without mixed features, associated with bipolar I disorder. This study also demonstrated the safety and tolerability of brexpiprazole in the study population of males and females aged 18 to 65 years (inclusive, at time of consent).

Arms:
arm 1: Participants received a starting dose of 2 milligrams (mg)/day brexpiprazole from Days 1 to 3, 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. arm 2: Matching placebo was administered in the same way as brexpiprazole to maintain the blind.

Interventions: intervention 1: Brexpiprazole intervention 2: Placebo
Intervention descriptions: intervention 1: Brexpiprazole was administered orally with flexible dosing from 2 to 4 mg/day; titrated to a maximum of 4 mg/day for 3 weeks. intervention 2: Administered orally daily for 3 weeks.

Protocol document:
Prot_000.pdf: 
Protocol 331-201-00080 


Protocol number: 331-201-00080 
Document title: A Multicenter, Randomized, Double-blind Trial of 
Brexpiprazole Versus Placebo for the Acute Treatment of Manic 
Episodes, With or Without Mixed Features, Associated With 
Bipolar I Disorder 
Version number: 2.0 
Date of the document:21Dec2017 


NCT number: NCT03259555 
Confidential - Proprietary Information 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Otsuka Pharmaceutical Development & Commercialization, Inc. 
Investigational Medicinal Product 
Brexpiprazole (OPC-34712) 
CLINICAL PROTOCOL 
A Multicenter, Randomized, Double-blind Trial of Brexpiprazole versus Placebo for the 
Acute Treatment of Manic Episodes, With or Without Mixed Features, Associated With 
Bipolar I Disorder 
Protocol No. 331-201-00080 
IND No. 134115 
EudraCT No. 2017-002222-20 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Clinical Development Phase: 
3 
Sponsor: 
Otsuka Pharmaceutical Development & 
Commercialization, Inc. 
2440 Research Boulevard 
Rockville, Maryland 20850, United States 
Immediately Reportable Event 
INC Research Pharmacovigilance & Drug 
Safety 
PPD 
Fax: 
PPD 
E-mail: 
Issue Dates: 
Original Protocol: 
Date of Amendment 1: 
24 May 2017 
21 Dec 2017 
Version No.: 
2.0 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka. 
1 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Protocol Synopsis 
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2 
Name of Sponsor: Otsuka Pharmaceutical 
Development & Commercialization, Inc. 
Name of Investigational Medicinal Product: 
Brexpiprazole (OPC-34712) 
 
Protocol No.: 
331-201-00080 
IND No.: 134115 
EudraCT No.: 
2017-002222-20 
Protocol Title: 
A Multicenter, Randomized, Double-blind Trial of 
Brexpiprazole versus Placebo for the Acute Treatment of 
Manic Episodes, With or Without Mixed Features, Associated 
With Bipolar I Disorder 
Clinical Phase/Trial 
Phase 3/Therapeutic use 
Type: 
 
Treatment Indication: Bipolar I disorder 
Objective(s): 
Primary: 
To demonstrate the efficacy of brexpiprazole for the acute 
treatment of manic episodes, with or without mixed features, 
in subjects with a diagnosis of bipolar I disorder. 
Secondary: 
To demonstrate the safety and tolerability of brexpiprazole in 
this same population. 
Trial Design: 
Multicenter, randomized, double-blind, placebo-controlled 
Subject Population: 
Men and women 18 to 65 years of age with a Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition 
diagnosis of bipolar I disorder displaying an acute manic 
episode with or without mixed features requiring 
hospitalization will be enrolled in the trial. Approximately 
60% of subjects will be randomized in North America and 
40% in Europe. 
Inclusion/Exclusion 
Subjects with bipolar I disorder, diagnosis will be confirmed 
Criteria: 
by the Mini International Neuropsychiatric Interview (MINI) 
and a history of at least 1 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. Eligible subjects must 
have a Young-Mania Rating Scale (YMRS) score ≥ 24 at 
screening and baseline. 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Trial Site(s): 
It is planned that approximately 320 subjects will be 
randomized into the trial at approximately 45 trial sites in 
North America and Europe. 
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration: 
During the double-blind period, subjects will receive a 
starting dose of 2 mg/day of brexpiprazole (or corresponding 
placebo) from Days 1 to 3, followed by titration to 3 mg/day 
brexpiprazole (or placebo) on Day 4. Subjects may be titrated 
(or re-titrated) to a higher dose of brexpiprazole (or placebo), 
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. 
Trial Assessments: 
Efficacy: YMRS, Clinical Global Impression-Bipolar 
(CGI-BP), CCI 
CCI 
CCI 
Safety: Adverse event (AE) reporting, clinical laboratory 
tests, 12-lead electrocardiogram (ECG), vital signs, body 
Screening/Other: Medical, psychiatric, and medication 
history, urine drug and alcohol screening, serum pregnancy 
test, MINI, lithium, valproate, and carbamazepine levels. 
Criteria for 
Evaluation: 
Primary Endpoint: Change from Baseline to Day 21 of the 
double-blind treatment phase in the YMRS Total Score 
Key Secondary Endpoint: Change from Baseline to Day 21 
in the double-blind treatment period in CGI-BP severity score 
in mania 
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CCI 
weight, physical examination (PE), CCI 
 
 
and CCI 
 
 
 
 
 
 
 
 
 
 
 
 
and 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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Safety Endpoints: 
Standard safety variables will include AEs, clinically 
significant changes in: ECGs, vital signs, clinical laboratory 
tests, use of concomitant medications, changes in body 
weight, and PE. 
Suicidality will be assessed using the C-SSRS. 
Statistical Methods: 
For analysis of the double-blind treatment phase data, 
baseline is defined as the last available measurement prior to 
the first dose of double-blind IMP. The primary analysis will 
be performed on the Efficacy Sample which includes all 
randomized subjects who took at least 1 dose of IMP in the 
double-blind treatment phase and who have both a baseline 
CCI 
 
 
 
 
 
 
 
 
 
CCI 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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5 
value and at least 1 post-randomization YMRS Total Score 
during the double blind treatment phase. CCI 
The primary efficacy endpoint is the change from baseline to 
Day 21 in the double-blind treatment phase in the YMRS 
Total Score. The trial will compare the placebo arm to the 
brexpiprazole arm, randomized at a ratio of 1:1, with an 
overall significance level of 0.05 for the primary endpoint. 
CCI 
The planned sample size of 304 
evaluable subjects (152 in each treatment arm) will yield at 
least 90% power to detect the treatment effects at a 2-tailed 
significance level of 0.05. 
A sufficient number of subjects will be enrolled and 
randomized to achieve approximately 304 evaluable subjects 
(160 in each treatment arm). 
In order to ensure 304 evaluable subjects, CCI 
 
 
 
 
 
 
in the double-blind treatment phase CCI 
the total number of subjects to be randomized is 320 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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CCI 
 
 
 
Trial Duration: 
The duration of this trial for an individual subject who 
completes the trial without early withdrawal is approximately 
8 weeks. This is inclusive of a maximum 14-day screening 
period, a 3-week double-blind treatment period, and a safety 
follow-up via telephone contact or clinic visit 21 (± 2) days 
after the last dose of IMP. Subjects who complete all trial 
visits through the Day 21 visit may be offered entry into an 
optional open-label rollover trial. 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Table of Contents 
Protocol Synopsis ......................................................................................... 2 
Table of Contents ......................................................................................... 7 
List of In-text Tables.................................................................................. 12 
List of In-text Figures ................................................................................ 13 
List of Appendices ...................................................................................... 14 
List of Abbreviations and Definitions of Terms ..................................... 15 
1 
1.1 
1.2 
1.3 
2 
2.1 
2.2 
2.3 
3 
3.1 
3.2 
3.3 
3.3.1 
3.3.2 
3.4 
3.4.1 
3.4.2 
3.4.3 
3.5 
3.5.1 
3.5.2 
3.5.3 
3.5.4 
3.5.5 
Introduction ....................................................................................... 17 
Nonclinical Data ............................................................................................... 17 
Clinical Data ..................................................................................................... 18 
Known and Potential Risks and Benefits .......................................................... 18 
Trial Rationale and Objectives ........................................................ 19 
Trial Rationale .................................................................................................. 19 
Dosing Rationale ............................................................................................... 19 
Trial Objectives ................................................................................................. 20 
Trial Design ....................................................................................... 20 
Type/Design of Trial ......................................................................................... 20 
Trial Treatments ................................................................................................ 24 
Trial Population ................................................................................................ 24 
Number of Subjects and Description of Population ....................................... 24 
Subject Selection and Numbering .................................................................. 25 
Eligibility Criteria ............................................................................................. 25 
Informed Consent ........................................................................................... 25 
Inclusion Criteria ............................................................................................ 26 
Exclusion Criteria ........................................................................................... 27 
Endpoints .......................................................................................................... 30 
Primary Endpoint ........................................................................................... 30 
Secondary Endpoints ...................................................................................... 30 
31 
31 
Safety Endpoints............................................................................................. 31 
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7 
CCI 
CCI 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
3.5.6 
3.6 
3.7 
3.7.1 
3.7.1.1 
3.7.1.2 
3.7.1.3 
3.7.1.4 
3.7.1.5 
3.7.1.6 
3.7.1.7 
3.7.1.8 
3.7.2 
3.7.2.1 
3.7.2.2 
3.7.2.3 
3.7.2.4 
3.7.2.4.1 
3.7.2.4.2 
3.7.3 
3.7.3.1 
3.7.3.2 
3.7.3.3 
3.7.3.3.1 
3.7.3.3.2 
3.7.3.4 
3.7.3.5 
3.7.3.5.1 
3.7.3.5.2 
3.7.3.5.3 
3.7.3.5.4 
3.7.3.5.5 
.32 
Measures to Minimize/Avoid Bias ................................................................... 32 
Trial Procedures ................................................................................................ 32 
Schedule of Assessments ............................................................................... 37 
Screening (Day -14 to -1) ........................................................................... 37 
Baseline (Day 1) ......................................................................................... 38 
Randomization ............................................................................................ 39 
Treatment Phase - Day 4 ............................................................................. 39 
Treatment Phase - Day 7 ............................................................................. 39 
Treatment Phase - Day 14 ........................................................................... 40 
End of Treatment Phase - Day 21/Early Termination Visit ........................ 40 
Post-treatment Follow-up Period ................................................................ 41 
Efficacy Assessments ..................................................................................... 41 
Young-Mania Rating Scale ......................................................................... 42 
Clinical Global Impression - Bipolar Version ............................................ 42 
42 
Other Assessments ...................................................................................... 42 
Mini International Neuropsychiatric Interview ....................................... 42 
.43 
Safety Assessments ........................................................................................ 43 
Adverse Events ........................................................................................... 43 
Clinical Laboratory Assessments ................................................................ 43 
Physical Examination and Vital Signs ........................................................ 45 
Physical Examination .............................................................................. 45 
Measurement of Vital Signs .................................................................... 46 
Electrocardiogram Assessments ................................................................. 46 
Other Safety Assessments ........................................................................... 47 
47 
48 
48 
Columbia-Suicide Severity Rating Scale ................................................ 49 
49 
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8 
CCI 
CCI 
CCI 
CCI 
.
CCI 
CCI 
CCI 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
3.7.4 
3.7.5 
3.7.5.1 
3.7.6 
3.7.7 
3.7.8 
3.8 
3.8.1 
3.8.2 
3.8.3 
3.8.3.1 
3.8.3.2 
3.8.3.3 
3.8.3.4 
3.8.3.5 
3.9 
3.10 
3.11 
3.12 
3.13 
Prior and Concomitant Medications ............................................................... 49 
CCI 
50 
50 
50 
CCI 
CCI 
End of Trial .................................................................................................... 50 
Independent Data Monitoring Committee ...................................................... 50 
Stopping Rules, Withdrawal Criteria, and Procedures...................................... 50 
Entire Trial ..................................................................................................... 50 
Individual Site ................................................................................................ 51 
Individual Subject Discontinuation ................................................................ 51 
Treatment Interruption ................................................................................ 51 
Treatment Discontinuation ......................................................................... 51 
Documenting Reasons for Treatment Discontinuation ............................... 51 
Withdrawal of Consent ............................................................................... 52 
Procedures to Encourage Continued Trial Participation ............................. 53 
Screen Failures .................................................................................................. 53 
Definition of Completed Subjects ..................................................................... 53 
Definition of Subjects Lost to Follow-up ......................................................... 54 
Subject Compliance .......................................................................................... 54 
Protocol Deviations ........................................................................................... 54 
4 
4.1 
4.1.1 
4.2 
5 
5.1 
5.2 
5.3 
5.4 
5.5 
5.6 
5.7 
Restrictions ........................................................................................ 55 
Prohibited Medications ..................................................................................... 55 
Use of Benzodiazepines During the Trial....................................................... 57 
Other Restrictions ............................................................................................. 58 
Reporting of Adverse Events ........................................................... 58 
Definitions ........................................................................................................ 58 
Eliciting and Reporting Adverse Events ........................................................... 60 
Immediately Reportable Events ........................................................................ 61 
Potential Serious Hepatotoxicity ....................................................................... 61 
Pregnancy .......................................................................................................... 61 
Procedure for Breaking the Blind ..................................................................... 63 
Follow-up of Adverse Events ........................................................................... 63 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
5.7.1 
5.7.2 
5.7.3 
Follow-up of Nonserious Adverse Events ...................................................... 63 
Follow-up of Serious Adverse Events ............................................................ 64 
Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact .................................................................................. 64 
6 
7 
7.1 
7.2 
7.3 
7.4 
7.4.1 
7.4.2 
7.4.3 
7.4.4 
7.4.5 
7.5 
7.6 
7.6.1 
7.6.2 
7.6.3 
7.6.4 
7.6.5 
8 
8.1 
8.2 
8.3 
8.4 
8.5 
8.5.1 
8.5.2 
8.5.3 
8.5.4 
64 
Statistical Analysis ............................................................................ 65 
Sample Size ....................................................................................................... 65 
Datasets for Analysis ........................................................................................ 65 
Handling of Missing Data ................................................................................. 66 
Primary and Secondary Endpoint Analyses ...................................................... 68 
Primary Endpoint Analysis ............................................................................ 68 
Secondary Endpoint Analysis ........................................................................ 69 
70 
70 
Interim Analysis ............................................................................................. 70 
Analysis of Demographic and Baseline Characteristics ................................... 70 
Safety Analysis ................................................................................................. 70 
Adverse Events ............................................................................................... 71 
Clinical Laboratory Data ................................................................................ 71 
Physical Examination and Vital Signs Data ................................................... 71 
Electrocardiogram Data .................................................................................. 71 
72 
Management of Investigational Medicinal Product ...................... 72 
Packaging and Labeling .................................................................................... 72 
Storage .............................................................................................................. 72 
Accountability ................................................................................................... 73 
Returns and Destruction .................................................................................... 73 
Reporting of Product Quality Complaints ........................................................ 73 
Eliciting and Reporting Product Quality Complaints ..................................... 74 
Information Required for Reporting Purposes ............................................... 74 
Return Process ................................................................................................ 74 
Assessment/Evaluation ................................................................................... 74 
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CCI 
CCI 
CCI 
CCI 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
9 
9.1 
9.2 
9.3 
9.4 
10 
10.1 
10.2 
11 
12 
13 
14 
15 
Records Management ....................................................................... 75 
Source Documents ............................................................................................ 75 
Data Collection ................................................................................................. 75 
File Management at the Trial Site ..................................................................... 76 
Records Retention at the Trial Site ................................................................... 77 
Quality Control and Quality Assurance ......................................... 77 
Monitoring ........................................................................................................ 77 
Auditing ............................................................................................................ 78 
Ethics and Responsibility ................................................................. 78 
Confidentiality ................................................................................... 78 
Amendment Policy ............................................................................ 79 
Publication Authorship Requirements ........................................... 79 
References .......................................................................................... 80 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
List of In-text Tables 
Dosing Schedule ............................................................................ 24 
Inclusion Criteria ........................................................................... 26 
Exclusion Criteria .......................................................................... 27 
Schedule of Assessments ............................................................... 33 
Clinical Laboratory Assessments .................................................. 43 
List of Medications Prohibited Before the Trial ............................ 55 
List of Medications Prohibited During the Trial ........................... 56 
Oral Benzodiazepine Rescue Therapy During the Trial ................ 57 
Schedule of Assessments ............................................................. 127 
Table 3.2-1 
Table 3.4.2-1 
Table 3.4.3-1 
Table 3.7-1 
Table 3.7.3.2-1 
Table 4.1-1 
Table 4.1-2 
Table 4.1.1-1 
Table 3.7-1 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
List of In-text Figures 
Trial Design Schematic ................................................................. 23 
Figure 3.1-1 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
List of Appendices 
Appendix 1 
Appendix 2 
83 
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance ......................................................................... 85 
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance ......................................................................... 86 
Criteria for Identifying Electrocardiogram Measurements of 
Potential Clinical Relevance .......................................................... 87 
Mini International Neuropsychiatric Interview ............................. 88 
Appendix 3 
Appendix 4 
Appendix 5 
Appendix 6 
Appendix 7 
Appendix 8 
Appendix 9 
Appendix 10 
Appendix 11 
Appendix 12 
Appendix 13 
Appendix 14 
Appendix 15 
91 
Young-Mania Rating Scale ........................................................... 92 
104 
Clinical Global Impression - Bipolar Version ............................. 108 
111 
112 
114 
Baseline Columbia-Suicide Severity Rating Scale ...................... 117 
Since Last Visit Columbia Suicide-Severity Rating Scale .......... 120 
Protocol Amendment(s)/Administrative Change(s) .................... 123 
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CCI 
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CCI 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
List of Abbreviations and Definitions of Terms 
Abbreviation 
5-HT 
ADME 
AE 
Definition 
Serotonin 
Absorption, distribution, metabolism, and excretion 
Adverse event 
ALT 
ANCOVA 
aPTT 
AST 
Alanine aminotransferase 
Analysis of covariance 
Activated partial thromboplastin time 
Aspartate aminotransferase 
BMI 
CGI-BP 
CMH 
CPK 
CRO 
C-SSRS 
Body mass index 
Clinical Global Impression- Bipolar 
Cochran-Mantel-Haenszel 
Creatine phosphokinase 
Clinical Research Organization 
Columbia-Suicide Severity Rating Scale 
DBP 
DNA 
DSM-5 
ECG 
EPS 
ET 
EudraCT 
Diastolic blood pressure 
Deoxyribonucleic acid 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
Electrocardiogram 
Extrapyramidal symptoms 
Early termination 
European Clinical Trial Data Base 
FDA 
Food and Drug Administration 
GCP 
HbA1c 
HIV 
IB 
ICF 
ICH 
ICMJE 
ID 
IEC 
IMP 
IND 
INR 
IRB 
IRE 
IWRS 
LOCF 
LOE 
Good Clinical Practice 
Glycosylated hemoglobin 
Human immunodeficiency virus 
Investigator’s brochure 
Informed consent form 
International Conference on Harmonisation 
International Committee of Medical Journal Editors 
Identification 
Independent ethics committee 
Investigational medicinal product 
Investigative new drug 
International normalized ratio 
Institutional review board 
Immediately reportable event 
Interactive web response system 
Last observation carried forward 
Lack of efficacy 
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CCI 
 
CCI 
 
CCI 
 
CCI 
 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
MAOI 
MDD 
MI 
MINI 
MMRM 
MNAR 
OC 
OPDC 
PE 
PK 
PQC 
PTSD 
QTcB 
QTcF 
QTcN 
Monoamine oxidase inhibitor 
Major depressive disorder 
Multiple imputation 
Mini International Neuropsychiatric Interview 
Mixed-effect model repeated measure 
Missing not at random 
Observed cases 
Otsuka Pharmaceutical Development & Commercialization, Inc. 
Physical examination 
Pharmacokinetics 
Product quality complaint 
Post-traumatic stress disorder 
QT interval corrected for heart rate by Bazett’s formula 
QT interval corrected for heart rate by Fridericia’s formula 
QT interval corrected for heart rate by the FDA Neuropharm Division 
formula 
Red blood cell 
Ribonucleic acid 
Serious adverse event 
Statistical analysis plan 
RBC 
RNA 
SAE 
SAP 
SBP 
TEAE 
TSH 
T4 
US or USA 
ULN 
WBC 
WOCBP 
YMRS 
Systolic blood pressure 
Treatment-emergent adverse event 
Thyroid stimulating hormone 
Free thyroxine 
United States or United States of America 
Upper limit of normal 
White blood cell 
Women of childbearing potential 
Young-Mania Rating Scale 
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CCI 
 
CCI 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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 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 in treating psychiatric conditions is unknown, the pharmacology 
of brexpiprazole is believed to be mediated by a combination of high binding affinity and 
functional activities at multiple monoaminergic receptors. It has modulatory activity at 
the serotonin (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 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 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 acute mania of bipolar I disorder. 
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 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
1.2 
Clinical Data 
Currently, brexpiprazole 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 
1.3 
Known and Potential Risks and Benefits 
Phase 1 data indicated that brexpiprazole 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 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; up to 3 mg/day as adjunctive therapy in elderly subjects (70-85 years of 
age) with MDD; and when administered to subjects with ADHD at doses of up to 4 
mg/day in combination with a marketed stimulant. 
Please refer to the current IB for a summary of available nonclinical and clinical safety 
data.7 
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18 
 
 
 
 
 
 
 
 
 
 
 
 
 
monotherapy for the treatment of schizophrenia. CCI 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
2 
2.1 
Trial Rationale and Objectives 
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 divalproex2,3,4,5 
Brexpiprazole is a novel 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 Brexpiprazole, like other atypical antipsychotics, targets the 
specific receptor profile of agents that have proven efficacy in the treatment of bipolar I 
disorder. This multicenter, randomized, double-blind, placebo-controlled trial will be 
conducted to evaluate the safety and efficacy of brexpiprazole monotherapy (2-4 mg/day, 
with a starting dose of 2 mg/day) for the acute treatment of manic episodes, with or 
without mixed features, in subjects with bipolar I disorder. 
2.2 
Dosing Rationale 
The dosing paradigm of brexpiprazole to be used in Trial 331-201-00080 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. 
During the double-blind period, subjects will receive a starting dose of 2 mg/day of 
brexpiprazole (or corresponding placebo) from Days 1 to 3, followed by titration to 
3 mg/day brexpiprazole (or placebo) on Day 4. Subjects may be titrated (or re-titrated) to 
a higher dose of brexpiprazole (or placebo), 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. This 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 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
clinical trial programs and labeling for other atypical antipsychotics, where similar 
differences are seen between schizophrenia and acute mania dosing paradigms with 
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 
Primary: 
To demonstrate the efficacy of brexpiprazole for the acute treatment of 
manic episodes, with or without mixed features, in subjects with a 
diagnosis of bipolar I disorder. 
To confirm the safety and tolerability of brexpiprazole in this same 
population. 
Secondary: 
3 
3.1 
Trial Design 
Type/Design of Trial 
This will be a 3-week, multicenter, randomized, double-blind, placebo-controlled trial of 
brexpiprazole in subjects diagnosed with bipolar I disorder (current manic episode with 
or without mixed features) according to the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5; updated terminology replaces “mixed episodes” with 
the descriptor of “mixed features”). The total duration of the trial is up to 8 weeks, 
including screening, double-blind treatment, and follow-up. See Figure 3.1-1 for a 
schematic of the trial design. 
The trial will be organized as follows: 
Screening Phase: The screening period will begin after written informed consent has 
been obtained and will take place between Day −14 and Day −1 prior to randomization. 
Hospitalization will begin with the signing of the informed consent form (ICF) for 
subjects who are not already hospitalized at the time of the initial screening visit. The 
purpose of the screening period is to assess eligibility criteria and to washout prohibited 
concomitant medication. Subjects will be between 18 and 65 years of age, inclusive, at 
the time of screening, will have a diagnosis of bipolar I disorder, and will be experiencing 
a manic episode with or without mixed features as defined by the DSM-5 criteria. An 
interactive web response system (IWRS) or equivalent will be used to obtain an 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
identification (ID) number for each subject with documented consent. Although the 
screening period will continue up to administration of the first dose of investigational 
medicinal product (IMP), screening procedures should be initiated with a sufficient 
amount of time allotted in order to obtain laboratory results and electrocardiogram (ECG) 
results from the central reader prior to randomization. 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. 
All subjects must agree to discontinue all prohibited medications during the screening 
period in order to meet the protocol-specified washout periods. 
Treatment Phase: Following the screening period, subjects who meet all inclusion 
criteria, including a score of ≥ 24 on the Young-Mania Rating Scale (YMRS)8 at 
screening and baseline, and meet none of the exclusion criteria, will be randomized in a 
1:1 ratio to receive either placebo or brexpiprazole for 3 weeks. Subjects will receive a 
starting dose of 2 mg/day of brexpiprazole (or corresponding placebo) from Days 1 to 3, 
followed by titration to 3 mg/day brexpiprazole (or placebo) on Day 4. Further dose 
increases up to 4 mg/day may occur no earlier than Day 7 at the investigator’s discretion 
based on treatment response.  Subjects who are unable to tolerate their current dose can 
be titrated down at any time to a minimum of 2 mg/day. Subjects may be re-titrated back 
to higher dose levels based on investigator discretion. 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. All subjects will remain hospitalized for a minimum of the 
first 2 weeks of the 3-week treatment phase.  However, subjects who, in the opinion of 
the investigator, have clinically improved from their baseline assessments with mild to no 
manic symptoms, and are stable enough to be treated on an outpatient basis, including no 
risk of suicide as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), 
may be discharged and will continue as outpatients for the last week of double-blind 
treatment. Subjects who do not meet these criteria will remain hospitalized for the 
duration of the 3 week treatment phase. 
A drug screen and alcohol test are required at the Day 21/Early Termination (ET) visit for 
subjects who are discharged from the hospital at the end of Week 2 (Day 14) to verify 
continued compliance with the protocol. 
Follow-up Phase: If any subject discontinues the trial early, every effort should be made 
to complete the Day 21/ET assessments as soon as possible and prior to starting any new 
medication or treatment. Subjects who complete all trial visits through the Day 21 visit 
and had no major protocol violations may be offered entry into an optional open-label 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
rollover trial. Subjects who do not enter the open-label trial will be followed up for 
safety reasons via telephone contact or in clinic visit 21 (± 2) days after the last dose of 
IMP. This contact also applies to subjects who are withdrawn prematurely from the trial. 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Inpatient Screening Period 
1-14 days 
Safety Follow-up 
21(±2) daysa 
Double-blind, Placebo-controlled Phase 
3 weeks (minimum of 2 weeks inpatient 
hospitalization) 
Brexpiprazole 
(n = 160) 
Placebo 
(n = 160) 
Screening/Check-in 
Hospitalization will begin when subject signs informed consent 
for subjects who are not already hospitalized at the time of the 
first screening visit. 
Telephone 
Contact or In 
Clinic Visit 
Discharge 
C-SSRS = Columbia-Suicide Severity Rating Scale. 
aSubjects who complete all trial visits through the Day 21 visit may be offered entry into an optional open-label rollover trial. 
Figure 3.1-1 
Trial Design Schematic 
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Randomization (1:1) 
Subjects who, in the opinion of the investigator, have 
clinically improved from their baseline assessments 
with mild to no manic symptoms, and are stable enough 
to be treated on an outpatient basis, including no risk of 
suicide as assessed by the C-SSRS, may be discharged 
and will continue as outpatients for the last week of 
double-blind treatment. 
Subjects who do not meet these criteria will remain 
hospitalized for the duration of the 3 week treatment 
phase. 
Eligible subjects with 
bipolar I disorder 
(n = 448 screened) 
(n = 320 randomized) 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
3.2 
Trial Treatments 
During the double-blind treatment phase, subjects will receive IMP consisting of 
brexpiprazole monotherapy or placebo, depending on the subject’s treatment assignment. 
As shown in Table 3.2-1, subjects will receive a starting dose of 2 mg/day of 
brexpiprazole (or corresponding placebo) from Days 1 to 3, followed by titration to 3 
mg/day brexpiprazole (or placebo) on Day 4. Subjects may be titrated (or re-titrated) to a 
higher dose of brexpiprazole (or placebo), 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. 
aDown titration can occur at any time due to tolerability after Day 4.  The minimum dose allowed is  
2 mg/day. 
bOption to titrate 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. 
All doses of IMP should be taken at the same time each day, if possible, and can be taken 
without regard to meals. If tolerability issues arise, the timing of administration of the 
IMP may be adjusted at the investigator’s discretion in order to achieve optimum 
tolerability and compliance. Subjects will be counseled on the importance of taking the 
IMP. 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Description of Population 
It is planned that approximately 320 subjects will be randomized into the trial at 
approximately 45 trial sites in the North America and Europe. Approximately 60% of 
subjects will be randomized in North America and 40% in Europe. 
The trial population will include men and women 18 to 65 years of age, inclusive, with a 
DSM-5 diagnosis of bipolar I disorder displaying an acute manic episode with or without 
mixed features requiring hospitalization. Diagnosis will be confirmed by the Mini 
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Table 3.2-1 
Dosing Schedule 
Dose 
Days 1-3 
Days 4a 
Days 7-21b 
Brexpiprazole 
2 mg 
3 mg 
2-4 mg 
Placebo 
Placebo 
Placebo 
Placebo 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
International Neuropsychiatric Interview (MINI)9,10 and a history of at least 1 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. Eligible subjects must also have an 
YMRS score ≥ 24 at screening and baseline. 
3.3.2 
Subject Selection and Numbering 
At screening, subjects will be assigned a unique subject 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 ICH (International Conference on Harmonisation) Good 
Clinical Practice (GCP) Guideline11 and local regulatory requirements. The investigator 
will ensure that the sponsor or its designee 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 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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. 
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. 
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Table 3.4.2-1 
Inclusion Criteria 
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 as required by IRB or 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; and 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 displaying an acute manic episode with or 
without mixed features requiring 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. 
YMRS score of ≥ 24 at screening and baseline. 
6. 
 
Subjects who, in the investigator’s judgment, require treatment with an atypical antipsychotic 
medication for their bipolar I disorder. 
7. 
 
Subjects willing to discontinue all prohibited medications to meet protocol-required washouts 
prior to and during the trial period. 
CCI 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
3.4.3 
Exclusion Criteria 
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1. 
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Table 3.4.3-1 
Exclusion Criteria 
 
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. 
 
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 whose current manic episode has lasted for more than 4 weeks overall, or who have 
required hospitalization > 21 days for the current acute episode at the time of the screening visit, 
excluding hospitalization for psychosocial reasons. 
5. 
 
Subjects who have had initiation of, or a change in, psychotherapy for the treatment of bipolar 
disorder symptoms within 28 days prior to the screening visit or if it is anticipated that the subject 
will have a change in psychotherapy during the trial. 
6. 
 
Subjects with manic symptoms that are better accounted for by another general medical condition 
or direct physiological effects of a substance (eg, medications). 
7. 
Subjects considered unresponsive to clozapine or who are only responsive to clozapine. 
8. 
 
Subjects with bipolar I disorder who are considered resistant or refractory to treatment for manic 
symptoms by history. 
9. 
Subjects who have had electroconvulsive treatment within the past 2 months. 
10. 
 
Use of psychotropic medications (other than benzodiazepines) within 7 days of the baseline 
YMRS. 
11. 
Rapid cyclers with more than 6 episodes in the previous year. 
12. 
 
Subjects with serum concentrations of lithium ≥ 0.6 mmol/L, serum concentrations of valproate 
≥ 50 μg/mL, or serum concentrations of carbamazepine ≥ 4 μg/mL (if any of these parameters are 
outside of the listed exclusionary range, they may be reassessed prior to randomization, if 
necessary). 
 
Medical History and Concurrent Diseases 
13. 
 
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. 
14. 
 
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. 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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Table 3.4.3-1 
Exclusion Criteria 
15. 
16. 
 
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.   
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. 
17. 
 
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 retest 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. 
18. 
 
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. 
19. 
 
Subjects with epilepsy or a history of seizures, except for a single seizure episode; for instance 
childhood febrile, post traumatic, or alcohol withdrawal seizure. 
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. 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body 
mass index; CPK = creatine phosphokinase; CYP = cytochrome P450; DBP = diastolic blood 
pressure; HbA1c = glycosylated hemoglobin; HIV = human immunodeficiency virus; 
IDDM = insulin-dependent diabetes mellitus; OTC = over-the-counter; QTcF = QT interval corrceted 
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Table 3.4.3-1 
Exclusion Criteria 
 
Physical and Laboratory Results 
21. 
 
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. 
22. 
 
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 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. 
 
Disallowed and Concomitant Medication 
23. 
 
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 (Section 4.1). 
24. 
 
Subjects who would be likely to require prohibited concomitant therapy during the trial 
(Section 4.1). 
25. 
 
Subjects who received brexpiprazole in any prior clinical trial or currently taking commercially 
available brexpiprazole (Rexulti®). 
26. 
Subjects who may require CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers during this trial. 
 
Allergies and Adverse Drug Reactions 
27. 
 
Subjects with a history of neuroleptic malignant syndrome, serotonin syndrome, or clinically 
significant tardive dyskinesia. 
28. 
 
Subjects with a history of true allergic response (ie, not intolerance) to more than 1 class of 
medications. 
29. 
Subjects who are known to be allergic or hypersensitive to brexpiprazole or other quinolinones. 
 
Other 
30. 
 
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. 
31. 
 
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. 
32. 
 
Any subject who, in the opinion of the sponsor, investigator, or medical monitor, should not 
participate in the trial. 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
for heart rate by Fridericia’s formula; SBP = systolic blood pressure; ULN = upper limit of normal; 
WOCBP = women of childbearing potential. 
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. 
During screening, 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 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. 
3.5 
Endpoints 
3.5.1 
Primary Endpoint 
The primary endpoint is change from baseline to Day 21 of the double-blind treatment 
phase in YMRS Total Score. 
3.5.2 
Secondary Endpoints 
The key secondary endpoint is the change from baseline to Day 21 in the double-blind 
treatment period in Clinical Global Impression – Bipolar (CGI-BP) Severity of Illness 
score in mania. 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
3.5.3 
3.5.4 
3.5.5 
Safety Endpoints 
Standard safety variables will include adverse events (AEs), clinical laboratory tests 
(hematology, serum chemistry [including prolactin and glycosylated hemoglobin 
(HbA1c)], coagulation parameters, and urinalysis), physical examinations, vital sign 
measurements, and ECGs. Body weight, height, and waist circumference will also be 
measured. 
The C-SSRS will be used to assess and classify reported suicidal behavior. 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
3.5.6 
3.6 
Measures to Minimize/Avoid Bias 
During the entire trial, treatment will be double-blind. In other words, neither the 
investigator nor the subject will have knowledge of the treatment assignment at any given 
visit. 
Treatment assignments will be based on a fixed-block computer-generated randomization 
code provided by the Otsuka Pharmaceutical Development & Commercialization, Inc. 
(OPDC) Biometrics Department. The randomization will be stratified by trial site and 
designed to allocate subjects to a treatment regimen in a 1:1 ratio. Sponsor personnel, 
including those involved in monitoring, data management, and data analysis, will not 
have access to the treatment code during the trial. Access to the treatment codes will be 
restricted to personnel charged with generating and maintaining randomization files, 
packaging IMP, operating the IWRS, and reporting serious adverse events (SAEs) to 
regulatory agencies. 
3.7 
Trial Procedures 
This trial is a phase 3, double-blind, placebo-controlled trial to investigate the efficacy, 
safety, and tolerability of brexpiprazole (2-4 mg/day) for the treatment of subjects with 
bipolar I disorder experiencing a manic episode with or without mixed features. The trial 
comprises a 3-week, double-blind treatment period with a 21 (± 2) day follow-up. 
Trial assessment time points are summarized in Table 3.7-1. 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Table 3.7-1 
Schedule of Assessments 
Screeninga 
Double-blind Treatment Phase 
Follow-upc 
Day -14 to -1 
Baseline 
(Day 1) 
Day 4 
(± 1 day) 
Day 7 
(± 1 day) 
Day 14 
(± 1 day) 
Day 21/ETb 
(± 2 days) 
21 (± 2) days 
after last dose 
Screening Assessments and Randomization 
Informed Consentd 
X 
Demographics 
X 
Medical History 
X 
Psychiatric History 
X 
MINI 
Concomitant Medicationse 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
X 
Randomization 
X 
Efficacy Assessments 
YMRSf 
X 
X 
X 
X 
X 
X 
CGI-BPg 
X 
X 
X 
X 
X 
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Safety Assessments 
Physical Examinationh 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
X 
12-lead ECGj 
X 
X 
X 
Clinical laboratory tests 
(hematology, serum chemistry, 
urinalysis), including prolactink 
HbA1cj 
X 
X 
X 
X 
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33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Table 3.7-1 
Schedule of Assessments 
Screeninga 
Double-blind Treatment Phase 
Follow-upc 
Day -14 to -1 
Baseline 
(Day 1) 
Day 4 
(± 1 day) 
Day 7 
(± 1 day) 
Day 14 
(± 1 day) 
Day 21/ETb 
(± 2 days) 
21 (± 2) days 
after last dose 
X 
X 
TSH, with reflex to T4 if TSH 
is abnormal 
Coagulation parameters (PT, 
aPTT, INR)k 
X 
X 
Lithium, Valproate, 
Carbamazepine Levelsl 
X 
HIV, HBsAg, and anti-HCV 
X 
Pregnancy Testm 
X 
X 
X 
Drug Screenn 
Blood Alcohol Testn 
X 
X 
X 
X 
C-SSRSo 
CCI 
X 
X 
X 
X 
X 
X 
AEsp 
X 
X 
X 
X 
X 
X 
X 
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Other 
IMP dispensingr 
X 
X 
X 
X 
IMP accountability 
X 
X 
X 
X 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
aPTT = activated partial thromboplastin time; HBsAg = Hepatitis B surface antigen; Anti-HCV = Antibodies to hepatitis C virus; INR = International 
Normalized Ratio; T4 = free thyroxine; TSH = thyroid-stimulating hormone. 
aScreening begins when the ICF is signed and will take place between Day −14 and Day −1; however, screening procedures should be initiated with a 
sufficient amount of time allotted in order to obtain laboratory results and ECG results from the central reader prior to randomization. Review of 
inclusion/exclusion criteria at baseline will be based on assessments performed during screening. Hospitalization will begin with the signing of the ICF for 
subjects who are not already hospitalized at the initial screening visit. Note: In the rare circumstance when a subject must leave the inpatient facility 
temporarily (eg, family emergency or doctor visit), a temporary day pass may be granted. For such a request, sites must first contact the medical monitor 
for explicit authorization and guidance on procedures. A medical monitor approved day pass is good for the day requested only, and subjects must return to 
the site the same day (eg, in the evening). 
bIf a subject discontinues prematurely before Day 21, procedures noted for Day 21 must be completed at the ET visit. 
cConsists of telephone contact or clinic visit (investigator’s discretion) for evaluation of safety 21 days after the last dose of IMP and applies only to subjects 
who do not enter the optional open-label rollover trial. 
dInformed consent must be obtained prior to any trial-related procedures. CCI 
 
eAll medications taken within 30 days of screening will be recorded. In addition, all prescription and non-prescription medications taken during the trial will 
be recorded as concomitant medications. 
fTo be eligible for the trial, subjects must have a YMRS score  24 at screening and baseline. 
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hTo include measurement of height at screening only and waist circumference at screening and Day 21. 
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. In addition, ECG results will 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. Subjects will be randomized based on screening ECG results from the central reader and baseline 
ECG results from the trial site. If the baseline ECG results from the central reader, when available, indicate a QT interval corrected for heart rate by 
Fridericia’s formula (QTcF) ≥ 450 msec in men and ≥ 470 msec in women, unless due to ventricular pacing, at baseline, the investigator must contact the 
medical monitor to discuss the subject’s continued participation in the trial. ECGs scheduled for the same visit as blood samples are to be completed before 
blood is drawn. 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
kSubjects must be fasting for a minimum of 8 hours prior to blood draws for screening laboratory assessments, if at all possible. If fasting blood samples are 
not feasible at screening, nonfasting blood samples may be obtained initially for determining eligibility for the trial. Clinical laboratory tests must be drawn 
after a minimum 8-hour fast at Day 21/ET. Vital sign and ECG assessments should be completed before any blood samples are collected. 
lIf lithium, valproate, or carbamazepine levels are outside of the listed exclusionary range, they may be reassessed prior to randomization. 
mAll 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. 
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. 
oThe “Baseline/Screening” C-SSRS form will be completed for all subjects at screening to determine elgibility and the “Since Last Visit” C-SSRS form will 
be completed at the baseline visit to assure that the subject continued to qualify for the trial. Any subject with suicidal ideation within the last 6 months, 
suicidal behaviors within the last 2 years, or who in the clinical judgment of the investigator presents a serious risk of suicide should be excluded from the 
trial (see Table 3.4.3-1). The “Since Last Visit” C-SSRS form will be completed at all visits after the baseline visit. 
pAdverse events will be recorded starting after the subject signs the ICF. 
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rSite staff will provide IMP to hospitalized subjects daily from assigned blister cards. If a subject is discharged at Day 14, the site should counsel the subject 
on the importance of taking IMP as directed. 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
3.7.1 
Schedule of Assessments 
3.7.1.1 
Screening (Day -14 to -1) 
The screening period begins after consent has been obtained. Consent should also be 
obtained for optional FBR for those subjects that want to participate. Although the 
screening period takes place between Day −14 and Day −1, subjects will participate in 
screening activities for a minimum of 1 day. After a subject has provided consent, sites 
will obtain a subject ID number for the subject by accessing the IWRS or equivalent. 
Screening evaluations will include the following: 
Hospitalization will begin once the subject signs the ICF for subjects who are not 
already hospitalized at the time of the screening visit. 


A qualified and certified rater will administer the YMRS 
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 screening) 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). 






The investigator (or qualified designee) who is adequately trained will complete the 
“Baseline/Screening” C-SSRS form to exclude subjects with a significant risk of 
suicidal behavior (see Table 3.4.3-1). 
A complete physical examination (including height and waist circumference) will be 
performed. 
Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded. Blood pressure and heart rate are to be measured in the 
following order: supine and standing after the subject has been in each position at 
least 3 minutes. See Table 3.4.3-1 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. 



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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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, and 
lithium, valproate, and carbamazepine levels) 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. Note: if lithium, valproate, or carbamazepine 
levels are outside of the listed exclusionary range, they may be reassessed prior to 
randomization. 
Samples will be obtained for blood alcohol testing. See Section 3.4.3 for details 
regarding subjects with a positive blood alcohol test. 


Urine will be collected from all potential subjects for urinalysis and urine screen(s) 
for drugs of abuse. See Section 3.4.3 for exclusions based on outcome of screening 
urinalysis and urine screen(s) for drugs of abuse. 
A urine pregnancy test will be performed for all women of childbearing potential 
(WOCBP). All positive results must be confirmed by a serum pregnancy test. 
Subjects with a positive serum pregnancy test result will be excluded from the trial. 
Adverse events will be recorded beginning with the completion of the consent 
process. 
Trial personnel will access the IWRS or equivalent to register the visit (initial visit 
only). 



3.7.1.2 
Baseline (Day 1) 
If the subject continues to be eligible for the trial after the screening period, the following 
procedures will be performed: 
An assessment of all inclusion and exclusion criteria will be made to confirm the 
subject’s eligibility for the trial. 
A qualified and certified rater will administer the YMRS, CGI-BP, CCI 
The investigator (or qualified designee) who is adequately trained will complete the 
“Baseline/Screening” C-SSRS form. 
Vital sign measurements (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 
Table 3.4.3-1 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. 
Adverse events and concomitant medications will be recorded. 



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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
3.7.1.3 
Randomization 
Once subject eligibility has been confirmed at baseline, the following will be performed 
on Day 1: 
 Trial personnel will access the IWRS or equivalent to register the visit and to obtain 
blister card assignment(s) for double-blind IMP. The assigned IMP will be dispensed 
to the subject. 
3.7.1.4 
Treatment Phase - Day 4 
The following procedures will be performed on Day 4 (± 1 day): 


A qualified and certified rater will administer the YMRS and CGI-BP. 
The investigator (or qualified designee) who is adequately trained will complete the 
“Since Last Visit” C-SSRS form. 

Vital sign measurements (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. 
A urine pregnancy test will be performed for all WOCBP. All positive results must 
be confirmed by a serum pregnancy test. Subjects with a positive serum pregnancy 
test result will be withdrawn from the trial. 
Adverse events and concomitant medications will be recorded. 
IMP will be dispensed to the subject (Days 4, 5, and 6). 
Drug accountability will be performed. 




3.7.1.5 
Treatment Phase - Day 7 
The following procedures will be performed on Day 7 (± 1 day): 


A qualified and certified rater will administer the YMRS and CGI-BP. 
The investigator (or qualified designee) who is adequately trained will complete the 
“Since Last Visit” C-SSRS form. 

Vital sign measurements (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. 
Adverse events and concomitant medications will be recorded. 

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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
 IMP will be dispensed to the subject (Days 7 through 13). 
 Drug accountability will be performed. 
3.7.1.6 
Treatment Phase - Day 14 
The following procedures will be performed on Day 14 (± 1 day): 


A qualified and certified rater will administer the YMRS, CGI-BP, 
The investigator (or qualified designee) who is adequately trained will complete the 
“Since Last Visit” C-SSRS form. 

Vital sign measurements (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. 
Adverse events and concomitant medications will be recorded. 
IMP will be dispensed to the subject (Days 14 through 21). 
Drug accountability will be performed. 
Subjects who, in the opinion of the investigator, have clinically improved from their 
baseline assessments with mild to no manic symptoms, and are stable enough to be 
treated on an outpatient basis, including no risk of suicide assessed by the C-SSRS, 
may be discharged and will continue as outpatients for the last week of double-blind 
treatment. 
Those subjects who are discharged early will be administered IMP for the last week 
of treatment that is clearly labeled with the trial number, subject ID, and subject 
initials. Subjects will be counseled on the importance of taking the IMP. 





3.7.1.7 
End of Treatment Phase - Day 21/Early Termination Visit 
All subjects will undergo a complete evaluation at Day 21 (± 2 days).  In addition,  
Day 21 evaluations are to be completed for any subject withdrawn at any time after 
randomization into the trial. Attempts should be made to complete all evaluations, 
particularly efficacy assessments, for the Day 21/ET visit prior to the administration of 
any new psychotropic medications. However, if the subject receives a new rescue 
medication for worsening manic symptoms prior to ET procedures prior to the 
Day 21/ET procedures, no efficacy assessments should be performed. 
The following procedures will be performed on Day 21(± 2 day) or the ET visit: 
 A qualified and certified rater will administer the YMRS, CGI-BP, 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
The investigator (or qualified designee) who is adequately trained will complete the 
“Since Last Visit” C-SSRS form. 



A complete physical examination 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. 
A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. 
Blood samples for clinical laboratory tests (hematology, coagulation parameters, and 
serum chemistry, including prolactin, HbA1c, and thyroid-stimulating hormone 
[TSH] with reflex to T4 if the result for TSH is abnormal) must be drawn after a 
minimum 8-hour fast. 
Samples will be obtained for blood alcohol testing. 
Urine will be collected from subjects for urinalysis and urine screen(s) for drugs of 
abuse. 
A urine pregnancy test will be performed for all WOCBP. All positive results must 
be confirmed by a serum pregnancy test. 






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
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


Adverse events and concomitant medications will be recorded. 
Trial personnel will access the IWRS or equivalent to register the visit. 
Drug accountability will be performed. 
3.7.1.8 
Post-treatment Follow-up Period 
Subjects will be contacted for a safety follow-up either via telephone or in-clinic visit (at 
the investigator’s discretion) scheduled 21 (± 2) days after the last dose of IMP. Adverse 
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. In 
addition, the raters must be certified for this trial to administer the YMRS 
scales. The number of raters within each trial center should be kept to a minimum. All 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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 OPDC or designee. 
3.7.2.1 
Young-Mania Rating Scale 
The YMRS consists of 11 items assessing the core symptoms of mania8 and is based on 
questions asked of the subject regarding his or her clinical condition. Additional 
information is based upon clinical observations made during the course of the clinical 
interview. Each item has 5 defined categories of severity with 4 items graded on a 0 to 8 
scale (irritability, speech, content, and disruptive-aggressive behavior) and 7 items graded 
on a 0 to 4 scale. A copy of the YMRS is provided in Appendix 7. 
3.7.2.2 
Clinical Global Impression - Bipolar Version 
The CGI-BP scale refers to the global impression of the subject with respect to bipolar 
disorder.12 The scale rates the subject’s Severity of Illness (CGI-BP Severity of Illness: 
mania, depression, and overall bipolar illness) based on a 7-point scale and rates the 
subject’s Change from Baseline (CGI-BP change from baseline: mania, depression, and 
overall bipolar illness) based on a 7-point scale. Severity of Illness (CGI-BP Severity of 
Illness) should be rated at visits indicated in Table 3.7-1. The CGI-BP Change from 
Baseline is not assessed at the baseline visit.  At each visit other than baseline, the 
Change from Baseline will be judged with respect to subject’s condition at baseline. It is 
important that the point of reference for assessing improvement or worsening on the 
CGI-BP Change from Baseline be the condition of the subject at the baseline visit and not 
the condition of the subject at any post-baseline visit preceding the current visit. A copy 
of the CGI-BP is provided in Appendix 9. 
3.7.2.3 
3.7.2.4 
3.7.2.4.1 
Other Assessments 
Mini International Neuropsychiatric Interview 
The MINI9,10,14 will be conducted at the screening visit to confirm the subject’s diagnosis 
of bipolar I disorder and to rule out exclusionary comorbid psychiatric diagnoses. 
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Detailed instructions for administration of this structured interview will be provided. 
copy of the score sheet is provided in Appendix 5. 
A 
3.7.2.4.2 
3.7.3 
Safety Assessments 
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 
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. The central laboratory will provide laboratory 
results electronically. A list of clinical laboratory assessments is provided in Table 
3.7.3.2-1. 
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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 
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 
 
 
 
 
 
 
 
 
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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. 
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 3 for criteria for identifying values of potential clinical 
relevance. 
The following laboratory test results at screening are exclusionary: 
 Platelets ≤ 75000/mm3 
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Table 3.7.3.2-1 
Clinical Laboratory Assessments 
Ketones 
Glucose 
Blood 
Microscopic analysis (performed only if any part of 
the urinalysis is not negative) 
Urine Drug Screens: 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
Marijuana 
Methadone 
Opiates 
Phencyclidine 
Propoxyphene 
Other: 
Blood Alcohol 
 
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  ration  (INR) 
HbA1c 
Additional Tests (screening only); 
HIV 
HbsAg 
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




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 per subject 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 
3.7.3.3.1 
Physical Examination and Vital Signs 
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). 
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.15 


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 
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16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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 
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 2 is included to assist 
investigators in their assessments of results that may be potentially medically significant, 
depending on the subject’s medical history and clinical presentation. 
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 
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Clinical Study Report 331-201-00080 
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Protocol 331-201-00080 
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 4 for a list of potentially clinically relevant ECG abnormalities to 
guide investigators for the assessment of potential ECG abnormalities for clinical 
significance postrandomization. Exclusion criteria for screening do not apply as 
mandatory discontinuation criteria for subjects who are already randomized. Please 
consult the medical monitor in case of questions. 
3.7.3.5 
C-SSRS. The number of raters 
within each trial center should be kept to a minimum. All efforts will be made to ensure 
that the same clinician administers the scales for a given subject. Notations in the 
subject’s trial records should substantiate the ratings. Training and materials for rating 
will be provided by Bracket. 
3.7.3.5.1 
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3.7.3.5.2 
3.7.3.5.3 
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3.7.3.5.4 
Columbia-Suicide Severity Rating Scale 
Suicidality will be monitored during the trial using the C-SSRS. This trial will use the 
“Baseline/Screening” and “Since Last Visit” versions of the scale. The 
“Baseline/Screening” version, which assesses the lifetime experience of the subject with 
suicide events and suicidal ideation and the occurrence of suicide events or ideation 
within a specified time period prior to entry into the trial, will be completed for all 
subjects at screening to determine eligibility. Any subject with active suicidal ideation 
within the last 6 months, suicidal behaviors within the last 2 years, or who in the clinical 
judgment of the investigator presents a serious risk of suicide should be excluded from 
the trial (Table 3.4.3-1). The “Since Last Visit” C-SSRS form will also be completed at 
all visits after screening. Copies of the C-SSRS forms are provided in Appendix 13and 
Appendix 14. 
3.7.3.5.5 
3.7.4 
Prior and Concomitant Medications 
The investigator will record all medications and therapies taken by the subject from 
30 days prior to signing of informed consent 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 
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AE until the end of the trial (defined as the last date of contact or date of final contact 
attempt) in the ePlatform. 
3.7.5 
3.7.5.1 
3.7.6 
3.7.7 
End of Trial 
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up ePlatform page for the last subject completing 
or withdrawing from the trial. 
3.7.8 
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. 
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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. 
3.8.3 
Individual Subject Discontinuation 
3.8.3.1 
Treatment Interruption 
All attempts should be made to avoid treatment interruption during the trial. For subjects 
who have an interruption of treatment, the investigator or designee will contact the 
medical monitor as soon as possible. The investigator and medical monitor will come as 
quickly as possible to a joint decision regarding the subject’s continuation in the trial. 
This decision will be documented by the investigator and the medical monitor. The 
treatment interruption will be recorded via eSource and also recorded as a protocol 
deviation (Section 3.13). 
3.8.3.2 
Treatment Discontinuation 
After randomization, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 3.8.3.5. 
3.8.3.3 
Documenting Reasons for Treatment Discontinuation 
A subject may discontinue IMP for a number of reasons including those listed below: 
 Reasons related to AE: 

Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard 
Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP) 
 SAE 
 Other potentially IMP-related safety concerns or AEs 

 Death 
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Clinical Study Report 331-201-00080 
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Protocol 331-201-00080 
Reasons unrelated to medical condition (provide detail and review AE history with 
subject) 
Withdrawal of informed consent 
Lost to follow-up 
Pregnancy (see Section 5.5) 
Termination of all or part of the trial by the sponsor 




If the subject discontinues IMP due to an AE, the investigator, or other trial personnel, 
will make every effort to follow the event until it has resolved or stabilized. Follow up 
procedures in 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). 




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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 discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.8.3.2). A subject may, however, indicate that further trial participation is 
creating a burden on their work or social schedule. Therefore, the investigator should 
follow the procedures outlined in Section 3.8.3.3 to determine if the subject can continue 
participation in the trial if modifications to his/her treatment 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 randomized or assigned 
trial treatment. 
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. 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 Day 21 visit will be defined as trial completers. 
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3.11 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before Day 21 visit during the treatment period, 
who do not have a known reason for discontinuation (eg, withdrew consent or AE), and 
for whom a survival status at the end of the trial cannot be determined will be classified 
as “lost to follow-up” as the reason for discontinuation. Survival status can be 
determined from a variety of sources, either by obtaining acceptable documentation for 
death (ie, death certificate, medical records, public records, statement by a family 
member or primary care physician) or acceptable documentation for life (ie, direct 
contact with the subject, medical records, successful telephone contact with the subject, 
statement by a family member or primary care physician, or public records). 
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status. 
3.12 
Subject Compliance 
Responsible trial personnel will dispense the IMP. 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. 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 medical 
monitor at the earliest possible time by telephone. The investigator and medical monitor 
will come as quickly as possible to a joint decision regarding the subject’s continuation in 
the trial. This decision will be documented by the investigator and the medical monitor, 
and reviewed by the site monitor. 
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4 
4.1 
Restrictions 
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 
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 randomization. Subjects 
with serum concentrations of lithium ≥ 0.6 mmol/L, valproate ≥ 50 μg/mL, or 
carbamazepine ≥ 4 μg/mL at screening may repeat a clinical laboratory test for these 
parameters prior to randomization. The results of the additional test will be reviewed and 
confirmed before the subject can be randomized into the trial. Other therapies restricted 
or prohibited prior to enrollment and during the trial are presented in Section 4.2. 
IR IM = immediate-release intramuscular; MAOIs = monoamine oxidase inhibitors. 
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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 inducers 
14 days 
 


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Protocol 331-201-00080 
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. 
Table 4.1-2 lists all medications prohibited during the trial, including exceptions, where 
appropriate. 
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 
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56 
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 
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.) 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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 IM benzodiazepines and continual use of oral benzodiazepines is prohibited 
during this trial. However, limited use of oral lorazepam as a rescue medication for the 
short-term management of treatment-emergent AEs (TEAEs) of anxiety, agitation, and 
insomnia will be allowed both during the washout period between the screening and 
baseline assessments, and during the treatment phase. 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. During the treatment phase, use of oral lorazepam must follow the daily dose 
schedule listed in Table 4.1.1-1 for Days 1 through 14. All benzodiazepine use, including 
lorazepam, is prohibited after Day 14. 
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 any 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. 
aIn countries or institutions where lorazepam is not commercially available, use of oral lorazepam 
equivalents, as described in Section 4.1.1and dosed based on the schedule in Table 4.1.1-1 is 
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57 
Table 4.1.1-1 
Oral Benzodiazepine Rescue Therapy During the Trial 
Oral 
Benzodiazepine 
Maximum Allowable Dose (mg/day) 
Days 1-4 
Days 5-7 
Days 8-10 
Days 11-14 
Lorazepama 
6 
4 
2 
1 
 


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Protocol 331-201-00080 
acceptable only with prior authorization from the medical monitor. All benzodiazepine use, 
including lorazepam, is prohibited after Day 14. 
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.19 
Triptans (eg, sumatriptan, naratriptan, almotriptan, frovatriptan, rizatriptan, eletriptan, 
and zolmitriptan), linezolid, and methylene blue since there have been rare post- 
marketing reports of serotonin syndrome or serotonin syndrome-like reactions (eg, 
mental status changes, hyperreflexia, autonomic effects, lack of coordination, and 
diarrhea) following the concomitant use of SSRIs or 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 
5.1 
Reporting of Adverse Events 
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 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
history at screening for preplanned procedures for which the underlying condition was 
known and no worsening occurred. An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the IMP and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality. 
An SAE includes any event that results in any of the following outcomes: 


Death 
Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred. It does not include an event 
that, had it occurred in a more severe form, might have caused death. 
Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions. 
Requires inpatient hospitalization or prolongs hospitalization. 
 Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported. 
 Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs. 
Congenital anomaly/birth defect. 
Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse. 




Nonserious adverse events are all AEs that do not meet the criteria for 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. 
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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: 
2 = Moderate: 
3 = Severe: 
Discomfort noticed, but no disruption to daily activity. 
Discomfort sufficient to reduce or affect normal daily activity. 
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. 
There is no temporal or causal relationship between the IMP and 
the AE. 
Not Related: 
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 within the eSource platform provided by the sponsor. All AE collection is to 
begin after a subject has signed the ICF. 
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Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition. 
A reported AE that undergoes a change in severity, seriousness, or toxicity should be 
reported as a new AE on the ePlatform. 
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 
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 ULN, a total 
bilirubin level should also be evaluated. If the total bilirubin is  2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the eSource. 
5.5 
Pregnancy 
Women of child-bearing potential 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 
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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 
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 ICF 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 (hCG) 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. 
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Protocol 331-201-00080 
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 
The investigator is encouraged to contact the sponsor/Clinical Research Organization 
(CRO) medical advisor to discuss their rationale for unblinding. However, to prevent 
delays to the investigator or medical personnel responding to a potentially emergent 
situation, unblinding of IMP will not be dependent upon the investigator receiving 
approval from the sponsor/CRO medical advisor (ie, the investigator will be able to 
obtain the code break information independent of the sponsor/CRO medical advisor). 
The investigator must contact the sponsor/CRO medical advisor by telephone or e-mail 
with an explanation of the need for opening the treatment assignment code within 24 
hours of opening the code. If the blind is broken, the Clinical Safety and 
Pharmacovigilance department must be notified immediately (see the cover page of this 
protocol for contact information). Documentation of breaking the blind should be 
recorded in the subject’s medical record with the date and time the blind was broken and 
the names of the personnel involved. Once the blind is broken for a subject, that subject 
may not reinitiate treatment with the IMP. 
5.7 
Follow-up of Adverse Events 
For this trial, information on AEs will be followed for up to 21 (+2) days after the last 
dose of IMP has been administered. 
5.7.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE ePlatform with the current status (ongoing or resolved/recovered) noted. 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 
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Protocol 331-201-00080 
analysis, additional relevant medical history information may be requested to further 
ascertain causality (including, but not limited to, information such as risk-related 
behavior, family history and occupation). 
5.7.2 
Follow-up of Serious Adverse Events 
This trial requires that subjects be actively monitored for SAEs up to 21 (+2) days after 
the last dose of IMP is administered. 
Serious AEs that are identified or ongoing at the last scheduled contact must be 
recorded on the AE 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, stabilized, or the subject is lost to follow-up. 
5.7.3 
Follow-up and Reporting of Serious Adverse Events Occurring 
after Last Scheduled Contact 
Any new SAEs reported by the subject to the investigator that occur after the last 
scheduled contact, and are determined by the investigator to be reasonably associated 
with the use of the IMP, should be reported to the sponsor. This may include SAEs that 
are captured on follow-up telephone contact or at any other time point after the defined 
trial period (ie, up to last scheduled contact). The investigator should follow SAEs 
identified after the last scheduled contact until the events are resolved, stabilized, or the 
subject is lost to follow-up. The investigator should continue to report any significant 
follow-up information to the sponsor up to the point the event has been resolved or 
stabilized. 
6 
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64 
 
 
 
 
 
 
 
 
CCI 
 
 


blind treatment phase in the YMRS Total Score. 
Based on the results from Abilify and other at ypical antipsychotic trials in the bipolar 
mania indication, it is reasonable to expect a between -group difference versus placebo of
–4.5 (standard deviation = 12) in the mean change from baseline to 
Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
7 
Statistical Analysis 
Complete details of the planned statistical analysis will be presented in the statistical 
analysis plan (SAP). 
7.1 
Sample Size 
It is anticipated that approximately 320 subjects will be randomized from an estimated 
45 sites in the US and Europe.  The primary efficacy endpoint is the change from 
baseline to Day 21 in the double-blind treatment phase in the YMRS Total Score. The 
trial will compare the placebo arm to the brexpiprazole arm, randomized at a ratio of 1:1, 
with an overall significance level of 0.05 (2-sided) for the primary endpoint. 
The planned sample size of 304 
evaluable subjects (152 in each treatment arm) will yield at least 90% power to detect the 
treatment effects at a 2-tailed significance level of 0.05. 
A sufficient number of subjects will be enrolled and randomized to achieve 
approximately 304 evaluable subjects in the double-blind treatment phase CCI 
the total number of subjects to be randomized is 320 
(160 in each treatment arm). 
In order to ensure 304 evaluable subjects, CCI 
7.2 
Datasets for Analysis 
The following analysis samples are defined for this trial: 
Enrolled Sample: comprises all subjects who signed an ICF for the trial and enrolled into 
the trial. 
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CCI 
 
 
 
 
 


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Randomized Sample: comprises all subjects who were randomized in the double-blind 
treatment phase. Subjects are considered randomized when they are assigned a treatment 
number by IWRS at the end of screening. A subject receiving IMP outside of the IWRS 
will not be considered randomized, but safety will be reported. 
Safety Sample: comprises those randomized subjects in the double-blind treatment phase 
who received at least 1 dose of double-blind IMP as indicated on the dosing record. 
Subjects will be excluded from this population only if there is documented evidence (ie, 
drug dispensed = drug returned or no IMP dispensed) that the subject did not take IMP. If 
a subject is dispensed IMP and is lost to follow up, he/she will be considered exposed. 
Efficacy Sample: the Full Analysis Set comprises all subjects in the Safety Sample who 
have a baseline value and at least 1 valid post-randomization efficacy evaluation for 
YMRS Total Score in the double-blind treatment phase. 
7.3 
Handling of Missing Data 
The YMRS is utilized as the primary efficacy assessment of a subject’s level of manic 
symptoms. The YMRS consists of 11 items: 1) elevated mood, 2) increased motor 
activity-energy, 3) sexual interest, 4) sleep, 5) irritability, 6) speech (rate and amount), 
7) language-thought disorder, 8) content, 9) disruptive-aggressive behavior, 
10)  appearance, and 11) insight. Seven items are rated on a 0- to 4-scale, while four 
items (Items 5, 6, 8, and 9) are rated on a 0- to 8-scale with 0, 2, 4, 6, and 8 being the 
possible scores (twice the weight of the other items). For all items, 0 is the “best” rating 
and the highest score (4 or 8) is the ‘worst’ rating. The YMRS Total Score is the sum of 
ratings for all 11 items; therefore, possible total scores range from 0 to 60. The YMRS 
Total Score is set to be missing if less than 9 of the 11 items are recorded. If 10 of the 11 
items are available and the item missing is from items 5, 6, 8 or 9, then the YMRS Total 
Score is the sum of scores for items 1 to 4, 7, 10 to 11 plus the mean of the recorded 
items from 5, 6, 8 and 9 times four. If 10 of the 11 items are available and the item 
missing is from items 1 to 4, 7, 10 to 11, then the YMRS Total Score is the sum of scores 
for items 5, 6, 8 and 9 plus the mean of the recorded items from 1 to 4, 7, 10 to 11 times 
seven.  If 9 of the 11 items are available and both missing items are from items 5, 6, 8 
and 9, then the YMRS Total Score is set to be missing. If 9 of the 11 items are available 
and both missing items are from items 1 to 4, 7, 10 to 11, then the Total Score was the 
sum of scores for items 5, 6, 8 and 9 plus the mean of the recorded items from 1 to 4, 7, 
10 to 11 times seven. If 9 of the 11 items are available and one of the missing items is 
from items 1 to 4, 7, 10 to 11, and one of the missing items is from items 5, 6, 8 and 9, 
then the YMRS Total Score is the mean of the recorded items from 5, 6, 8 and 9 times 
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Clinical Study Report 331-201-00080 
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Protocol 331-201-00080 
four, plus the mean of the recorded items from 1 to 4, 7, 10 to 11 times seven. 
imputed scores are rounded to the first decimal place. 
All 
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7.4 
Primary and Secondary Endpoint Analyses 
7.4.1 
Primary Endpoint Analysis 
The primary efficacy endpoint is the change from baseline to Day 21 of the double-blind 
treatment phase in YMRS Total Score. For analysis of the double-blind treatment phase 
data, baseline is defined as the last available measurement prior to the first dose of 
double-blind IMP. 
The primary analysis will be performed on the Efficacy Sample which includes all 
randomized subjects who took at least 1 dose of IMP in the double-blind treatment phase 
and who have both a baseline value and at least 1 post-randomization YMRS Total Score 
during the double-blind treatment phase.  The primary efficacy analysis will be 
performed by fitting a mixed-effect model repeated measure (MMRM) analysis with an 
unstructured variance covariance structure in which the change from the baseline in 
YMRS Total Score during the double-blind treatment phase will be the dependent 
variable based on the observed cases (OC) data set. CCI 
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s will be provided in SAP 
All small centers will be pooled to form “pseudo centers” for the purpose of anal ysis 
according to the following algorithm. Small centers will be ordered from the largest to 
the smallest based on the number of evaluable subjects (ie, subjects who have baseline 
and at least 1 post -baseline value for the primary endpoint in the double -blind treatment 
phase). The process will start by pooling the largest of the small centers with the smallest 
of the small centers until a no n-small center is formed. This process will be repeated 
using the centers left out of the previous pass. In case of ties in center size, the center 
with the smallest center code will be selected. If any centers are left out at the end of this 
process, th ey will be pooled with the smallest pseudo centers, or if no pseudo centers 
exist, they will be pooled with the smallest non -small center. 
In the case of gross violations of the linear model assumptions, nonparametric van 
Elteren test will be performed to compare treatment effect at 
Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
7.4.2 
Secondary Endpoint Analysis 
The key secondary efficacy endpoint is the change from baseline to Day 21 in the 
double-blind treatment phase in CGI-BP Severity of Illness score in mania. This endpoint 
will be analyzed by fitting the same MMRM model described in the primary analysis. 
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7.4.3 
7.4.4 
7.4.5 
Interim Analysis 
Not applicable. 
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. 
7.6 
Safety Analysis 
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, and physical examinations.  In addition, data from the following safety scales will 
be evaluated: assessments of suicidality (C-SSRS) and 
Safety analysis will be conducted based on the Safety Sample defined in 
Section 7.2. In general, baseline of a safety variable is defined as the last observation of 
the variable before taking the first dose of IMP, unless specified otherwise. Prospectively 
defined criteria will be used to identify potentially clinically relevant abnormal values for 
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clinical laboratory tests, vital signs, ECGs, and body weight. Details of safety analyses 
will be provided in the SAP. 
7.6.1 
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidence of the following events will be 
summarized by treatment group: 






TEAEs 
TEAEs by severity 
TEAEs potentially causally related to the IMP 
TEAEs with an outcome of death 
Serious TEAEs 
TEAEs leading to discontinuation of the IMP 
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP. 
7.6.2 
Clinical Laboratory Data 
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements and prolactin concentrations will be provided. In addition, the incidence 
of potentially clinically relevant values identified using prospectively defined in the SAP 
criteria for laboratory tests will be summarized. 
7.6.3 
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. 
7.6.4 
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. 
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: 
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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 
Results will be summarized by visit. 
7.6.5 
Suicidality (eg, C-SSRS) will be summarized by treatment group based on the OC dataset 
of the Safety Sample. Details will be described in SAP. 
8 
Management of Investigational Medicinal Product 
For full details on IMP management, please refer to the OPC-34712 IB.7 
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. 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. 
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8.3 
Accountability 
The investigator or designee must maintain an inventory record of IMP (including 
investigational, active control, or placebo) received, dispensed, administered, and 
returned. 
8.4 
Returns and Destruction 
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, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving: 








Failure/malfunction of a product to meet any of its specifications 
Incorrect or missing labeling 
Packaging issues (eg, damaged, dirty, crushed, missing product) 
Blister defects (eg, missing, empty blisters) 
Bottle defects (eg, under/over-fill, no safety seal) 
Vial defects 
Product defect (eg, odor, chipped, broken, embossing illegible) 
Loss or theft of product 
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8.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor, or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing. The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail 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 
PPD 
Phone - Rocky Mountain Call Center at PPD 
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 ID (eg, subject, investigator, site, etc.) 
Reporter contact information (eg, address, phone number, e-mail address) 
ID of material (product/compound name, coding) 
Clinical protocol reference (number and/or trial name) 
Dosage form/strength (if known) 
Pictures (if available) 
Availability for return 
8.5.3 
Return Process 
Indicate during the report of the PQC if the complaint sample is available for return. If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by the sponsor. 
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
8.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
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9 
9.1 
Records Management 
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, and duration of any AEs and the investigator's assessment of 
relationship to IMP must also be recorded; 
Any changes in concomitant medications or dosages; 
A general reference to the procedures completed; 
The signature (or initials) and date of all clinicians who made an entry in the progress 
notes. 





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 
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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. 
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. 
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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. 
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. 
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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, FDA regulations, ICH GCP 
Guideline (E6), international ethical principles derived from the Declaration of Helsinki 
and Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations. Each trial site will seek approval/favorable opinion 
by an IRB or IEC according to regional requirements, and the investigator will provide 
that documentation to the sponsor. The IRB/IEC will evaluate the ethical, scientific and 
medical appropriateness of the trial. Further, in preparing and handling ePlatform, 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 ID code will be 
used to identify each subject. 
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator. 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region(s) where the trial  
is conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  All IMPs, subject bodily fluids, and/or other  
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the sponsor. 
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Subjects will be identified only by unique subject numbers in the ePlatform. If further 
subject ID 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 or favorable opinion by the IRB or 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 
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 
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2. 
3. 
4. 
Drafting the work or revising it critically for important intellectual content; AND 
Final approval of the version to be published; AND 
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. 
No publication will be made without Otsuka authorization. 
15 
1 
References 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition. Washington, DC: American Psychiatric Association; 2013. 
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, et al. 
Canadian Network for Mood and Anxiety Treatments (CANMAT) and International 
Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines 
for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 
2013;15(1):1-44. 
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. 2016;00(00):1-16. 
Ostacher MJ, Tandon R, Suppes T. Florida best practice psychotherapeutic 
medication guidelines for adults with bipolar disorder: A novel, practical, patient- 
centered guide for clinicians. J Clin Psychiatry. 2016;77(7):920-6. 
The Management of Bipolar Disorder Working Group. VA/DoD clinical practice 
guideline for management of bipolar disorder in adults. Washington, DC: 
Department of Veterans Affairs and Department of Defense; 2010. 
Tohen M, Vieta E. Antipsychotic agents in the treatment of bipolar mania. Bipolar 
Disord. 2009:11 Suppl 2:S45-54. 
Otsuka Pharmaceutical Co, Ltd., Otsuka Pharmaceutical Development & 
Commercialization, Inc., H. Lundbeck A/S. Brexpiprazole (OPC-34712, OPC-331, 
and Lu AF41156) Investigator's Brochure, edition 12. Otsuka Report, issued 18 Aug 
2016. 
2 
3 
4 
5 
6 
7 
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8 
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: Reliability, 
validity and sensitivity. Br J Psychiatry. 1978;133:429-35. 
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, et al. 
The Mini International Neuropsychiatric Interview (M.I.N.I): The development and 
validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J 
Clin Psychiatry. 1998;59(Suppl 20):22-33. 
Sheehan D, Janavs J, Harnett-Sheehan K, Sheehan M, Gray C, Lecrubier Y, et al. 
Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic 
Disorders Studies, Version 6.0.0. Copyright 1992-2010 Sheehan DV & Lecrubier Y. 
International Conference on Harmonisation. Guideline For Good Clinical Practice: 
E6(R1). Geneva, Switzerland: International Conference on Harmonisation; 1996. 
Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the 
Clinical Global Impressions (CGI) Scale for Use in Bipolar Illness (BP): the CGI-BP. 
Psychiatry Res. 1997;73:159-71. 
9 
10 
11 
12 
13 
14 Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Janavs J, Weiller E, Keskiner A, et al. 
The validity of the Mini International Neuropsychiatric Interview (MINI) according 
to the SCID-P and its reliability. Eur Psychiatry. 1997;12:232-41. 
National Institutes of Health, National Heart, Lung and Blood Institute, North 
American Association for the Study of Obesity. The practical guide: Identification, 
evaluation, and treatment of overweight and obesity in adults. Bethesda, MD: 
National Institutes of Health; 2000. NIH publication 00-4084. 
Guy W. ECDEU Assessment Manual for Psychopharmacology – Revised. Rockville, 
MD: US Department of Health, Education, and Welfare; 1976:534-7. DHEW 
Publication ADM 76-338. 
CCI 
15 
16 
17 
18 CCI 
19 Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal bleeding due to 
interaction between selective serotonin uptake inhibitors and non-steroidal anti- 
inflammatory drugs. Aliment Pharmacol Ther. 2008;27:31-40. 
Siddiqui O, Hung JHM, O'Neill R. MMRM vs. LOCF: A comprehensive comparison 
based on simulation study and 25 NDA datasets. J Biopharmaceutical Stats. 2009; 
19(2):227-46. 
Diggle P, Kenward MG. Informative drop-out in longitudinal data analysis. Applied 
Statistics. 1994;43:49-93. 
20 
21 
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22 Ali MW, Siddiqui O. Multiple imputation compared with some information dropout 
procedures in the estimation and comparison of rates of change in longitudinal 
clinical trials with dropouts. J Biopharmaceutical Stats. 2000;10(2):165-81. 
Hedeker D, Gibbons RD. Application of random effects pattern-mixture models for 
missing data in longitudinal studies. Psychological Methods. 1997;2:64-78. 
Little RJA. Pattern-mixture models for multivariate incomplete data. J Am Stat 
Assoc. 1993;88:125-34. 
Little RJA. Modeling the drop-out mechanism in repeated measures studies. J Am 
Stat Assoc. 1995;90:1112-21. 
Wu MC, Bailey KR. Estimation and comparison of changes in the presence of 
informative right censoring: Conditional linear model. Biometrics. 1989;45:939-55. 
23 
24 
25 
26 
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Appendix 1 
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Protocol 331-201-00080 
Appendix 2 
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance 
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Protocol 331-201-00080 
Appendix 3 
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance 
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Appendix 4 
Criteria for Identifying Electrocardiogram Measurements of 
Potential Clinical Relevance 
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Mini International Neuropsychiatric Interview 
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Appendix 7 
Young-Mania Rating Scale 
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Protocol 331-201-00080 
Appendix 9 
Clinical Global Impression - Bipolar Version 
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16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Appendix 13 
Baseline Columbia-Suicide Severity Rating Scale 
PPD 
 
PPD 
 
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16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Appendix 14 
Since Last Visit Columbia Suicide-Severity Rating Scale 
PPD 
 
PPD 
 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Appendix 15 
Protocol Amendment(s)/Administrative Change(s) 
Amendment Number: 
1 
Issue Date: 
21 Dec 2017 
PURPOSE: 
The purpose of amending the Protocol 331-201-00080, issued 24 May 2017, was to: 

Update the document with minor wording revisions for grammatical and 
administrative clarification 
Remove an incorrect exclusion criteria in Section 3.1 
Add clarifying details on administration of the Clinical Global Impressions – Bipolar 
Scale assessment 
Add information on retesting subjects with elevated lithium, valproate, or 
carbamazepine at screening 
Add information on use of anticholinergics 
Update the efficacy scales in the appendices to match the licensed versions currently 
available 





BACKGROUND: 
The rationale for the changes in this protocol amendment is as follows: 

The exclusion criteria of ≥ 30% decrease in YMRS between screening and baseline 
was removed from Section 3.1 because the criteria was inadvertently left in the 
document from earlier drafts of the protocol. This criteria was removed in all other 
sections of the protocol and this removal is an administrative change only. 
Instructions were added to clarify how the 2 different parts of the alternate version of 
the CGI-BP should be administered. Specifically, there is no change to the way the 
Severity of Illness portion of the CGI-BP is administered. The CGI-BP Change from 
Baseline portion of the scale uses the baseline visit as the frame of reference. At each 
visit subsequent to baseline visit, the subject is scored based on change from the 
baseline visit. In the previous version of the scale, the reference point was "preceding 
phase" and this caused some confusion among raters. As a result, the version of the 
CGI-BP that uses “change from baseline” was used to avoid any confusion about the 
point of reference will be used 
The use of anticholinergics was intended from the beginning of study, as this is 
consistent with current clinical practice, but was omitted by accident in original 
version of the protocol. This change is not based on any new findings from the 
ongoing studies. 


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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
 The efficacy scales in the appendices were updated to match the licensed versions 
currently available. No changes to the scale grading system or scoring were made, 
and the correct versions of the scales have been used since the initiation of the trial 
MODIFICATIONS TO PROTOCOL: 
General Revisions: 
All changes by section are provided below. 
Sectional Revisions: 
Location 
Old Text 
Updated Text 
Title Page 
A Multicenter, Randomized, Double- 
blind Trial of Brexpiprazole versus 
Placebo for the Acute Treatment 
Manic Episodes, With or Without 
Mixed Features, Associated With 
Bipolar I Disorder 
A Multicenter, Randomized, Double- 
blind Trial of Brexpiprazole versus 
Placebo for the Acute Treatment of 
Manic Episodes, With or Without 
Mixed Features, Associated With 
Bipolar I Disorder 
Title Page 
Issue Date: 24 May 2017 
Issue Dates: 
Original Protocol: 24 May 2017 
Date of Amendment 1: 21 Dec 2017 
Version No.: 1.0 
Version No.: 2.0 
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Section 3.1, 
Type/Design of Trial 
Screening Phase: An interactive web 
response system (IWRS) will be used 
to obtain an identification (ID) 
number for each subject with 
documented consent. 
Screening Phase: An interactive web 
response system (IWRS) or equivalent 
will be used to obtain an identification 
(ID) number for each subject with 
documented consent. 
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Location 
Old Text 
Updated Text 
Section 3.1, 
Type/Design of Trial 
 
Treatment Phase: Following the 
screening period, subjects who meet 
all inclusion criteria, including a score 
of ≥ 24 on the Young-Mania Rating 
Scale (YMRS)8 at screening and 
baseline, and meet none of the 
exclusion criteria, including ≥ 30% 
decrease in YMRS between screening 
and baseline, will be randomized in a 
1:1 ratio to receive either placebo or 
brexpiprazole for 3 weeks. 
Treatment Phase: Following the 
screening period, subjects who meet all 
inclusion criteria, including a score of ≥ 
24 on the Young-Mania Rating Scale 
(YMRS)8 at screening and baseline, and 
meet none of the exclusion criteria, will 
be randomized in a 1:1 ratio to receive 
either placebo or brexpiprazole for 
3 weeks. 
 
Section 3.1, 
Type/Design of Trial 
 
Follow-up Phase: If any subject 
discontinues the trial early,  every 
effort should be made to complete the 
Day 21/ET assessments as soon as 
possible and prior to starting any new 
medication  or  treatment.  Subjects 
who complete all trial visits through  
the Day 21 visit may be offered entry 
into an optional open-label rollover 
trial. Subjects who do not enter the 
open-label trial will be followed up for 
safety reasons via telephone contact or 
in clinic visit 21 (± 2) days after the 
last dose of IMP. This contact also 
applies to subjects who are withdrawn 
prematurely from the trial. 
 
Follow-up Phase: If any subject 
discontinues the trial early, every effort 
should be made to complete the Day 
21/ET assessments as soon as possible 
and prior to starting any new  
medication or treatment. Subjects who 
complete all trial visits through the Day 
21 visit and had no major protocol 
violations may be offered entry into an 
optional open-label rollover trial. 
Subjects who do not enter the open- 
label trial will be followed up for safety 
reasons via telephone contact or in 
clinic visit 21 (± 2) days after the last 
dose of IMP. This contact also applies 
to subjects who are withdrawn 
prematurely from the trial. 
Section 3.4.1, 
Informed Consent 
 
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. 
 
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. 
Table 3.4.3-1, 
Exclusion Criteria 12 
 
Subjects with serum concentrations of 
lithium ≥ 0.6 mmol/L, serum 
concentrations of valproate ≥ 50 
μg/mL, or serum concentrations of 
carbamazepine ≥ 4 μg/mL (may be 
reassessed at randomization, if 
necessary). 
 
Subjects with serum concentrations of 
lithium ≥ 0.6 mmol/L, serum 
concentrations of valproate  ≥  50 
μg/mL, or serum concentrations of 
carbamazepine ≥ 4 μg/mL (if any of 
these parameters are outside of the 
listed exclusionary range, they may be 
reassessed prior to randomization, if 
necessary). 
 


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16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Location 
  
 
Old Text 
  
 
Updated Text 
CCI 
 
Table 3.7-1 
Changes to Table 3.7-1 are summarized on the next page and are indicated by 
bold, underlined text. 
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16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Table 10.2-1 
Schedule of Assessments 
Screeninga 
Double-blind Treatment Phase 
Follow-upc 
Day -14 to -1 
Baseline 
(Day 1) 
Day 4 
(± 1 day) 
Day 7 
(± 1 day) 
Day 14 
(± 1 day) 
Day 21/ETb 
(± 2 days) 
21 (± 2) days 
after last dose 
Screening Assessments and Randomization 
Informed Consentd 
X 
Demographics 
X 
Medical History 
X 
Psychiatric History 
X 
MINI 
Concomitant Medicationse 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
X 
Randomization 
X 
Efficacy Assessments 
YMRSf 
X 
X 
X 
X 
X 
X 
CGI-BPg 
X 
X 
X 
X 
X 
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Safety Assessments 
Physical Examinationh 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
X 
12-lead ECGj 
X 
X 
X 
Clinical laboratory tests 
(hematology, serum chemistry, 
urinalysis), including prolactink 
X 
X 
HbA1cj 
X 
X 
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16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Table 10.2-1 
Schedule of Assessments 
Screeninga 
Double-blind Treatment Phase 
Follow-upc 
Day -14 to -1 
Baseline 
(Day 1) 
Day 4 
(± 1 day) 
Day 7 
(± 1 day) 
Day 14 
(± 1 day) 
Day 21/ETb 
(± 2 days) 
21 (± 2) days 
after last dose 
X 
X 
TSH, with reflex to T4 if TSH 
is abnormal 
Coagulation parameters (PT, 
aPTT, INR)k 
X 
X 
Lithium, Valproate, 
Carbamazepine Levelsl 
X 
HIV, HBsAg, and anti-HCV 
X 
Pregnancy Testm 
X 
X 
X 
Drug Screenn 
Blood Alcohol Testn 
X 
X 
X 
X 
C-SSRSo 
CCI 
X 
X 
X 
X 
X 
X 
AEsp 
X 
X 
X 
X 
X 
X 
X 
CCI 
Other 
IMP dispensingr 
X 
X 
X 
X 
IMP accountability 
X 
X 
X 
X 
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Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
aPTT = activated partial thromboplastin time; HBsAg = Hepatitis B surface antigen; Anti-HCV = Antibodies to hepatitis C virus; INR = International 
Normalized Ratio; T4 = free thyroxine; TSH = thyroid-stimulating hormone. 
aScreening begins when the ICF is signed and will take place between Day −14 and Day −1; however, screening procedures should be initiated with a 
sufficient amount of time allotted in order to obtain laboratory results and ECG results from the central reader prior to randomization. Review of 
inclusion/exclusion criteria at baseline will be based on assessments performed during screening. Hospitalization will begin with the signing of the ICF for 
subjects who are not already hospitalized at the initial screening visit. Note: In the rare circumstance when a subject must leave the inpatient facility 
temporarily (eg, family emergency or doctor visit), a temporary day pass may be granted. For such a request, sites must first contact the medical 
monitor for explicit authorization and guidance on procedures. A medical monitor approved day pass is good for the day requested only, and 
subjects must return to the site the same day (eg, in the evening). 
bIf a subject discontinues prematurely before Day 21, procedures noted for Day 21 must be completed at the ET visit. 
cConsists of telephone contact or clinic visit (investigator’s discretion) for evaluation of safety 21 days after the last dose of IMP and applies only to subjects 
who do not enter the optional open-label rollover trial.
CCI 
eAll medications taken within 30 days of screening will be recorded. In addition, all prescription and non-prescription medications taken during the trial will 
be recorded as concomitant medications. 
fTo be eligible for the trial, subjects must have a YMRS score  24 at screening and baseline. 
. 
hTo include measurement of height at screening only and waist circumference at screening and Day 21. 
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. In addition, ECG results will 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. Subjects will be randomized based on screening ECG results from the central reader and baseline 
ECG results from the trial site. If the baseline ECG results from the central reader, when available, indicate a QT interval corrected for heart rate by 
Fridericia’s formula (QTcF) ≥ 450 msec in men and ≥ 470 msec in women, unless due to ventricular pacing, at baseline, the investigator must contact the 
medical monitor to discuss the subject’s continued participation in the trial. ECGs scheduled for the same visit as blood samples are to be completed before 
blood is drawn. 
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CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
kSubjects must be fasting for a minimum of 8 hours prior to blood draws for screening laboratory assessments, if at all possible. If fasting blood samples are 
not feasible at screening, nonfasting blood samples may be obtained initially for determining eligibility for the trial. Clinical laboratory tests must be drawn 
after a minimum 8-hour fast at Day 21/ET. Vital sign and ECG assessments should be completed before any blood samples are collected. 
lIf lithium, valproate, or carbamazepine levels are outside of the listed exclusionary range, they may be reassessed prior to randomization. 
mAll 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. 
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. 
oThe “Baseline/Screening” C-SSRS form will be completed for all subjects at screening to determine elgibility and the “Since Last Visit” C-SSRS form will 
be completed at the baseline visit to assure that the subject continued to qualify for the trial. Any subject with suicidal ideation within the last 6 months, 
suicidal behaviors within the last 2 years, or who in the clinical judgment of the investigator presents a serious risk of suicide should be excluded from the 
trial (see Table 3.4.3-1). The “Since Last Visit” C-SSRS form will be completed at all visits after the baseline visit. 
pAdverse events will be recorded starting after the subject signs the ICF. 
rSite staff will provide IMP to hospitalized subjects daily from assigned blister cards. If a subject is discharged at Day 14, the site should counsel the subject 
on the importance of taking IMP as directed. 
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CCI 
 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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131 
Section 3.7.1.1, 
Screening (Day -14 to 
-1) 
 
After a subject has provided consent, 
sites will obtain a subject ID number 
for the subject by accessing the IWRS. 
 
After a subject has provided consent, 
sites will obtain a subject ID number 
for the subject by accessing the IWRS 
or equivalent. 
Section 3.7.1.1, 
Screening (Day -14 to 
-1) 
 
 
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, and 
lithium valproate and 
carbamazepine levels) should be 
drawn after a minimum 8-hour 
fast at screening. See Table 
3.4.4-1 for exclusions based on 
outcome of screening clinical 
laboratory tests. Note: if lithium, 
valproate, or  carbamazepine 
levels are outside of the listed 
exclusionary range, they may be 
reassessed prior to randomization. 
 
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, and lithium, valproate, 
and carbamazepine levels) should 
be drawn after a minimum 8-hour 
fast at screening. See Table 3.4.4-1 
for exclusions based on outcome of 
screening clinical laboratory tests. 
Note: if lithium, valproate, or 
carbamazepine levels are outside 
of the listed exclusionary range, 
they may be reassessed prior to 
randomization. 
 
Section 3.7.1.4, 
Treatment Phase - 
Day 4 
The following procedures will be 
performed on Day 4: 
 
The following procedures will be 
performed on Day 4 (± 1 day): 
 
Section 3.7.1.5, 
Treatment Phase - 
Day 7 
The following procedures will be 
performed on Day 7: 
 
The following procedures will be 
performed on Day 7 (± 1 day): 
 
Section 3.7.1.6, 
Treatment Phase - 
Day 14 
The following procedures will be 
performed on Day 14: 
 
The following procedures will be 
performed on Day 14 (± 1 day): 
 
Section 3.7.1.7, End of 
Treatment Phase - Day 
21/Early Termination 
Visit 
 
Not applicable (newly added text) 
 
All subjects will undergo a complete 
evaluation at Day 21 (± 2 day). In 
addition, Day 21 evaluations are to be 
completed for any subject withdrawn 
at any time after randomization into 
the trial. Attempts should be made 
to complete all evaluations, 
particularly efficacy assessments, for 
the Day 21/ET visit prior to the 
administration of any new 
psychotropic medications. However, 
if the subject receives a new rescue 
medication for worsening manic 
symptoms prior to ET procedures 
prior to the Day 21/ET procedures, 
no efficacy assessments should be 
performed. 
The following procedures will be 
performed on Day 21(± 2 day) or the 
ET visit: 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Section 3.7.2.2, 
Clinical Global 
Impression - Bipolar 
Version 
The scale rates the subject’s severity 
of illness (CGI-BP severity of illness: 
mania, depression, and overall bipolar 
illness) and Change from Preceding 
Phase (CGI-BP change  from 
preceding phase: mania, depression, 
and overall bipolar illness) based on a 
The scale rates the subject’s Severity of 
Illness (CGI-BP Severity of Illness: 
mania, depression, and overall bipolar 
illness) based on a 7-point scale and 
rates the subject’s Change from 
Baseline (CGI-BP change from 
Baseline: mania, depression, and 
overall bipolar illness) based on a 7- 
Section 3.7.3.2, 
Clinical Laboratory 
Assessments 
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. 
The central laboratory will provide 
laboratory results electronically. 
Section 3.8.3.1, 
Treatment Interruption 
No treatment interruptions are 
permitted in this trial. 
All attempts should be made to avoid 
treatment interruption during the 
trial. For subjects who have an 
interruption of treatment, the 
investigator or designee will contact 
the medical monitor as soon as 
possible. The investigator and 
medical monitor will come as quickly 
as possible to a joint decision 
regarding the subject’s continuation 
in the trial. This decision will be 
documented by the investigator and 
the medical monitor. The treatment 
interruption will be recorded via 
eSource and also recorded as a 
protocol deviation (Section 3.13). 
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132 
 
 
  
 
 
 
 
  
 
 
 
CCI 
 
point scale. 
7-point scale. CCI 
 
 
 
 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
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133 
Section 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. 
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 medical monitor at the 
earliest possible time by telephone. 
The investigator and medical monitor 
will come as quickly as possible to a 
joint decision regarding the subject’s 
continuation in the trial. This decision 
will be documented by the investigator 
and the medical monitor, and reviewed 
by the site monitor. 
Section 4.1, Prohibited 
Medications 
 
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 
randomization. Other therapies 
restricted or prohibited prior to 
enrollment and during the trial are 
presented in Section 4.2. 
 
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 randomization. 
Subjects with serum  concentrations 
of lithium ≥ 0.6 mmol/, valproate ≥ 50 
μg/mL, or carbamazepine ≥ 4 μg/mL 
at screening may repeat a clinical 
laboratory test for these parameters 
prior to  randomization.  The results 
of the additional test will be reviewed 
and confirmed before the subject can 
be randomized into the trial. Other 
therapies restricted or  prohibited  prior 
to enrollment and during the trial are 
presented in Section 4.2. 
Section 4.2, Other 
Restrictions 
 
Not applicable (newly added text) 
 
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. 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Section 5.1, 
Definitions 
Pregnancies are also defined as IREs. 
Although normal pregnancy is not an 
AE, it will mandate IMP 
discontinuation and must be reported 
on an IRE form to the sponsor. 
Pregnancy will only be documented 
on the AE ePlatform if there is an 
abnormality or complication. 
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. 
Section 5.2, Eliciting 
and Reporting Adverse 
Events 
All AEs (serious and nonserious) 
reported by the subject must be 
recorded within the esource provided 
by the sponsor. 
CCI 
All AEs (serious and nonserious) 
reported by the subject must be 
recorded within the eSource platform 
provided by the sponsor. 
Section 7.4.2, 
Secondary Endpoint 
Analysis 
Appendix 7, Young- 
Mania Rating Scale 
CCI 
Assessment updated to the latest version. 
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134 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Protocol 331-201-00080 
Agreement 
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement. 
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, brexpiprazole (OPC-34712), the 
concurrent medications, the efficacy and safety parameters and the conduct of the trial in general.   
I am aware that this protocol must be approved by the Institutional Review Board (IRB) or receive   
a favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in    
the clinical trial facility where brexpiprazole (OPC-34712) will be tested prior to commencement of 
this trial. I agree to adhere strictly to the attached protocol (unless amended in the manner set   
forth in the sponsor's Clinical Trial Agreement, at which time I agree to adhere strictly to the  
protocol as amended). 
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate   
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways, such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor and  designee  monitors  and 
auditors full access to all medical records at the research facility for subjects screened or enrolled 
in the trial. 
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations. 
I agree to provide all subjects with informed consent 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 
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135 
 
 
 
 


Clinical Study Report 331-201-00080 
16.1.1 Protocol and Protocol Amendments 
Otsuka Pharmaceutical Development & Commercialization, Inc. 
This page is a manifestation of an electronically captured signature 
OPC-34712 
SIGNATURE PAGE 
Document Name: Protocol 331-201-00080 Amendment 1 
Document Number: 0001260106 
Document Version: 4.0 
Clinical Approval 
22-Dec-2017 21:01 GMT+00 
Biostatistics Approval 
23-Dec-2017 15:11 GMT+00 
Clinical Pharmacology 
02-Jan-2018 14:53 GMT+00 
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136 
PPD 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
 

SAP_001.pdf: 
Protocol 331-201-00080 


Protocol number: 331-201-00080 
Document title: A Multicenter, Randomized, Double-blind Trial of 
Brexpiprazole Versus Placebo for the Acute Treatment of Manic 
Episodes, With or Without Mixed Features, Associated With Bipolar 
I Disorder 
Version number: 2.0 
Date of the document: 11Dec2018 


NCT number: NCT03259555 
Confidential - Proprietary Information 
 


Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
Documentation of Statistical Methods 
Table of Contents 
Table of Contents.................................................................................................. 
Statistical Analysis Plan; Final: 11 Dec 2018....................................................... 
1 
3 
STAT-1 
Adjusted Mean Change from End of Baseline in YMRS Line 
Items at End of Treatment - MMRM (Efficacy Sample) ........... 
MMRM Output for Test on Treatment by Gender Interaction 
at End of Treatment (Efficacy Sample)...................................... 
MMRM Output for Test on Treatment by Race Interaction at 
End of Treatment (Efficacy Sample).......................................... 
MMRM Output for Test on Treatment by Age Interaction at 
End of Treatment (Efficacy Sample).......................................... 
MMRM Output for Test on Treatment by Region Interaction 
at End of Treatment (Efficacy Sample)...................................... 
Proc Mixed Output for Change from End of Baseline in 
YMRS Total Score, MMRM (UN), 
DDFM=KENWARDROGER (Efficacy Sample) ...................... 
Proc Mixed Output for Change from End of Baseline in 
YMRS Total Score, MMRM (UN), 
DDFM=SATTERTHWAITE (Efficacy Sample)....................... 
Proc GLM Output for Change from End of Baseline in 
YMRS Total Score, LOCF (Efficacy Sample)........................... 
Proc GLM Output for Change from End of End of Baseline 
in YMRS Total Score, OC (Efficacy Sample) ........................... 
Proc GLM Output for Treatment by Center Interaction at 
Day 21 in YMRS Total Score, LOCF (Efficacy Sample) .......... 
Summary of Mean Change at Day 21 from Baseline in 
YMRS Total Score - By Center - LOCF (Efficacy Sample)...... 
Differences in Unadjusted Mean Changes of YMRS Total 
Score at Day 21 Among Treatment Groups - By Center - 
LOCF (Efficacy Sample)............................................................ 
Unadjusted Mean Change from Baseline to End of 
Treatment by Study Week YMRS Total Score, LOCF 
(Efficacy Sample) ....................................................................... 
Unadjusted Mean Change from Baseline to End of 
Treatment by Study Week YMRS Total Score, OC (Efficacy 
Sample)....................................................................................... 
Non-Parametric Stratified by Center Analysis of Mean 
Change from Baseline to End of Treatment by Study Week 
in YMRS Total Score, LOCF (Efficacy Sample)....................... 
Residual at Day 21 from Proc Mixed for Change from 
Baseline in YMRS Total Score, Primary Efficacy Analysis 
Model (Efficacy Sample) ........................................................... 
44 
STAT-3.1 
46 
STAT-3.2 
61 
STAT-3.3 
76 
STAT-3.4 
91 
STAT-4.1.1 
106 
STAT-4.1.2 
120 
STAT-4.2 
131 
STAT-4.3 
136 
STAT-4.4 
141 
STAT-4.5.1 
143 
STAT-4.5.2 
145 
STAT-4.6 
147 
STAT-4.7 
155 
STAT-4.8 
163 
STAT-4.9 
167 
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1 
 


Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
STAT-4.10 
Proc Mixed Output Using Heterogeneous Variance Structure 
for Treatment Groups (Efficacy Sample) ................................... 
Proc Mixed Output for Change from Baseline in CGI-BP 
Severity Score in Mania, MMRM (UN) (Efficacy Sample) ...... 
Proc GLM Output for Change from Baseline to End of 
Treatment in CGI-BP Severity Score in Mania, LOCF 
(Efficacy Sample) ....................................................................... 
Proc GLM Output for Change from Baseline to End of 
Treatment in CGI-BP Severity Score in Mania, OC (Efficacy 
Sample)....................................................................................... 
Shapiro-Wilk Test for Residual by Week from Proc Mixed 
for Change from Baseline in YMRS Total Score, Primary 
Efficacy Analysis Model (Efficacy Sample) .............................. 
Residual by Week from Proc Mixed for Change from 
Baseline in YMRS Total Score, Primary Efficacy Analysis 
Model (Efficacy Sample) ........................................................... 
176 
STAT-5.1 
191 
STAT-5.2 
202 
STAT-5.3 
207 
STAT-6.1.1 
212 
STAT-6.1.2 
213 
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2 
 


26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
Otsuka Pharmaceutical Development & Commercialization, Inc. 
Investigational New Drug 
Brexpiprazole (OPC-34712) 
A Multicenter, Randomized, Double-blind Trial of Brexpiprazole versus Placebo for the 
Acute Treatment of Manic Episodes, With or Without Mixed Features, Associated With 
Bipolar I Disorder 
Protocol No. 331-201-00080 
IND No. 134115 
EudraCT No. 2017-002222-20 
Statistical Analysis Plan 
Version: Final 
Date: December 11, 2018 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc. 
Confidential - Proprietary Information 
1 
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3 
 


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26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
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 331-201-00080. All amendments to the protocol are taken into 
consideration in developing this SAP. 
2 
Study Objectives 
Primary: To demonstrate the efficacy of brexpiprazole for the acute treatment of manic 
episodes, with or without mixed features, in subjects with a diagnosis of bipolar I disorder. 
Secondary: To confirm the safety and tolerability of brexpiprazole in this same population. 
3 
3.1 
Trial Details 
Study Design 
This will be a 3-week, multicenter, randomized, double-blind, placebo-controlled trial of 
brexpiprazole in subjects diagnosed with bipolar I disorder (current manic episode with or 
without mixed features) according to the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5; updated terminology replaces “mixed episodes” with the 
descriptor of “mixed features”). The total duration of the trial is up to 8 weeks, including 
screening, double-blind treatment, and follow-up. See Figure 3.1-1 for a schematic of the trial 
design. 
The trial will be organized as follows: 
Screening Phase: The screening period will begin after written informed consent has been 
obtained and will take place between Day −14 and Day −1 prior to randomization. 
Hospitalization will begin with the signing of the informed consent form (ICF) for subjects 
who are not already hospitalized at the time of the initial screening visit. The purpose of the 
screening period is to assess eligibility criteria and to washout prohibited concomitant 
medication. Subjects will be between 18 and 65 years of age, inclusive, at the time of 
screening, will have a diagnosis of bipolar I disorder, and will be experiencing a manic 
episode with or without mixed features as defined by the DSM-5 criteria. An interactive web 
response system (IWRS) will be used to obtain an identification (ID) number for each subject 
with documented consent. Although the screening period will continue up to administration 
of the first dose of investigational medicinal product (IMP), screening procedures should be 
Confidential - Proprietary Information 
4 
11 December 2018 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka. 
6 
 


26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
initiated with a sufficient amount of time allotted in order to obtain laboratory results and 
electrocardiogram (ECG) results from the central reader prior to randomization. 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. 
All subjects must agree to discontinue all prohibited medications during the screening period 
in order to meet the protocol-specified washout periods. 
Treatment Phase: Following the screening period, subjects who meet all inclusion criteria, 
including a score of ≥ 24 on the Young-Mania Rating Scale (YMRS) at screening and 
baseline, and meet none of the exclusion criteria, will be randomized in a 1:1 ratio to receive 
either placebo or brexpiprazole for 3 weeks. Subjects will receive a starting dose of 2 mg/day 
of brexpiprazole (or corresponding placebo) from Days 1 to 3, followed by titration to 3 
mg/day brexpiprazole (or placebo) on Day 4. Further dose increases up to 4 mg/day may 
occur no earlier than Day 7 at the investigator’s discretion based on treatment response. 
Subjects who are unable to tolerate their current dose can be titrated down at any time to a 
minimum of 2 mg/day. Subjects may be re-titrated back to higher dose levels based on 
investigator discretion. 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. All 
subjects will remain hospitalized for a minimum of the first 2 weeks of the 3-week treatment 
phase. However, subjects who, in the opinion of the investigator, have clinically improved 
from their baseline assessments with mild to no manic symptoms, and are stable enough to be 
treated on an outpatient basis, including no risk of suicide as assessed by the Columbia- 
Suicide Severity Rating Scale (C-SSRS), may be discharged and will continue as outpatients 
for the last week of double-blind treatment. Subjects who do not meet these criteria will 
remain hospitalized for the duration of the 3-week treatment phase. 
A drug screen and alcohol test are required at the Day 21/Early Termination (ET) visit for 
subjects who are discharged from the hospital at the end of Week 2 (Day 14) to verify 
continued compliance with the protocol. 
Subjects will be evaluated at Baseline (Day 1), Day 4, Day 7, Day 14 and Day 21 during the 
double-blind treatment phase. 
Follow-up Phase: If any subject discontinues the trial early, every effort should be made to 
complete the Day 21/ET assessments as soon as possible and prior to starting any new 
medication or treatment. Subjects who complete all trial visits through the Day 21 visit may 
be offered entry into an optional open-label rollover trial. Subjects who do not enter the open- 
Confidential - Proprietary Information 
5 
11 December 2018 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka. 
7 
 


26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
label trial will be followed up for safety reasons via telephone contact or in clinic visit 21 (± 
2) days after the last dose of IMP. 
prematurely from the trial. 
This contact also applies to subjects who are withdrawn 
Confidential - Proprietary Information 
6 
11 December 2018 
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. 
8 
 


26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
C-SSRS = Columbia-Suicide Severity Rating Scale. 
aSubjects who complete all trial visits through the Day 21 visit may be offered entry into an optional open-label rollover trial. 
Figure 3.1-1 
Trial Design Schematic 
Confidential - Proprietary Information 
7 
11 December 2018 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated 
or re-distributed without prior written consent of Otsuka. 
9 
 


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26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
6.3 
Protocol Deviation 
Protocol deviations will be summarized by center and type of deviation for randomized subjects 
by treatment group. A listing of protocol deviations will be provided. 
7 
7.1 
Baseline Characteristics
Baseline Definition 
For analyses of the double-blind treatment period data, the baseline is the Baseline 
measurement (expected to be at Day 1). Baseline measurement is defined as the last available 
measurement prior to the start of double-blind IMP. 
7.2 
Demographic Characteristics 
Baseline demographic characteristics include age, sex, race, ethnicity, height, weight, waist 
circumference, and body mass index (BMI). For the Randomized Sample, demographic 
characteristics will be summarized by treatment group. 
Mean, range and standard deviation will be used to describe continuous variables such as age. 
Frequency distributions will be tabulated for categorical variables such as race. 
7.3 
Medical and Psychiatric History 
A summary of medical, psychiatric, and bipolar I disorder history will be presented for the 
Randomized Sample (by treatment group and overall). 
7.4 
Neuropsychiatric Diagnosis 
A summary of the MINI International Neuropsychiatric Interview (M.I.N.I.) will be presented 
for the Randomized Sample (by treatment group and overall). Summarized will be the number 
and percentage of patients who meet each diagnosis criteria, and number and percentage of 
patients with each primary diagnosis. 
7.5 
Baseline Psychiatric Evaluation 
For the Randomized Sample, baseline psychiatric scale evaluation will be summarized by 
treatment group and overall. The mean, median, range and standard deviation will be used to 
summarize the assessments of: YMRS Total Score, Clinical Global Impression – Bipolar 
Confidential - Proprietary Information 
12 
11 December 2018 
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. 
14 
 


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26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
A separate incidence table will be provided for DILI cases, and the corresponding listing will 
be provided for Safety Sample during the double-blind treatment period. 
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 
treatment group using the following criteria. 
¹ BASELINE IS CALCULATED FROM WEEK 1. 
¹ BASELINE IS CALCULATED FROM WEEK 1. 
Confidential - Proprietary Information 
22 
11 December 2018 
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. 
24 
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 
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 
 


26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
9.3 
Vital Signs 
Summary statistics for vital signs will be provided. For the double-blind treatment period, 
vital signs, change from baseline will be summarized for the Safety Sample by treatment 
group. 
Potentially clinically relevant vital signs measurements identified in the double-blind 
treatment period for the Safety Sample will be summarized by treatment group. Criteria for 
identifying vital signs of potential clinical relevance are provided in Appendix 1. All 
potentially clinically relevant events or changes will be listed and included in summary tables. 
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 
QTcF is the length of the QT interval corrected for heart rate by the Fridericia formula: 
QTcF=QT/(RR)0.33 
QTcN is the length of the QT interval corrected for heart rate by the FDA Neuropharm 
Division formula: QTcN=QT/(RR)0.37 
2) 
3) 
Potentially clinically relevant changes in the 12-lead ECG identified in the double-blind 
treatment period for the Safety Sample will be listed and summarized by treatment group. 
Criteria for identifying ECG measurements of potential clinical relevance are provided in 
Appendix 3. 
Categorical changes in ECG parameters during the double-blind treatment period will be 
summarized based on the following criteria: 
Confidential - Proprietary Information 
23 
11 December 2018 
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. 
25 
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 
New onset (≥ 450 Msec for men and (≥ 470 Msec 
for women) in QTc means a subject who attains a 
 


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26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
10.3.8 
C-SSRS 
Suicidality will be monitored during the trial using the C-SSRS. This trial will use the 
“baseline/screening” and “Since Last Visit” versions of the scale. The “baseline/screening” 
version, which assesses the lifetime experience of the subject with suicide events and suicidal 
ideation and the occurrence of suicide events and/or ideation within a specified time period 
prior to entry into the trial, will be completed for all subjects at screening to determine 
eligibility. Any subject with active suicidal ideation within the last 6 months, suicidal 
behaviors within the last 2 years, or who in the clinical judgment of the investigator presents a 
serious risk of suicide should be excluded from the trial. The “Since Last Visit” C-SSRS form 
will also be completed at all visits after screening. 
Confidential - Proprietary Information 
30 
11 December 2018 
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. 
32 
 


26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
11 
1 
References 
Siddiqui O, Hung JHM, O'Neill R. MMRM vs. LOCF: A comprehensive comparison 
based on simulation study and 25 NDA datasets. J Biopharmaceutical Stats. 2009; 
19(2):227-46. 
Diggle P, Kenward MG. Informative drop-out in longitudinal data analysis. Applied 
Statistics. 1994; 43:49-93. 
Little RJA. Pattern-mixture models for multivariate incomplete data. J Am Stat Assoc. 
1993; 88:125-34. 
Little RJA. Modeling the drop-out mechanism in repeated measures studies. J Am Stat 
Assoc. 1995; 90:1112-21. 
Hedeker D, Gibbons RD. Application of random effects pattern-mixture models for 
missing data in longitudinal studies. Psychological Methods. 1997; 2:64-78. 
Ali MW, Siddiqui O. Multiple imputation compared with some information dropout 
procedures in the estimation and comparison of rates of change in longitudinal clinical 
trials with dropouts. J Biopharmaceutical Stats. 2000;10(2):165-81. 
Wu MC, Bailey KR. Estimation and comparison of changes in the presence of informative 
right censoring: Conditional linear model. Biometrics. 1989; 45:939-55. 
van Elteren, PH. On the combination of independent two sample tests of Wilcoxon. Bull 
Int Stat Inst. 1960; 37:351-61. 
Mehrotra D, Li X, Liu J, Lu K. Analysis of Longitudinal Clinical Trials with Missing 
Data Using Multiple Imputation in Conjunction with Robust Regression. Biometrics 
2012; 68:1250-1259. 
Cortina, J. M., & Nouri, H. (2000). Effect size for ANOVA designs. Thousand Oaks, Calif.: 
Sage Publications. 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Confidential - Proprietary Information 
31 
11 December 2018 
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. 
33 
 


26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
12 Potential Clinical Relevance Criteria from Protocol 
Appendix 1 
Criteria for Identifying Vital Signs of Potential Clinical Relevance 
Criterion Valuea 
Change Relative to Baselinea 
Variable 
Heart Rateb 
 15 bpm increase 
 15 bpm decrease 
> 120 bpm 
< 50 bpm 
Systolic Blood Pressureb 
 20 mmHg increase 
 20 mmHg decrease 
> 180 mmHg 
< 90 mmHg 
Diastolic Blood Pressureb 
 15 mmHg increase 
 15 mmHg decrease 
> 105 mmHg 
< 50 mmHg 
 20 mmHg decrease in systolic blood 
pressure and a  25 bpm increase in 
heart rate from supine to 
sitting/standing 
Orthostatic Hypotension 
Not Applicable 
(baseline status not considered) 
 7% increase 
 7% decrease 
Weight 
- 
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). 
Confidential - Proprietary Information 
32 
11 December 2018 
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. 
34 
 
 
 
 


26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
Appendix 2 
Criteria for Identifying Laboratory Values of Potential Clinical 
Relevance 
Laboratory Tests 
Criteria 
Chemistry 
AST (SGOT) 
ALT (SGPT) 
Alkaline phosphatase 
Lactate dehydrogenase (LDH) 
Blood urea nitrogen (BUN) 
Creatinine 
Uric Acid 
Men 
Women 
Bilirubin (total) 
Creatine phosphokinase (CPK) 
Prolactin 
 3 x upper limit of normal (ULN) 
 3 x ULN 
 3 x ULN 
 3 x ULN 
 30 mg/dL 
 2.0 mg/dL 
 10.5 mg/dL 
 8.5 mg/dL 
 2.0 mg/dL 
 3 x ULN 
> ULN 
Hematology 
Hematocrit 
Men 
Women 
 37 % and decrease of  3 percentage points from Baseline 
 32 % and decrease of  3 percentage points from Baseline 
Hemoglobin 
Men 
Women 
White blood count 
Eosinophils 
Neutrophils 
Absolute neutrophil count 
Platelet count 
Urinalysis 
Protein 
Glucose 
Casts 
Additional Criteria 
Chloride 
Potassium 
Sodium 
Calcium 
Glucose 
Fasting 
Non-Fasting 
Total Cholesterol, Fasting 
LDL Cholesterol, Fasting 
HDL Cholesterol, Fasting 
Men 
Women 
Triglycerides, Fasting 
 11.5 g/dL 
 9.5 g/dL 
 2,800/ mm3 or  16,000/ mm3 
 10% 
 15% 
 1,000/ mm3 
 75,000/ mm3 or  700,000/ mm3 
Increase of  2 units 
Increase of  2 units 
Increase of  2 units 
 90 mEq/L or  118 mEq/L 
 2.5 mEq/L or  6.5 mEq/L 
 126 mEq/L or  156 mEq/L 
 8.2 mg/dL or  12 mg/dL 
 100 mg/dL 
 200 mg/dL 
 240 mg/dL 
 160 mg/dL 
< 40 mg/dL 
< 50 mg/dL 
 150 mg/dL 
Confidential - Proprietary Information 
33 
11 December 2018 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka. 
35 
 
 
 
 


26 November 2018 
Clinical Study Report 331-201-00080 
16.1.9 Documentation of Statistical Methods 
SAP 331-201-00080 
Appendix 3 
Relevance 
Criteria for Identifying ECG Measurements of Potential Clinical 
Criterion Valuea
Change Relative to Baselinea
Variable 
Rate 
 120 bpm 
 50 bpm 
Tachycardia 
Bradycardia 
Rhythm 
Sinus tachycardiab
Sinus bradycardiac
Supraventricular premature beat 
Ventricular premature beat 
Supraventricular tachycardia 
Ventricular tachycardia 
Atrial fibrillation 
Atrial flutter 
Conduction 
1 atrioventricular  block 
2 atrioventricular  block 
3 atrioventricular block 
Left bundle-branch block 
Right bundle-branch block 
Pre-excitation syndrome 
Other intraventricular conduction blockd 
Infarction 
Acute or subacute 
Old 
 120 bpm 
 50 bpm 
all 
all 
all 
all 
all 
all 
PR  200 msec 
all 
all 
all 
all 
all 
QRS  120 msec 
increase of ≥ 15 bpm 
decrease of ≥ 15 bpm 
increase of ≥ 15 bpm 
decrease of ≥ 15 bpm 
not present  present 
not present  present 
not present  present 
not present  present 
not present  present 
not present  present 
increase 
of 
≥ 
50 
msec not present  
present not present  
present not present  
present not present  
present not present  
present increase of ≥ 
20 msec 
all 
all 
not present  present 
not present  present 
 12 weeks post study entry 
ST/T Morphological 
Myocardial Ischemia 
Symmetrical T-wave inversion 
Increase in QTc 
not present  present 
not present  present 
all 
all 
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. 
Confidential - Proprietary Information 
34 
11 December 2018 
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. 
36 


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