Conditions: Borderline Personality Disorder
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 201
Healthy volunteers: no

Brief summary:
This study evaluates the safety and tolerability of brexpiprazole in the treatment of adults with borderline personality disorder.

Detailed description:

Arms:
arm 1: Participants who received blinded brexpiprazole 2 to 3 milligrams per day (mg/day) in the previous double-blind trial (NCT04100096), received open-label brexpiprazole 2 to 3 mg/day tablets, orally for up to 12 weeks. arm 2: Participants who received blinded brexpiprazole matching placebo in the previous double-blind trial (NCT04100096), received open-label brexpiprazole 2 to 3 mg/day tablets, orally for up to 12 weeks.

Interventions: intervention 1: Brexpiprazole
Intervention descriptions: intervention 1: Administered as tablets.

Protocol document:
Prot_000.pdf: 
NCT Number: 
Document Date: 
A Multicenter, Open-label Trial to Evaluate the Safety and 
Tolerability of Brexpiprazole in the Treatment of Adult 
Subjects With Borderline Personality Disorder
 NCT04186403
Protocol Amendment Version 1: 01 July 2020
Official Title: 


Otsuka Pharmaceutical Development & Commercialization, Inc. 
Investigational Medicinal Product 
Brexpiprazole (OPC-34712) 
REVISED CLINICAL PROTOCOL 
A Multicenter, Open-label Trial to Evaluate the Safety and Tolerability of Brexpiprazole 
in the Treatment of Adult Subjects With Borderline Personality Disorder 
Open-label Trial of Brexpiprazole in the Treatment of Borderline Personality Disorder 
Protocol No. 331-201-00195 
IND No. 141091 
EudraCT No. 2019-002897-30 
CONFIDENTIAL  PROPRIETARY INFORMATION 
Clinical Development Phase: 
2/3 
Sponsor: 
Otsuka Pharmaceutical 
Development & Commercialization, Inc. 
2440 Research Boulevard 
Rockville, Maryland 20850, United States 
Immediately Reportable Event 
Syneos Health Pharmacovigilance & Drug 
Safety 
Amendment 1 Approval: 
01 Jul 2020 
Original Approval: 
21 Aug 2019 
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Trial Conduct for COVID-19 
All procedures and assessments in this protocol are to be followed to the fullest 
extent possible. The sponsor, in coordination with the site, investigator(s), and 
medical monitor, will continuously monitor and evaluate the benefits and risks to 
subject participation in the clinical trial as it relates to COVID-19. If any 
protocol-specified activities were not able to be performed, or cannot be performed 
due to COVID-19 considerations, refer to the COVID-19 Addendum for the 
appropriate measures to be followed. Appropriate measures may include replacing 
in-person visits with virtual visits (phone or video) as deemed necessary by the 
investigator to ensure subject safety and maintain protocol requirements. 


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Table of Contents 
Trial Conduct for COVID-19 ....................................................................... 2
Table of Contents ........................................................................................... 3
List of In-text Tables ..................................................................................... 8
List of In-text Figures .................................................................................... 9
1 
Protocol Summary .............................................................................. 10
1.1 
Synopsis.............................................................................................................10 
1.2 
Schema ..............................................................................................................16 
1.3 
Schedule of Assessments...................................................................................17 
2 
Introduction ........................................................................................ 21
2.1 
Trial Rationale ...................................................................................................22 
2.2 
Background .......................................................................................................22 
2.3 
Known and Potential Risks and Benefits ..........................................................23 
3 
Objectives and Endpoints .................................................................. 24
4 
Trial Design ......................................................................................... 25
4.1 
Type/Design of Trial .........................................................................................25 
4.2 
Scientific Rationale for Trial Design.................................................................27 
4.3 
Dosing Rationale ...............................................................................................27 
4.4 
End of Trial Definition ......................................................................................27 
4.5 
Definition of Completed Subjects .....................................................................28 
5 
Trial Population .................................................................................. 28
5.1 
Subject Selection and Numbering .....................................................................28 
5.2 
Eligibility Criteria..............................................................................................28 
5.2.1 
Inclusion Criteria ............................................................................................29 
5.2.2 
Exclusion Criteria ...........................................................................................29 
5.3 
Lifestyle Considerations ....................................................................................31 
5.3.1 
Meals and Dietary Restrictions .......................................................................31 
5.3.2 
Caffeine, Alcohol, and Tobacco .....................................................................31 
5.3.3 
Activity ...........................................................................................................32 
5.4 
Screen Failures ..................................................................................................32 
6 
Trial Treatments ................................................................................. 32


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6.1 
Trial Treatments Administered .........................................................................32 
6.1.1 
Medical Devices .............................................................................................33 
6.2 
Management of Investigational Medicinal Product ..........................................33 
6.2.1 
Packaging and Labeling ..................................................................................33 
6.2.2 
Storage ............................................................................................................33 
6.2.3 
Accountability .................................................................................................34 
6.2.4 
Returns and Destruction .................................................................................34 
6.2.5 
Reporting of Product Quality Complaints ......................................................34 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints .................................35 
6.2.5.2 
Information Required for Reporting Purposes ............................................35 
6.2.5.3 
Return Process .............................................................................................35 
6.2.5.4 
Assessment/Evaluation ...............................................................................35 
6.3 
Measures to Minimize/Avoid Bias ....................................................................35 
6.4 
Subject Compliance ...........................................................................................36 
6.5 
Concomitant Medications or Therapies ............................................................36 
6.5.1 
Prohibited Medications ...................................................................................36 
6.5.2 
Benzodiazepine Use During the Trial .............................................................38 
6.5.3 
Permitted Medications or Therapies ...............................................................38 
6.5.4 
Rescue Medications ........................................................................................39 
6.6 
Intervention after the End of the Trial ...............................................................39 
7 
Stopping Rules, Withdrawal Criteria, and Procedures .................. 39 
7.1 
Entire Trial or Treatment ...................................................................................39 
7.2 
Individual Site ...................................................................................................39 
7.3 
Individual Subject Discontinuation ...................................................................39 
7.3.1 
Treatment Interruption ....................................................................................39 
7.3.2 
Treatment Discontinuation .............................................................................40 
7.3.3 
Documenting Reasons for Treatment Interruption or Discontinuation ..........40 
7.3.4 
Withdrawal of Consent ...................................................................................41 
7.3.5 
Procedures to Encourage Continued Trial Participation ................................42 
7.4 
Definition of Subjects Lost to Follow-up ..........................................................42 
8 
Trial Procedures ................................................................................. 42 
8.1 
Efficacy Assessments ........................................................................................43 


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44 
 
44 
 
44 
8.2 
Pharmacokinetic Assessments ...........................................................................44 
8.3 
Pharmacodynamic Assessments ........................................................................44 
8.4 
Pharmacogenomic Assessments ........................................................................44 
8.5 
Biomarker Assessments ....................................................................................45 
8.6 
Future Biospecimen Research Samples ............................................................45 
8.7 
Safety Assessments ...........................................................................................45 
8.7.1 
Clinical Laboratory Assessments ...................................................................45 
8.7.2 
Physical Examination .....................................................................................46 
8.7.3 
Vital Signs ......................................................................................................47 
8.7.4 
Electrocardiogram ...........................................................................................47 
8.7.5 
Suicidality Monitoring - Columbia-Suicide Severity Rating Scale ................48 
8.7.6 
Other Safety Variables ....................................................................................48 
8.7.6.1 
Simpson Angus Scale ..................................................................................49 
8.7.6.2 
Abnormal Involuntary Movement Scale .....................................................49 
8.7.6.3 
Barnes Akathisia Rating Scale ....................................................................50 
8.8 
Adverse Events ..................................................................................................50 
8.8.1 
Definitions ......................................................................................................50 
8.8.2 
Eliciting and Reporting Adverse Events .........................................................52 
8.8.3 
Immediately Reportable Events ......................................................................53 
8.8.4 
Medical Device Incidents (Including Malfunctions) ......................................53 
8.8.5 
Adverse Events of Special Interest .................................................................53 
8.8.6 
Potential Serious Hepatotoxicity ....................................................................53 
8.8.7 
Procedure for Breaking the Blind ...................................................................53 
8.8.8 
Follow-up of Adverse Events .........................................................................53 
8.8.8.1 
Follow-up of Nonserious Adverse Events ..................................................53 
8.8.8.2 
Follow-up of Immediately Reportable Events ............................................54 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact ....................................................54 
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8.9 
Treatment of Overdose ......................................................................................55 
8.10 
Subject Assessment Recording .........................................................................55 
 
55 
 
55 
 
55 
 
55 
8.11 
Other Assessments ............................................................................................55 
9 
Statistical Considerations .................................................................. 56 
9.1 
Sample Size .......................................................................................................56 
9.2 
Datasets for Analysis .........................................................................................56 
9.3 
Handling of Missing Data for Primary and Secondary Endpoint Analysis ......56 
9.4 
Statistical Analyses............................................................................................56 
 
56 
9.4.2 
Safety Analysis ...............................................................................................56 
9.4.2.1 
Adverse Events............................................................................................57 
9.4.2.2 
Clinical Laboratory Data .............................................................................57 
9.4.2.3 
Physical Examination and Vital Signs Data................................................57 
9.4.2.4 
Electrocardiogram Data ..............................................................................57 
9.4.2.5 
Other Safety Data ........................................................................................58 
9.4.3 
Other Analyses ................................................................................................58 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics .............................58 
9.4.3.2 
Pharmacokinetic Analysis ...........................................................................58 
9.4.3.3 
Pharmacodynamic Analysis ........................................................................58 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis ............................................58 
9.4.3.5 
Pharmacogenomic Analysis ........................................................................59 
 
59 
9.5 
Interim Analysis and Adaptive Design .............................................................59 
9.5.1 
Data Monitoring Committee ...........................................................................59 
10 
Supporting Documentation and Operational Considerations ....... 60 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations .............60 
10.1.1 
Ethics and Responsibility ...............................................................................60 
10.1.2 
Informed Consent ...........................................................................................60 
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10.1.3 
Confidentiality ................................................................................................61 
10.1.4 
Quality Control and Quality Assurance ..........................................................62 
10.1.4.1 
Monitoring ..................................................................................................62 
10.1.4.2 
Auditing ......................................................................................................62 
10.1.5 
Protocol Deviations ........................................................................................62 
10.1.6 
Records Management .....................................................................................63 
10.1.6.1 
Source Documents ......................................................................................63 
10.1.6.2 
Data Collection............................................................................................63 
10.1.6.3 
File Management at the Trial Site ...............................................................64 
10.1.6.4 
Records Retention at the Trial Site .............................................................65 
10.1.6.5 
Publication Authorship Requirements ........................................................65 
10.2 
Appendix 2: Clinical Laboratory Tests .............................................................67 
10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information ........................................................................................................68 
10.4 
Appendix 4: Abbreviations ...............................................................................70 
10.5 
Appendix 5: Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .............................................................................................72 
10.6 
Appendix 6: Criteria for Identifying Vital Signs of Potential Clinical 
Relevance ..........................................................................................................73 
10.7 
Appendix 7: Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance .............................................................................................74 
10.8 
Appendix 8: Protocol Amendments ..................................................................75 
10.8.1 
Protocol Amendment(s)/Administrative Change(s) .......................................76 
10.8.1.1 
Protocol Amendment 1 ...............................................................................76 
11 
References ............................................................................................ 78 
 


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List of In-text Tables 
Table 1.3-1 
Schedule of Assessments .............................................................. 17 
Table 3-1 
Trial Objectives and Endpoints ..................................................... 24 
Table 6.1-1 
Dosing Schedule ........................................................................... 33 
Table 6.5.1-1 
List of Medications Prohibited During the Trial........................... 37 
Table 10.2-1 
Clinical Laboratory Assessments .................................................. 67 
 
 


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List of In-text Figures 
Figure 1.2-1 
Trial Design Schematic ................................................................. 16 
 
 


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1 
Protocol Summary 
1.1 
Synopsis 
Name of Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. 
Name of Investigational Medicinal Product: Brexpiprazole (OPC-34712) 
Protocol No.: 331-201-00195 
IND No.: 141091 
EudraCT No.: 2019-002897-30 
Protocol Title: A Multicenter, Open-label Trial to Evaluate the Safety and Tolerability of 
Brexpiprazole in the Treatment of Adult Subjects With Borderline Personality Disorder 
Protocol Lay Person Short Title: Open-label Trial of Brexpiprazole in the Treatment of 
Borderline Personality Disorder  
Clinical Phase/Trial Type: Phase 2/3 / Therapeutic use 
Treatment/Indication: For the treatment of borderline personality disorder (BPD) 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary Safety: To evaluate the 
safety and tolerability of 
brexpiprazole for the treatment of 
subjects with a diagnosis of BPD. 
 
Primary Safety: Frequency and severity of AEs. 
 
Secondary Safety: 
• Changes in: ECGs, vital signs, clinical 
laboratory tests including prolactin, changes 
in body weight, and physical examinations; 
• EPS: SAS, AIMS, and BARS; 
• Suicidal ideation and behavior will be 
assessed using the C-SSRS. 


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Objectives 
Endpoints 
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating 
Scale; 
 
 
; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EPS = extrapyramidal 
symptom; ET = early termination; 
; 
; 
; 
SAS = Simpson Angus Scale; 
 
Schedule; 
 
Note: The assessments from the last scheduled treatment visit of the previous double-blind trial will 
serve as the baseline measures for Trial 331-201-00195. 
 
Trial Design: 
This will be a 12-week, multicenter, open-label trial designed to evaluate the safety and 
tolerability of brexpiprazole treatment in adult subjects diagnosed with BPD. Subjects 
will receive 2 to 3 mg/day brexpiprazole. 
Enrollment into the trial will be drawn from eligible subjects who completed the last visit 
of the previous double-blind, brexpiprazole BPD trials (and took the investigational 
medicinal product [IMP] through the last scheduled treatment visit) and, in the 
investigator’s judgment, could potentially benefit from treatment with brexpiprazole for 
BPD. 
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Subjects will be screened for eligibility at the last scheduled treatment visit of the 
previous double-blind trial. Subjects will sign a separate informed consent form (ICF) at 
the last scheduled treatment visit of the previous double-blind trial for participation in 
Trial 331-201-00195 before any procedures specific to the open-label trial are performed. 
The assessments from the last scheduled treatment visit of the previous double-blind trial 
will serve as the baseline measures for Trial 331-201-00195 for any assessment that is not 
new (unique) to the open-label trial. Medical history will be updated, if necessary. 
Informed consent cannot be obtained after the last scheduled treatment visit of the 
previous double-blind trial without all screening/baseline assessments being repeated. If a 
subject is unable to rollover immediately, up to 3 days may be permitted between the end 
of the double-blind trial and the start of IMP in the open-label extension trial; however, 
this must be discussed with the medical monitor (Note: assessments from the last 
scheduled treatment visit in the previous double-blind trial that are going to be used as 
the baseline measures for Trial 331-201-00195 will not need to be repeated if the subject 
enters Trial 331-201-00195 within 3 days). 
Eligible subjects will receive up to 12 weeks of daily treatment with open-label 
brexpiprazole. A safety follow-up telephone contact or clinic visit will occur 
21 (± 3) days after the last dose of brexpiprazole. 
Trial Population: 
The trial population will consist of eligible male and female subjects diagnosed with BPD 
and who, in the investigator’s judgment, could potentially benefit from treatment with 
brexpiprazole for BPD according to the following criteria: 
• Subjects who participated in a double-blind brexpiprazole BPD trial will be eligible 
for Trial 331-201-00195 if they have completed the last scheduled treatment visit of 
the previous double-blind trial and did not terminate early.  
• Subjects must qualify for Trial 331-201-00195 at the last scheduled treatment visit of 
the previous double-blind trial and must be able to continue treatment without 
interruption between the double-blind and open-label trials (if a subject is unable to 
rollover immediately, up to 3 days may be permitted between the end of the 
double-blind trial and the start of IMP in the open-label extension trial; however, this 
must be discussed with the medical monitor).  
 


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Key Inclusion/Exclusion Criteria: 
Male or female outpatients, ages 18 to 65 years (at the time of informed consent of the 
previous double-blind trial), with a BPD diagnosis who completed the last treatment visit 
of the previous double-blind brexpiprazole BPD trial and who, in the opinion of the 
investigator, could potentially benefit from administration of brexpiprazole for the 
treatment of BPD. Eligible subjects must not have a major protocol deviation during the 
course of their participation in the previous double-blind brexpiprazole BPD trial (if the 
major protocol deviation is due to the coronavirus disease of 2019 [COVID-19], 
eligibility for the subject to continue can be discussed with medical monitor).  
Trial Site(s):  
This trial will be conducted at multiple sites globally. 
Investigational Medicinal Product(s), Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration: 
All subjects will receive a starting dose of 1 mg/day at the screening/baseline visit, 
followed by an increase to 2 mg/day at the end of Week 1. Subjects may increase their 
dose to 3 mg/day at the investigator’s discretion on or after the Week 2 visit, depending 
on treatment response and tolerability. Subjects taking 3 mg/day may down-titrate to 
2 mg/day based on tolerability at any time during the course of the trial. Subjects unable 
to tolerate 2 mg/day will be discontinued from the trial. Dose adjustments to 
brexpiprazole must be made in increments of 1 mg/day. Dose decreases for brexpiprazole 
can occur at unscheduled visits and dose increases for brexpiprazole can only occur at 
scheduled visits. 
As applicable, dose changes of background antidepressant therapy (ADT) can be 
modified to achieve optimum efficacy and tolerability. Dose adjustments of ADT should 
not occur at the same visit as a dose adjustment of brexpiprazole and a recommended 
minimum of 5 days should occur between any dose adjustments of brexpiprazole or ADT 
at any point during the trial. 
Dosing Schedule 
IMP 
Screening/Baseline - Week 1 
Week 1 - Week 2 
Week 2 - Week 12a 
Brexpiprazole 
1 mg/day 
2 mg/day 
2 or 3 mg/dayb 
aDown titration can occur at any time due to tolerability after Week 2. The minimum dose allowed is 
2 mg/day. 
bOption to titrate to 2 or 3 mg/day (ie, 2 mg, or 3 mg) based on clinical response and tolerability; 
changes must occur in 1 mg/day increments. 
 


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Trial Assessments: 
 
 
 
 
 
 
 
Assessments for Pharmacokinetics/Pharmacodynamics: None. 
Assessments for Safety: Adverse event (AE) reporting, clinical laboratory tests (including 
prolactin and glycosylated hemoglobin [HbA1c]), electrocardiogram (ECG), vital signs, 
physical examination, Simpson Angus Scale (SAS), Abnormal Involuntary Movement 
Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Columbia-Suicide Severity 
Rating Scale (C-SSRS). 
Screening/Other: Medical, psychiatric, and medication history; urine drug and blood 
alcohol screening; and urine pregnancy test. 
Data Monitoring Committee: None. 
Statistical Methods: 
The sample size is not based on statistical power considerations but on the number of 
subjects rolling over from the lead-in trials. The trial population will be derived from 
eligible subjects who completed the previous double-blind brexpiprazole BPD trials. The 
number of eligible subjects will be limited by the number of subjects enrolled into the 
double-blind trials.  
The primary safety analysis is the frequency and severity of AEs in the open-label 
treatment phase. All AEs will be coded by system organ class and the Medical Dictionary 
for Regulatory Activities preferred term. The incidence of the following events will be 
summarized by the prior treatment group: 
1) Treatment-emergent adverse events (TEAEs) 
2) TEAEs by severity, 
3) TEAEs potentially causally related to the IMP, 
4) TEAEs with an outcome of death, 
5) Serious TEAEs, 
6) TEAEs leading to discontinuation of the IMP, 
7) Adverse events of special interest (AESI). 
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A TEAE is defined as an AE that starts after the first dose of IMP or an AE that is 
reported at baseline and increases in intensity or becomes serious or IMP-related or 
results in death, discontinuation, interruption or reduction of IMP. Information about new 
onset or exacerbation of “Pathological Gambling and Other Compulsive Behaviors” will 
be collected and analyzed as an AE of special interest. 
Complete details of the planned statistical analysis will be presented in the statistical 
analysis plan. 
Trial Duration: 
Each subject in this trial is expected to participate in the following periods of the trial 
(approximate durations listed), for approximately 15 weeks: 
• Eligibility screening period (1 day) (If a subject is unable to rollover immediately, up 
to 3 days may be permitted between the end of the double-blind trial and the start of 
IMP in the open-label extension trial; however, this must be discussed with the 
medical monitor.) 
• Treatment period (12 weeks) 
• Post-treatment follow-up period (21 ± 3 days) 
 
Eligible subjects from the previous double-blind trials will be eligible to roll over into 
this open-label extension trial. Overall, the trial duration from first ICF signed to the final 
subject assessment is expected to be several years. 


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1.2 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
aThe last visit of the previous double-blind BPD trial will serve as the baseline measures for Trial 331-201-00195. If a subject is unable to 
rollover immediately, up to 3 days may be permitted between the end of the double-blind trial and the start of IMP in the open-label extension trial; 
however, this must be discussed with the medical monitor. 
bTelephone contact or clinic visit. 
cTelephone contact will be made at Weeks 1, 6, and 10 to assess AEs and concomitant therapy. 
 
Figure 1.2-1 
Trial Design Schematic 
 
 
Open -label Brexpiprazole (2 mg/day to 3 mg/day ) 
Treatment Phase
Screening/Baseline a 
Visits at end of Weeks 2, 4, 8, and 12 (unscheduled visits as necessary for IMP dose decreases) 
Safety Follow-Up 
Last visit of the previous
double -blind BPD trial 
b 
Week 1c 
Week 2 
Week 4 
Week 8 
Eligible subjects who 
completed a double-blind BPD 
trial and who, in the opinion of 
the investigator, could 
potentially benefit from the 
administration of brexpiprazole 
for the treatment of BPD  
Week 6c 
Week 10c 
Week 12/ET 
Week 15 
(21 [± 3] days 
after last dose) 


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1.3 
Schedule of Assessments 
Table 1.3-1 
Schedule of Assessments 
Assessment 
Visit 
Treatment Period 
 
Screening/ 
Baselinea,b 
Week 1c,d 
Week 2c 
Week 4c 
Week 6 c,d 
Week 8c 
Week 10c,d 
Week 12 
or ETc,e 
Post-
treatment 
Follow-upf 
 
± 3 days 
21 ± 3 days 
ENTRANCE CRITERIA 
Informed consentg 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteriag 
X 
 
 
 
 
 
 
 
 
Confirmation of eligibilityg 
X 
 
 
 
 
 
 
 
 
Medical historyg 
X 
 
 
 
 
 
 
 
 
Psychiatric history, including BPD 
historyg 
X 
 
 
 
 
 
 
 
 
SAFETY 
Physical examinationi 
X 
 
 
 
 
 
 
X 
 
Vital signsj 
X 
 
X 
X 
 
X 
 
X 
 
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Table 1.3-1 
Schedule of Assessments 
Assessment 
Visit 
Treatment Period 
 
Screening/ 
Baselinea,b 
Week 1c,d 
Week 2c 
Week 4c 
Week 6 c,d 
Week 8c 
Week 10c,d 
Week 12 
or ETc,e 
Post-
treatment 
Follow-upf 
 
± 3 days 
21 ± 3 days 
Clinical laboratory tests 
(hematology [including HbA1c], 
serum chemistry [including 
prolactin], urinalysis) 
Xk 
 
 
 
 
 
 
Xl 
 
ECGm 
X 
 
 
 
 
 
 
X 
 
Urine pregnancy test (FOCBP 
only)n 
X 
 
 
X 
 
X 
 
X 
 
Urine drug screen and blood 
alcohol testo 
X 
 
 
 
 
 
 
X 
 
C-SSRSp 
X 
 
X 
X 
 
X 
 
X 
 
EPS scales (SAS, AIMS, BARS) 
X 
 
 
X 
 
X 
 
X 
 
Adverse eventsq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapyr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OTHER PROCEDURES 
IMP dispensingg 
X 
 
X 
X 
 
X 
 
 
 
IMP accountability 
 
 
X 
X 
 
X 
 
X 
 
Dose adjustments 
 
 
X 
X 
 
X 
 
X 
 
Schedule optional telephone 
contact/other communicationt 
 
 
X 
X 
X 
X 
X 
 
 
FOCBP = female of childbearing potential. 
aScreening for Trial 331-201-00195 occurs on the same day as baseline but prior to any procedures specific to the open-label trial. Informed consent for 
Trial 331-201-00195 should be signed at the start of the last double-blind treatment visit. The screening/baseline for Trial 331-201-00195 will be the same 
day as the last visit of the previous double-blind trial. 


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bThe assessments from the last scheduled treatment visit of the previous double-blind trial will serve as the baseline measures for Trial 331-201-00195 for any 
assessment that is not new (unique) to the open-label trial. If a subject is unable to rollover immediately, up to 3 days may be permitted between the end of 
the double-blind trial and the start of IMP in the open-label extension trial; however, this must be discussed with the medical monitor (Note: assessments 
from the last scheduled treatment visit in the previous double-blind trial that are going to be used as the baseline measures for Trial 331-201-00195 will not 
need to be repeated if the subject enters Trial 331-201-00195 within 3 days). 
cWeek designations correspond to the end of the week (eg, Week 4 visit occurs at the end of week 4 of the trial). 
dTelephone contact will be made at Weeks 1, 6, and 10 to assess AEs and concomitant therapy. 
eIf a subject discontinues early, every effort should be made to complete the Week 12/ET evaluations as soon as possible and, whenever possible, prior to 
starting any new medication or treatment. 
fTelephone contact or clinic visit (investigator’s discretion) for evaluation of safety, 21 days after the last dose. 
gNew (unique) assessments for Trial 331-201-00195 include informed consent, inclusion/exclusion criteria, confirmation of eligibility, changes in medical 
and psychiatric history, and dispensing of IMP. 
hAny post-screening/baseline visit should refer to screening/baseline when assessing change. 
iTo include measurement of waist circumference. 
jVital sign measurements include body weight, body temperature, systolic blood pressure, diastolic blood pressure, 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. 
kSubjects should be fasting for a minimum of 8 hours prior to blood draws for screening/baseline laboratory assessments, if at all possible. If fasting blood 
samples are not feasible at screening/baseline, nonfasting blood samples may be obtained initially for determining eligibility for the trial and need to be 
repeated at the next visit at the discretion of the investigator. 
lBlood samples for clinical laboratory tests should be drawn after a minimum 8-hour fast at Week 12/ET, if possible. Vital sign and ECG assessments should 
be completed before any blood samples are collected. 
mStandard ECGs will be performed after the subject has been supine and at rest for ≥ 5 minutes prior to the ECG. Subjects will be enrolled in 
Trial 331-201-00195 based on the screening/baseline ECG results from the trial site. Any ECGs scheduled for the same visit as blood samples are to be 
completed before blood is drawn.  
nAll positive urine pregnancy test results must be confirmed by a serum test. Pregnancy tests can be performed at any point during the trial if pregnancy is 
suspected. 
oA 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. See the exclusion criteria for exclusions based on urine drug screen and blood alcohol tests at screening/baseline. 
pThe “Since Last Visit” C-SSRS form will be completed at all visits for all subjects. 


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qAdverse events recording will begin with the signing of the ICF for Trial 331-201-00195 and through the last scheduled trial visit (immediately reportable 
events will be collected through the last trial contact). 
rAll prescription and non-prescription therapy (pharmacological or other therapy) taken during the trial will be recorded. Details of prohibited therapies are 
provided in Section 6.5.1. 
sSee Section 6.1 for dose adjustment details. 
tSchedule an optional telephone call or other form of communication with the subject approximately 1 week (± 2 days) after the visit (eg, at Weeks 3, 5, 7, 9, and 
11) to check on status. 
 


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2 
Introduction 
Borderline personality disorder (BPD) is a mental disorder consisting of a pervasive 
pattern of instability in regulation of emotions, impulse control, interpersonal 
relationships, and self-image.1,2 Patients with BPD are prone to self-harm (including 
suicide), other dangerous behaviors, substance abuse, depression and eating disorders.3 
The prevalence of BPD has been reported to be as high as 5.9% in the general 
population4 but represents 15% to 29% of patients in psychiatric clinics and hospitals.5,6 
Because the personality of children and adolescents is developing, the features of BPD do 
not become recognizable until late adolescence or early adulthood.7,8 There is a high 
comorbidity of BPD with other psychiatric disorders (84.5%), including anxiety, mood, 
impulse control, and substance disorders.9  
Brexpiprazole (REXULTI®) is a novel atypical antipsychotic that is a 
serotonin-dopamine activity modulator and is indicated in the United States (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 major depressive disorder 
(MDD; 2 - 3 mg/day).10  
While the precise mechanism of action of brexpiprazole in treating psychiatric conditions 
is unknown, the pharmacology of brexpiprazole is believed to be mediated by a 
combination of high-binding affinity and functional activities at multiple monoaminergic 
receptors. It has modulatory activity at the serotonin and dopamine systems that 
combines partial agonist activity at serotonergic 5-HT1A and at dopaminergic D2 
receptors with antagonist activity at serotonergic 5-HT2A receptors, with similar high 
affinities at all of these receptors (inhibition constant [Ki]: 0.1 - 0.5 nM). Brexpiprazole 
also shows antagonist activity at noradrenergic α1B/2C receptors with affinity in the same 
sub-nanomolar Ki range (Ki: 0.2 - 0.6 nM). The 5-HT1A/D2 receptor partial agonist 
activity in combination with 5-HT2A and α1B/2C receptors antagonism of brexpiprazole 
may correlate with antipsychotic and antidepressant efficacy, reduced impulsive 
behavior, and cognitive improvement.10  
Please refer to the Investigator’s Brochure (IB) for more detailed information. 


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2.1 
Trial Rationale 
There are currently no pharmacological treatments approved for BPD. The first-line of 
treatment is psychotherapy, including dialectical behavior therapy to manage emotions, 
help with tolerating distress, and managing relationships.7 Pharmacotherapy is used to 
treat targeted symptoms that fall within the following categories: 1) affective 
dysregulation, mood lability, and anger, 2) impulsive and self-harming behavior, and 
3) cognitive perceptual symptoms. Based on off-label prescribing practices and on 
clinical trial data, there is evidence that atypical antipsychotics may be efficacious at 
treating patients with BPD, especially symptoms of mood, self-harm, impulsivity, and 
aggression. Reductions in overall BPD symptomatology have been demonstrated in 
clinical trials of quetiapine,11 olanzapine,12,13,14 clozapine,15,16 and aripiprazole.17,18 
This receptor activity profile of brexpiprazole may allow for effective pharmacotherapy 
for the treatment of BPD. More specifically, the serotonergic and dopaminergic 
stabilization and normalization provided by brexpiprazole may directly address the 
pathways implicated in the BPD features of impulse aggression (serotonergic) and 
emotional dysregulation and impulsivity (dopaminergic). 
The proposed 12-week, open-label trial (Trial 331-201-00195) will be conducted to 
evaluate the safety and tolerability of brexpiprazole for the treatment of subjects 
diagnosed with BPD. 
2.2 
Background 
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 IB.10 
Currently, brexpiprazole is approved in multiple countries for use in adult patients for the 
treatment of schizophrenia, and for the use as an adjunctive therapy to antidepressants for 
the treatment of MDD. Additionally, the current clinical development program is 
designed to show safety and efficacy of brexpiprazole for the treatment of the following 
indications: treatment of adult post-traumatic stress disorder (PTSD), bipolar mania, 
adolescent schizophrenia, and the treatment of agitation in Alzheimer’s dementia 
(AAD).10  
As of 17 Apr 2018, the brexpiprazole clinical development program consisted of a total 
of 74 clinical trials conducted in North America, Latin America, Europe, and Asia 
(66 completed and 8 ongoing). This includes 67 trials conducted under US 
Investigational New Drug (IND) Applications (59 completed and 8 ongoing) for 


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schizophrenia, adjunctive treatment of MDD, adjunctive treatment of 
attention-deficit/hyperactivity disorder (ADHD), AAD, PTSD, or bipolar; and 7 non-US 
IND trials (7 completed and 0 ongoing) in either South Korea or Japan conducted in 
healthy subjects or subjects with schizophrenia.10  
Please refer to the current IB for a detailed summary of available clinical data.10  
2.3 
Known and Potential Risks and Benefits 
As of 17 Apr 2018, a total of 9153 unique subjects were exposed to single or multiple 
doses of brexpiprazole (either alone or with another marketed drug) in US IND trials. 
This total includes 877 subjects in the collective phase 1 clinical pharmacology trials 
(593 healthy subjects or subjects in special populations and 284 subjects diagnosed with 
either schizophrenia or schizoaffective disorder [N = 236], MDD [N = 36], or ADHD 
[N = 12]) and 8276 subjects diagnosed with either schizophrenia or schizoaffective 
disorder (N = 2404), MDD (N = 5265), AAD (N = 429), ADHD (N = 155), or PTSD 
(N = 23) in the collective phase 2 and phase 3/3b trials.  
Overall, the total number of subject years of exposure (SYE) in the completed phase 1 
clinical pharmacology trials (N = 877) and all phase 2 and phase 3/3b trials combined 
(N = 8276) was 28.5 and 3590.3 SYEs, respectively. Exposure to brexpiprazole in the 
completed phase 2 and phase 3/3b US IND trials is summarized by duration of exposure 
and indication in the current IB.10 The majority of subjects within each of the 
5 indications have received at least 6 weeks of brexpiprazole, including 3139 subjects 
with at least 26 weeks of exposure and 1612 subjects with at least 52 weeks of exposure. 
Completed phase 2 and phase 3 clinical trials have evaluated multiple oral doses up to 
6 mg/day in subjects with schizophrenia, up to 3 mg/day when coadministered with 
marketed antidepressant therapy in subjects with MDD, up to 3 mg/day in subjects with 
PTSD, up to 2 mg/day when coadministered with marketed stimulant therapy in subjects 
with ADHD, and up to 2 mg/day in subjects with AAD. Dose selection for the ongoing 
multiple-dose trials was derived from the collective safety, efficacy, and receptor 
occupancy data from completed phase 1, phase 1b, phase 2, and phase 3 trials of 
brexpiprazole. 


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Overall, 9062 subjects received brexpiprazole either alone or coadministered with 
another marketed medication from the 59 completed brexpiprazole trials conducted under 
US INDs. Overall, 6403/9062 subjects (70.7%) reported at least 1 treatment-emergent 
adverse event (TEAE) compared with 1498/2781 subjects (53.9%) who received placebo 
either alone or coadministered with another marketed medication. The most frequently 
reported TEAEs (incidence ≥ 5% of the total brexpiprazole group and more than total 
placebo) in all subjects who received brexpiprazole were increased weight (12.1%), 
headache (9.1%), insomnia (7.8%), akathisia (7.2%), somnolence (6.2%), and dizziness 
(5.3%). In the total placebo group, headache (8.2%) was the most frequently reported 
TEAE (incidence ≥ 5% of subjects). 
Please refer to the current IB for a summary of available nonclinical and clinical safety 
data.10 Trial sites will receive updated versions of the IB, when available, and trial sites 
should refer to the most current version as needed. 
3 
Objectives and Endpoints 
Table 3-1 
Trial Objectives and Endpoints 
Objectives 
Endpoints 
Primary Safety: To evaluate the 
safety and tolerability of 
brexpiprazole for the treatment of 
subjects with a diagnosis of BPD. 
 
Primary Safety: Frequency and severity of 
AEs. 
 
Secondary Safety: 
• Changes in: ECGs, vital signs, clinical 
laboratory tests including prolactin, 
changes in body weight, and physical 
examinations; 
• EPS: SAS, AIMS, and BARS; 
• Suicidal ideation and behavior will be 
assessed using the C-SSRS. 


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Table 3-1 
Trial Objectives and Endpoints 
Objectives 
Endpoints 
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating 
Scale; 
; 
 
; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EPS = extrapyramidal 
symptom; ET = early termination; 
; 
; 
 
SAS = Simpson Angus Scale; 
 
Schedule; 
. 
Note: The assessments from the last scheduled treatment visit of the previous double-blind trial will 
serve as the baseline measures for Trial 331-201-00195. 
 
Section 9.4 describes the statistical analysis of the endpoints. 
4 
Trial Design 
4.1 
Type/Design of Trial 
This is a 12-week, multicenter, open-label trial designed to evaluate the safety and 
tolerability of brexpiprazole treatment in adult subjects diagnosed with BPD. Subjects 
will receive 2 to 3 mg/day brexpiprazole. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Enrollment into the trial will be drawn from eligible subjects who completed the last 
treatment visit of the previous double-blind brexpiprazole BPD trials (and took the 
investigational medicinal product [IMP] through the last scheduled treatment visit) and, 
in the investigator’s judgment, could potentially benefit from treatment with 
brexpiprazole for BPD.  
The trial will be organized as follows: 
Screening/Baseline: Subjects will be screened for eligibility at the last scheduled 
treatment visit of the previous double-blind trial. Subjects will sign a separate informed 
consent form (ICF) at the last scheduled treatment visit of the previous double-blind trial 
for participation in this trial before any procedures specific to the open-label trial are 
performed. The assessments from the last scheduled treatment visit of the previous 
double-blind trial will serve as the baseline measures for this trial for any assessment that 
is not new (unique) to the open-label trial. Medical history will be updated, if necessary. 
Informed consent cannot be obtained after the last scheduled treatment visit of the 
previous double-blind trial without all screening/baseline assessments being repeated. If a 
subject is unable to rollover immediately, up to 3 days may be permitted between the end 
of the double-blind trial and the start of IMP in the open-label extension trial; however, 
this must be discussed with the medical monitor (Note: assessments from the last 
scheduled treatment visit in the previous double-blind trial that are going to be used as 
the baseline measures for Trial 331-201-00195 will not need to be repeated if the subject 
enters Trial 331-201-00195 within 3 days). 
Treatment Phase: Eligible subjects will receive daily treatment with open-label 
brexpiprazole beginning at the screening/baseline visit, as described in Section 6.1. Visits 
will occur at the end of Weeks 2, 4, 8, and 12. Telephone contact will be made at 
Weeks 1, 6, and 10 to assess adverse events (AEs) and concomitant therapy. In addition, 
an optional telephone call or other form of communication will be made with the subject 
approximately 1 week (± 2 days) after the visit (eg, at Weeks 3, 5, 7, 9, and 11) to check 
on status. All subjects will receive up to 12 weeks of open-label treatment in this trial. 
Follow-up: Subjects will be followed for safety via telephone contact or clinic visit 
21 (± 3) days after the last dose of open-label brexpiprazole. 
See Figure 1.2-1 for a schematic of the trial design.  


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4.2 
Scientific Rationale for Trial Design 
Given its clinical efficacy in treating both schizophrenia and MDD as well as its 
multimodal mechanism of action, brexpiprazole may offer added benefit to patients 
suffering from BPD. Like other psychological disorders, BPD has been linked to 
aberrations in monoaminergic neurotransmission. While dysfunctions related to 
dopamine and serotonin have been historically cited, recent evidence has also implicated 
noradrenergic dysfunction in BPD as well.19,20,21,22 
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, as noted in Section 2. Together, the broad pharmacological profile of 
brexpiprazole may provide for a unique treatment strategy for BPD. More specifically, 
the serotonergic and dopaminergic stabilization and modulation provided by 
brexpiprazole may directly address some of the key features and symptoms noted in the 
disease including impulsivity, aggression, affective instability, and suicidality. It is 
anticipated that the brexpiprazole safety profile for BPD will be comparable to the safety 
profiles of the currently approved indications.  
Trial 331-201-00195 is being conducted to evaluate the safety and tolerability of 
brexpiprazole in subjects diagnosed with BPD who have completed a double-blind BPD 
trial. 
4.3 
Dosing Rationale 
The dosing paradigm of brexpiprazole to be used in Trial 331-201-00195 has been 
determined based on the dosing ranges investigated in other related psychiatric 
indications (bipolar I disorder, MDD, PTSD, and schizophrenia) and the dosing ranges 
used in the previous double-blind trials for the open-label extension.10  
In other psychiatric indications, brexpiprazole has been shown to be safe and well 
tolerated within the proposed dose range to be investigated in this trial (ie, 2 to 
3 mg/day). In addition, the effective dose range for approved indications (MDD and 
schizophrenia) is 2 to 4 mg/day; the 1 mg/day dose has not been shown to be effective. 
4.4 
End of Trial Definition 
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 page in eSource for the last subject completing 
or withdrawing from the trial. 


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4.5 
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 Week 12 visit will be defined as trial completers. 
5 
Trial Population 
The trial population will consist of eligible male and female subjects diagnosed with BPD 
and who, in the investigator’s judgment, could potentially benefit from treatment with 
brexpiprazole for BPD according to the following criteria: 
• Subjects who participated in a double-blind brexpiprazole BPD trial will be eligible 
for Trial 331-201-00195 if they have completed the last scheduled treatment visit of 
the previous double-blind trial and did not terminate early.  
• Subjects must qualify for Trial 331-201-00195 at the last scheduled treatment visit of 
the previous double-blind trial and must be able to continue treatment without 
interruption between the double-blind and open-label trials (if a subject is unable to 
rollover immediately, up to 3 days may be permitted between the end of the 
double-blind trial and the start of IMP in the open-label extension trial; however, this 
must be discussed with the medical monitor).  
 
Decisions regarding inclusion of subjects at the time of enrollment and assessment of 
subject safety throughout the trial primarily remain at the discretion of the investigator; 
however, the medical monitor may recommend exclusion or discontinuation of a subject 
based on individual subject data. 
5.1 
Subject Selection and Numbering 
All subjects will retain a unique subject identifier (ID; site number [3 digits] + subject 
number ['S' + 5 digits] that was given upon providing consent [or assent if applicable]) 
for the previous double-blind trial.  
5.2 
Eligibility Criteria 
Exceptions for eligibility criteria will not be permitted during the trial, neither by the 
investigator nor by the medical monitor. 


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5.2.1 
Inclusion Criteria 
Subjects are required to meet the following inclusion criteria at the time points described 
in the schedule of assessments (Table 1.3-1). 
1) Subjects, who completed the last treatment visit of the previous double-blind 
brexpiprazole BPD trial and who, in the opinion of the investigator, could 
potentially benefit from administration of brexpiprazole for the treatment of BPD. 
2) Male or female outpatients, ages 18 to 65 years, inclusive, at the time of informed 
consent of the previous double-blind brexpiprazole BPD trial. 
3) Subjects who are able to complete the consent process and/or consent obtained 
from a legally acceptable representative (as required by the institutional review 
board [IRB]/independent ethics committee [IEC]) prior to the initiation of any 
protocol-required procedures. 
4) 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 the written word in order to be reliably rated on assessment scales. 
 
5.2.2 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria at the time 
points described in the schedule of assessments (Table 1.3-1). 
Sex and Reproductive Status 
1) Sexually active males or females of childbearing potential (FOCBP) 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, intrauterine 
device, birth control pill, birth control implant, birth control depot injection, 
condom with spermicide, sponge with spermicide, or occlusive cap (vaginal 
diaphragm or cervical/vault cap) with spermicide. 
Consensual sexual activity that cannot biologically result in pregnancy may not be 
subject to required birth control methods, following discussion with the medical 
monitor. 
Male subjects must also agree not to donate sperm from trial screening/baseline 
through 30 days after the last dose of IMP. 
2) Women who are breastfeeding and/or who have a positive pregnancy test result 
prior to receiving IMP. 


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Medical History and Concurrent Disease 
3) Subjects who fulfill the following criteria related to suicide and/or suicidal 
ideation at entry are excluded: 
• Subjects who have a significant risk of committing violent acts, serious 
self-harm, or suicide, or those who are homicidal or considered to be a high 
risk to others, or subjects with a response of “yes” on the Columbia-Suicide 
Severity Rating Scale (C-SSRS) Suicidal Ideation Item 5 (Active Suicidal 
Ideation with Specific Plan and Intent), OR  
• Subjects with a response of “yes” on the C-SSRS Suicidal Behavior Items 
Actual Attempt, Interrupted Attempt, or Aborted Attempt 
• Subjects who endorse engaging in preparatory acts and/or non-suicidal 
self-injury may be included according to investigator judgment, provided the 
behavior has not increased significantly in frequency or severity during the 
preceding double-blind trial period, and after discussion and approval by the 
medical monitor. 
Note that subjects with a response of “yes” on the C-SSRS Suicidal Ideation 
Item 4 (Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
and Intent) may be included following discussion with the medical monitor. 
Physical and Laboratory Results 
4) Subjects with abnormal laboratory tests results, vital signs results, or 
electrocardiogram (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.  
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 
• Aspartate aminotransferase (AST) > 2 × the 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 
• QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
≥ 450 msec in men and ≥ 470 msec in women, unless due to ventricular 
pacing. 
Tests with exclusionary results should be repeated to ensure reproducibility of the 
abnormality before excluding a subject based on the criteria noted above. For 
ECGs, perform 3 consecutive recordings. If 2 of the 3 remain exclusionary then 
the subject must be excluded. 


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5) 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 cannabis, or prescription or over-the counter 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. Subjects with positive results for alcohol use will require 
consultation and approval by the medical monitor in order to verify use does not 
indicate a substance-use disorder. 
Other 
6) Subjects with a major protocol deviation during the course of their participation in 
the previous double-blind brexpiprazole BPD trial. Minor deviations such as 
occasional visits outside of the acceptable window or a missing blood draw will 
not exclude a subject from participation in Trial 331-201-00195; however, 
continual lack of compliance with the visit schedule, trial assessments, or 
treatment regimen in the previous double-blind trial would be considered a major 
deviation that would result in exclusion from Trial 331-201-00195. If the major 
protocol deviation is due to the coronavirus disease of 2019 (COVID-19), 
eligibility for the subject to continue can be discussed with medical monitor. The 
medical monitor should be contacted if the investigator is unsure of any subject’s 
eligibility. 
7) Subjects who participated in a clinical trial within 90 days prior to 
screening/baseline (with the exception of a previous brexpiprazole double-blind 
BPD trial) or who participated in more than 2 clinical trials within a year prior to 
screening/baseline. 
8) Any subject who, in the opinion of the sponsor, investigator, or medical monitor, 
should not participate in the trial. 
 
A definition of childbearing potential can be found in Section 10.3. 
Subjects must agree to restrictions to medications described in Section 6.5. No 
restrictions to activity, food, caffeine, alcohol, or tobacco or any other lifestyle 
considerations are needed during this trial. 
5.3 
Lifestyle Considerations 
Not applicable. 
5.3.1 
Meals and Dietary Restrictions 
Not applicable. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
Not applicable. 


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5.3.3 
Activity 
Not applicable. 
5.4 
Screen Failures 
A screen failure is a subject from whom informed consent is obtained and is documented 
in writing (ie, subject signs an ICF), but who is not assigned trial treatment. 
If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded in eSource: 
• Date of informed consent 
• Visit date (screening/baseline visit) 
• Demographics (collection date, birth date, sex) 
• Result of eligibility assessment 
• Screen failure date 
• Reason for screen failure 
 
Rescreening of subjects is not permitted. 
6 
Trial Treatments 
6.1 
Trial Treatments Administered 
The first dose of open-label brexpiprazole will be taken one day after the last dose of 
double-blind IMP is taken for the previous double-blind, brexpiprazole BPD trial so that 
treatment continues without interruption. It is anticipated that the last dose of IMP of the 
double-blind trial will be taken the day of the treatment last visit of the previous 
double-blind brexpiprazole BPD trial (ie, the day of the screening/baseline visit for the 
open-label trial). If a subject is unable to rollover immediately, up to 3 days may be 
permitted between the end of the double-blind trial and the start of IMP in the open-label 
extension trial; however, this must be discussed with the medical monitor. 
All subjects will receive a starting dose of 1 mg/day at the screening/baseline visit, 
followed by an increase to 2 mg/day at the end of Week 1 (Table 6.1-1). Subjects may 
increase their dose to 3 mg/day at the investigator’s discretion on or after the Week 2 
visit, depending on treatment response and tolerability. Subjects taking 3 mg/day may 
down-titrate to 2 mg/day based on tolerability at any time during the course of the trial. 
Subjects unable to tolerate 2 mg/day will be discontinued from the trial. Dose 
adjustments to brexpiprazole must be made in increments of 1 mg/day. Dose decreases 


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for brexpiprazole can occur at unscheduled visits and dose increases for brexpiprazole 
can only occur at scheduled visits. 
As applicable, dose changes of background antidepressant therapy (ADT) can be 
modified to achieve optimum efficacy and tolerability. Dose adjustments of ADT should 
not occur at the same visit as a dose adjustment of brexpiprazole and a recommended 
minimum of 5 days should occur between any dose adjustments of brexpiprazole or ADT 
at any point during the trial. 
Table 6.1-1 
Dosing Schedule 
IMP 
Screening/Baseline - Week 1 
Week 1 - Week 2 
Week 2 - Week 12a 
Brexpiprazole 
1 mg/day 
2 mg/day 
2 or 3 mg/dayb 
 
aDown titration can occur at any time due to tolerability after Week 2. The minimum dose allowed is 
2 mg/day. 
bOption to titrate to 2 or 3 mg/day (ie, 2 mg, or 3 mg) based on clinical response and tolerability; 
changes must occur in 1 mg/day increments. 
 
For information regarding the dose regimen and treatment period(s), including any 
follow-up period(s), see Section 4.1. 
6.1.1 
Medical Devices 
Not applicable. 
6.2 
Management of Investigational Medicinal Product 
For full details on IMP management, please refer to the brexpiprazole IB.10  
6.2.1 
Packaging and Labeling 
Investigational medicinal product 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 cards used in the dosing period will be 
labeled to clearly disclose the subject ID, compound ID, trial number, sponsor’s name 
and address, instructions for use, route of administration, and appropriate precautionary 
statements. 
6.2.2 
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 conditions indicated on the IMP label.  


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The clinical site staff will maintain a temperature log in the IMP storage area to record 
the temperature. 
6.2.3 
Accountability 
The investigator or designee must maintain an inventory record of IMP (including 
investigational, active control, or placebo) received, dispensed, administered, and 
returned. Neither the investigator nor any designees may provide IMP to any subject not 
participating in this protocol. 
6.2.4 
Returns and Destruction 
The IMP will be destroyed by the clinical trial site. 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. Accountability of the IMP must be completed and verified by the assigned 
trial monitor prior to destruction. The trial site(s) may utilize qualified third-party 
vendors for IMP destruction.  
6.2.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) is any written, electronic, or oral communication by 
a healthcare professional, consumer, subject, medical representative, regulatory agency, 
partner, or other third party that alleges deficiencies related to the identity, quality, 
durability, reliability, safety, effectiveness, or performance of a medical device or 
medicinal product or a falsified, tampered, or diverted product after it is released for 
distribution to a clinical trial. 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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6.2.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing. The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail within 24 hours of 
becoming aware of the PQC according to the procedure outlined below. 
x Send PQC reporting information to the OPDC IMP complaints mailbox email: 
 
Also indicate whether or not the complaint sample is available for return. 
 
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow the reporting mechanism above. 
6.2.5.2 
Information Required for Reporting Purposes 
x Description of complaint 
x Reporter identification (eg, subject, investigator, site, etc.) 
x Reporter contact information (eg, address, phone number, e-mail address) 
x ID of material (product/compound name, coding) 
x Clinical protocol reference (number and/or trial name) 
x Dosage form/strength (if known) 
x Pictures of complaint sample (if available) 
x Availability of complaint sample for return 
 
6.2.5.3 
Return Process 
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the return instructions 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. 
6.2.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
6.3 
Measures to Minimize/Avoid Bias 
This trial is open-label. 
CCI


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6.4 
Subject Compliance 
Responsible trial personnel will dispense the IMP (ie, brexpiprazole). Accountability and 
compliance verification should be documented in the subject’s trial records. Subjects 
must be counseled on the importance of taking the IMP as directed at all trial visits. If 
poor compliance continues (eg, multiple missed doses resulting in less than 80% overall 
compliance at any point in the trial), discontinuation of the subject from the trial should 
be considered. Subjects who habitually miss visits or habitually attend visits outside of 
the protocol-defined visit window are also noncompliant and should be considered for 
discontinuation. The medical monitor should be contacted if the investigator is uncertain 
whether a subject’s lack of compliance merits discontinuation from the trial. 
6.5 
Concomitant Medications or Therapies 
The investigator will record all medications and therapies taken by the subject from the 
screening/baseline visit through the end of the evaluation period (defined as the time 
period during which subjects are evaluated for primary and/or secondary objectives) in 
eSource. The investigator will also record all medications and therapies taken by the 
subject for treatment of an AE or which caused an AE until the end of the trial (defined as 
the last date of contact or date of final contact attempt) in eSource. 
For concomitant medications, the following will be recorded in eSource: medication, 
indication, dose, frequency, route, start date, and end date. For concomitant therapy, the 
following will be recorded in eSource: therapy, indication, start date, end date, and 
frequency. 
6.5.1 
Prohibited Medications 
Table 6.5.1-1 lists all medications prohibited during the trial, including exceptions, where 
appropriate. This table is consistent with the prohibited medications across the 
double-blinded trials. However, in this open-label extension, exceptions to prohibited 
medications or dose adjustments to allowed medications (ie, benzodiazepines) may be 
considered on a case-by-case basis following discussion with the medical monitor. This 
will provide greater flexibility in treatment as subject needs arise. 


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Table 6.5.1-1 
List of Medications Prohibited During the Trial 
1. 
Psychotropic agents including, but not limited to, the following: 
a) Antipsychotics, including depot or long-acting injectable formulations 
b) Anticonvulsants (except for gabapentin when used to treat anxiety or pain, after discussion 
with the medical monitor) 
c) Monoamine oxidase inhibitors, tricyclic antidepressants,a trazodone,a nefazodone, fluoxetine 
(> 60 mg/day), and paroxetine (> 50 mg/day) 
d) Mood stabilizers (ie, lithium) 
e) Benzodiazepine use is restricted to chronic, stable treatment or when used to manage TEAEs 
such as agitation and anxietyb 
f) Hypnotics, including ramelteonc 
g) Stimulants and atomoxetine  
h) Opioid analgesics, unless approval is obtained from the medical monitor. Approval 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. Buprenorphine is also excluded. 
i) Nutritional supplements and non-prescription herbal preparations with central nervous 
system effects (eg, St. John’s Wort, omega-3 fatty acids, kava extracts, gamma-aminobutyric 
acid supplements, etc) 
j) Disulfiram 
k) Prazosin - allowed if currently being taken for an appropriate indication at a stable dose. 
Should be continued throughout trial participation. 
2. 
Investigational agents 
3. 
CYP2D6 inhibitors or CYP3A4 inhibitors and inducers. Selected CYP2D6 inhibitors are: 
celecoxib, hydroxyzine, chloroquine, methadone, chlorpheniramine, moclobemide, clemastine, 
clomipramine, pyrilamine, diphenhydramine, quinidine, terbinafine, halofantrine, and 
tripelennamine. Selected CYP3A4 inhibitors are: amiodarone, amprenavir, indinavir, aprepitant, 
itraconazole, chloramphenicol, ketoconazole, cimetidine, nefazodone, clarithromycin, nelfinavir, 
clotrimazole (if used orally), quinupristin/dalfopristin, delavirdine, ritonavir, diltiazem, 
saquinavir, erythromycin, troleandomycin, fluconazole, and verapamil. Selected CYP3A4 
inducers are: carbamazepine, oxcarbazepine, phenytoin, dexamethasone, primidone, efavirenz, 
rifampin, nevirapine, St. John’s Wort, phenobarbitol, and troglitazone. The medical monitor 
should be consulted for any questions regarding the potential for PK interactions with 
concomitant medications used by subjects during the trial. 
4. 
Barbiturates 
5. 
Beta receptor antagonistsd  
6. 
Anticholinergic agents are prohibited within 8 hours of scheduled EPS scale assessments. 
CYP = cytochrome P450. 
aUnless they are being used for sleep management (further discussion with the medical monitor is 
required before allowing these medications). 
bSee Section 6.5.2. 
cChronic, stable (ie, regularly scheduled maintenance dose that has not changed during the previous 
double-blind trial) use of non-benzodiazepine sleep aids (ie, zolpidem, zaleplon, and eszopiclone 
only) is permitted for the management of sleep but not on the same day as administration of a 
benzodiazepine, regardless of indication. Intermittent use of specific non-benzodiazepine sleep aids is 
permitted for the short-term management of TEAEs related to sleep problems. For the 
non-benzodiazepine sleep aids, only 1 of the listed medications that are approved for this indication in 
the respective countries should be used 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. Other changes to hypnotic medications must be discussed with the medical 
monitor. 


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dPropranolol is permitted for akathisia or tremor up to a maximum of 20 mg 3 times daily (total of 
60 mg/day). Propranolol must not be administered within 8 hours prior to scheduled efficacy and 
safety assessments, including EPS scales. Other changes to beta receptor antagonists must be 
discussed with the medical monitor. 
 
6.5.2 
Benzodiazepine Use During the Trial 
Chronic, stable (ie, regularly scheduled maintenance dose that has not changed during the 
previous double-blind trial) use of specific oral benzodiazepines is permitted for the 
treatment of anxiety up to a maximum of 2 mg/day lorazepam (or equivalent) or 
1 mg/day clonazepam in divided doses. Intermittent use of specific oral benzodiazepines 
is permitted for the short term management of TEAEs up to a maximum of 2 mg/day 
lorazepam (or equivalent) or 1 mg/day clonazepam in divided doses. Short-acting 
benzodiazepines are to be used whenever possible. In countries where no short-acting 
benzodiazepines are commercially available, use of oral clonazepam may be acceptable if 
prior authorization is obtained from the medical monitor. The following guide should be 
used to determine approximate lorazepam equivalents: 1 mg lorazepam = 15 mg 
oxazepam = 0.5 mg alprazolam = 5 mg diazepam = 0.5 mg clonazepam. If required for 
intermittent treatment of agitation, 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 should not be administered within 
8 hours prior to scheduled efficacy and safety assessments, including extrapyramidal 
symptom (EPS) scales. Investigators are encouraged to delay scale administration until 
8 hours have elapsed, if at all possible. However, if delaying administration of efficacy 
and safety scales is not feasible, the scales should still be administered and the use of 
benzodiazepine documented, including a notation of the drug name, dose, and time of 
administration in eSource. For subjects entering the trial on regularly scheduled 
maintenance doses of benzodiazepines, routine doses may be taken at scheduled times 
per investigator instructions as long as the drug name, dose, date, and time taken are 
clearly documented in eSource. 
6.5.3 
Permitted Medications or Therapies 
Initiation of treatment with new medications or initiation of dose changes in current 
medications should not occur without discussion with the medical monitor. For subjects 
who are on ADT treatment at trial entry, dose changes of brexpiprazole and dose changes 
of ADT, if applicable, should not occur at the same visit and should have a minimum of 
5 days occurring between a dose change. Doses of paroxetine cannot exceed 50 mg/day 
and doses of fluoxetine cannot exceed 60 mg/day. 


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Initiation of psychotherapy or change in current psychotherapy treatment during the trial 
may be considered after consultation with the medical monitor. 
6.5.4 
Rescue Medications 
Not applicable. 
6.6 
Intervention after the End of the Trial 
Not applicable. 
7 
Stopping Rules, Withdrawal Criteria, and Procedures 
7.1 
Entire Trial or Treatment 
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. 
7.2 
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 Good Clinical Practice (GCP). 
The investigator will notify the sponsor promptly if the trial is terminated by the 
investigator or the IRB/IEC at the site. 
7.3 
Individual Subject Discontinuation 
7.3.1 
Treatment Interruption 
All attempts should be made to avoid treatment interruptions during the trial. If a 
subject’s IMP treatment must be interrupted for medical or surgical reasons; liver test 
abnormalities; use of a prohibited concomitant medication; or other reasons (eg, hospital 
admission for an invasive procedure, a major medical condition, surgery, dental work, or 
a temporary situation that prevents subject compliance with the IMP dosing schedule), 
the subject’s IMP should be resumed as early as the situation allows (see Section 7.3.4). 
If > 4 consecutive doses of IMP are missed, a discussion should occur with the medical 
monitor to determine if the subject should be discontinued from the trial as a result of the 
treatment interruption. 


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7.3.2 
Treatment Discontinuation 
After starting open-label IMP, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 7.3.5. 
7.3.3 
Documenting Reasons for Treatment Interruption or 
Discontinuation 
A subject may temporarily interrupt or discontinue IMP for the reasons listed below: 
• Adverse event 
− Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard 
− Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP) 
• Serious adverse event (SAE) 
• Other potentially IMP-related safety concerns or AEs 
• Death 
• Lack of efficacy 
• Lost to follow-up 
• Noncompliance with IMP 
• Physician decision 
• Pregnancy (see Section 10.3) 
• Protocol deviation 
• Site terminated by sponsor 
• Trial terminated by sponsor 
• Withdrawal by subject 
 
If the subject temporarily interrupts or discontinues IMP due to an AE, the investigator, 
or other trial personnel, will make every effort to follow the event until it has resolved or 
stabilized. Follow-up procedures in Section 7.3.1 and Section 7.3.2 must be followed. 


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7.3.4 
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: 
• Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit). 
• Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff). 
• Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives. 
• Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician). 
• Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
 
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to interrupt or modify or discontinue IMP 
administration, which is not equivalent to a complete withdrawal of consent for further 
participation (see Section 7.3.1 and Section 7.3.2, respectively). A subject may, however, 
indicate that further trial participation is creating a burden on their work, school, or social 
schedule. Therefore, the investigator should follow the procedures outlined in 
Section 7.3.3 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. 


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Only subjects who withdraw their permission for all of the above methods of follow-up 
are considered to have completely withdrawn their consent to participate in the trial. 
7.3.5 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be instructed to meet and discuss (without undue coercion) 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. 
7.4 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before Week 12 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”. 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. 
If the subject was classified as “lost to follow-up”, “Were you able to contact the 
subject?”, “Date of contact/Date of final contact attempt” and “Contact method” will be 
recorded in the source documents. 
8 
Trial Procedures 
Each subject in this trial is expected to participate in the following periods of the trial 
(approximate durations listed), for approximately 15 weeks: 
• Eligibility screening period (1 day) (If a subject is unable to rollover immediately, up 
to 3 days may be permitted between the end of the double-blind trial and the start of 
IMP in the open-label extension trial; however, this must be discussed with the 
medical monitor.) 
• Treatment period (12 weeks) 
• Post-treatment follow-up period (21 ± 3 days) 


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Eligible subjects from the previous double-blind trials will be able to roll over into this 
open-label extension trial. Overall, the trial duration from first ICF signed to the final 
subject assessment is expected to be several years. 
The assessments to be conducted during the trial are summarized in Table 1.3-1. 
8.1 
Efficacy Assessments 
It is required that trained and experienced clinicians administer all rating scales. The 
number of raters within each trial site should be kept to a minimum. All efforts will be 
made to ensure that the same clinician administers the scales for a given subject. 
Notations in the subject’s trial records should substantiate the ratings. Training, 
certification, and materials for rating will be provided by OPDC or designee.  
Subject assessment recordings are summarized in Section 8.10. 
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8.2 
Pharmacokinetic Assessments 
Not applicable. 
8.3 
Pharmacodynamic Assessments 
Not applicable. 
8.4 
Pharmacogenomic Assessments 
Not applicable. 
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8.5 
Biomarker Assessments 
Not applicable. 
8.6 
Future Biospecimen Research Samples 
Not applicable. 
8.7 
Safety Assessments 
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8. 
8.7.1 
Clinical Laboratory Assessments 
Clinical laboratory samples will be collected at the time points described in the schedule 
of assessments (Table 1.3-1) to perform the clinical laboratory assessments described in 
Section 10.2. Refer to Section 10.5 for criteria for identifying laboratory values of 
potential clinical relevance. 
A central laboratory designated by the sponsor will be used for all laboratory testing 
(hematology [including HbA1c], serum chemistry [including prolactin], and urinalysis) 
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/baseline, nonfasting blood samples may be obtained 
initially for determining eligibility for the trial and need to be repeated at the next visit at 
the discretion of the investigator. Additional urine and blood samples may be collected 
for further evaluation of safety as warranted by the investigator’s judgment. Reports from 
the central laboratory should be filed with the source documents for each subject. The 
central laboratory will provide laboratory results to the sponsor electronically. 
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 at 
screening/baseline, the subject will NOT be enrolled into the trial without the permission 
of the medical monitor. In addition, 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. 


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Refer to Appendix 5 (Section 10.5) for criteria for identifying values of potential clinical 
relevance.  
The total volume of blood to be collected during the trial will be documented in the ICF. 
A pregnancy test will be conducted in FOCBP (refer to Section 10.3 for definition) 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. 
8.7.2 
Physical Examination 
Physical examinations will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). 
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 mucosa. At 
screening/baseline, height will be measured with a stadiometer, measuring stick or tape. 
Repeat measurement of height is not required at the physical examinations scheduled for 
the Week 12/early termination (ET) visit. Waist circumference will be measured at each 
physical examination (screening/baseline and Week 12/ET), using the provided 
measuring tape. The following procedures will aid in the standardization of these 
measurements: 
• The subject should be minimally clothed (ie, lightweight clothing; no heavy 
overgarments). 
• Waist circumference should be recorded before a subject’s meal and at approximately 
the same time at each visit. 
• Measurement will be accomplished by locating the upper hip bone and the top of the 
right iliac crest and placing a weighted measuring tape in a horizontal plane around 
the abdomen at the level of the crest. Before reading the tape measure, the assessor 
should assure that the tape is snug, but does not compress the skin, and is parallel to 
the floor. The measurement is to be made at the end of a normal exhalation.24  
 
The investigator (or designee) is responsible for performing the physical examination. If 
the appointed designee is to perform the physical examination, he or she must be 
permitted by local regulations and his or her name must be included on the delegation of 
authority log. Whenever possible, the same individual should perform all physical 
examinations. Any condition present at the post-treatment physical examination that was 
not present at the baseline examination should be documented as an AE and followed to a 
satisfactory conclusion. 


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8.7.3 
Vital Signs 
Vital signs will be collected at the time points described in the schedule of assessments 
(Table 1.3-1). Subjects should be monitored for potentially clinically significant vital 
signs values (Section 10.9). 
Vital sign measurements will include body weight, body temperature, systolic blood 
pressure (SBP), diastolic blood pressure (DBP), and heart rate. The following guidelines 
will aid in the standardization of body weight measurements: 
• The same scale should be used to weigh a given subject each time, if possible. 
• Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session. 
• A subject should void prior to being weighed and be minimally clothed (ie, no shoes 
or heavy overgarments). 
• Weight should be recorded before a subject’s meal and at approximately the same 
time at each visit. 
 
Blood pressure and heart rate measurements will be made in the supine and standing 
positions after the subject has been lying for at least 3 minutes. The supine measurements 
will be performed first, followed by standing.  
Subjects with uncontrolled hypertension (screening/baseline DBP > 95 mmHg in any 
position) or symptomatic hypotension at screening/baseline are excluded from the trial as 
are subjects with orthostatic hypotension, which is defined as a decrease of ≥ 30 mmHg 
in SBP or a decrease of ≥ 20 mmHg in DBP within 3 minutes of standing compared to 
the previous supine blood pressure or development of symptoms. In addition, subjects 
should be excluded if they have any other vital sign measurement at screening/baseline 
that, in the investigator’s judgment, is medically significant in that it would impact the 
safety of the subject or the interpretation of the trial results. However, any abnormal 
screening/baseline vital sign result(s) considered to be clinically significant should be 
repeated to confirm the finding(s) before excluding the subject from the trial.  
8.7.4 
Electrocardiogram 
Electrocardiograms will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). Subjects should be monitored for potentially clinically 
significant ECG results (Section 10.7). 
Electrocardiogram recordings will be obtained after the subject has been supine and at 
rest for at least 5 minutes. Additional ECGs may be obtained at the investigator’s 
discretion and should always be obtained in the event of an ET. The principal investigator 


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(or qualified designee) will review, sign, and date each ECG reading, noting whether or 
not any abnormal results are of clinical significance. The ECG will be repeated if any 
results are considered to be clinically significant. A central ECG service will be used for 
reading all ECGs in order to standardize interpretations for the safety analysis. 
Rollover subjects will be enrolled in trial based on the screening/baseline ECG results 
from the trial site. If at screening/baseline, according to the investigator's judgment, any 
abnormal ECG finding is deemed medically significant (impacting the safety of the 
subject or the interpretation of the trial results), the subject should be excluded from the 
trial. Abnormal results for ECGs should be repeated once at screening/baseline 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. If the screening/baseline ECG results from the central reader, when available, 
indicate a QTcF ≥ 450 msec in men and ≥ 470 msec in women (unless due to ventricular 
pacing at screening/baseline), the investigator must contact the medical monitor to 
discuss the subject's continued participation in the trial. 
8.7.5 
Suicidality Monitoring - Columbia-Suicide Severity Rating Scale 
Suicidality monitoring will occur at the time points described in the schedule of 
assessments (Table 1.3-1). 
Suicidality will be monitored during the trial using the C-SSRS. The “Since Last Visit” 
version of the scale will be completed at all visits for all subjects. Any subject with active 
suicidal ideation and intent at entry or who has engaged in prohibited suicidal behaviors, 
or who, in the clinical judgment of the investigator, presents a serious risk of suicide 
should be excluded from the trial (see Section 5.2.2).  
8.7.6 
Other Safety Variables 
It is required that an adequately trained and experienced clinician administer the safety 
assessments, including the EPS scales (Simpson Angus Scale [SAS], Abnormal 
Involuntary Movement Scale [AIMS], and Barnes Akathisia Rating Scale [BARS]). The 
number of raters within each trial site should be kept to a minimum. All efforts will be 
made to ensure that the same clinician administers the scales for a given subject. 
Notations in the subject’s trial records should substantiate the ratings. Training and 
materials for rating will be provided by a rater training group. 


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8.7.6.1 
Simpson Angus Scale 
The SAS25 consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, 
shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, 
salivation, and akathisia). Each item will be rated on a 5-point scale, with a score of zero 
representing absence of symptoms and a score of 4 representing a severe condition. The 
SAS total score is the sum of the scores for all 10 items. Anticholinergics, propranolol, 
benzodiazepines, and non-benzodiazepine sleep aids are not permitted within 8 hours of 
scale administration (see Section 6.5.1). Investigators are encouraged to delay scale 
administration until the required time frame has elapsed, if at all possible. However, if 
delaying administration of the scale is not feasible, the SAS should still be administered 
and the use of the medication documented, including a notation of the drug name, dose, 
and time of administration in eSource. 
8.7.6.2 
Abnormal Involuntary Movement Scale 
The AIMS23 assessment consists of 10 items describing symptoms of dyskinesia. Facial 
and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk 
movements (item 7) will be observed unobtrusively while the subject is at rest (eg, in the 
waiting room), and the investigator will also make global judgments on the subject’s 
dyskinesias (items 8 through 10). Each item will be rated on a 5-point scale, with a score 
of zero representing absence of symptoms (for item 10, no awareness), and a score of 4, 
indicating a severe condition (for item 10, awareness, severe distress). For this scale, the 
subject is to be sitting on a hard, firm chair. In addition, the AIMS includes 2 yes or no 
questions that address the subject’s dental status. Anticholinergics, propranolol, 
benzodiazepines, and non-benzodiazepine sleep aids are not permitted within 8 hours of 
scale administration (see Section 6.5.1). Investigators are encouraged to delay scale 
administration until the required time frame has elapsed, if at all possible. However, if 
delaying administration of the scale is not feasible, the AIMS should still be administered 
and the use of the medication documented, including a notation of the drug name, dose, 
and time of administration in eSource.  
The AIMS Movement Rating Score is defined as the sum of items 1 through 7 (ie, items 
1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, 
trunk movements). 


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8.7.6.3 
Barnes Akathisia Rating Scale 
The BARS26 consists of 4 items related to akathisia: objective observation of akathisia by 
the investigator, subjective feelings of restlessness by the subject, subjective distress due 
to akathisia, and global clinical assessment of akathisia. The first 3 items will be rated on 
a 4-point scale, with a score of zero representing absence of symptoms and a score of 3 
representing a severe condition. The global clinical evaluation will be made on a 6-point 
scale, with zero representing absence of symptoms and a score of 5 representing severe 
akathisia. To complete this scale, subjects will be observed while they are seated and then 
standing for a minimum of 2 minutes in each position. Symptoms observed in other 
situations (eg, while engaged in neutral conversation or engaged in other activity) may 
also be rated. Subjective phenomena are to be elicited by direct questioning. 
Anticholinergics, propranolol, benzodiazepines, and non-benzodiazepine sleep aids are 
not permitted within 8 hours of scale administration (see Section 6.5.1). Investigators are 
encouraged to delay scale administration until the required time frame has elapsed, if at 
all possible. However, if delaying administration of the scale is not feasible, the BARS 
should still be administered and the use of the medication documented, including a 
notation of the drug name, dose, and time of administration in eSource. 
8.8 
Adverse Events 
8.8.1 
Definitions 
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered an IMP and which does not necessarily have a causal relationship with this 
treatment. Adverse events would not include information recorded as medical history at 
screening/baseline for pre-planned procedures for which the underlying condition was 
known and no worsening occurred. An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the IMP and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality. 
Treatment-emergent AEs are defined as AEs with an onset date on or after the start of 
open-label treatment. In more detail, TEAEs are all AEs which started after start of 
open-label IMP treatment; or if the event was continuous from baseline and was 
worsening, serious, IMP related, or resulted in death, discontinuation, interruption or 
reduction of IMP. 


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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 nonmedical need) are not considered 
SAEs. 
− Prescheduled hospitalization to address a condition that has existed prior to the 
signing of the ICF should not be considered an SAE. 
• 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 AEs are all AEs that do not meet the criteria for a "serious" AE. 
Adverse Events of Special Interest (AESIs): A noteworthy event for the particular 
product/IMP or class of products that a sponsor may wish to monitor carefully. All AESIs 
are to be reported as immediately reportable events (IREs). 
Immediately Reportable Event:  
• Any SAE. 
• Any AE related to occupational exposure. 
• Any AESIs (Pathological Gambling and Other Compulsive Behaviors) 
• Potential serious hepatotoxicity (see Section 8.8.6). 
• 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 and the 
Pregnancy Surveillance Form(s) to the sponsor. Pregnancy will only be documented 
on the AE page in eSource if there is an abnormality or complication. This includes 
pregnancy of the subject or the partner of the subject. 
 


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Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of laboratory tests for each individual subject as they become available. This 
review will be documented by the investigator’s dated signature on the laboratory report. 
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 (ie, clinically significant) 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 in 
eSource. The severity of an adverse experience is defined as follows: 
1 = Mild:  
Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: 
Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: 
Inability to work or perform normal daily activity. 
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE. 
Not Related:  
There is no temporal or causal relationship between the IMP and 
the AE. 
 
8.8.2 
Eliciting and Reporting Adverse Events 
The investigator will regularly assess subjects for the occurrence of AEs. To avoid bias in 
eliciting AEs, subjects should be asked the nonleading question: “How have you felt 
since your last visit?” All AEs (serious and nonserious) reported by the subject must be 
recorded on the source documents provided by the sponsor and in eSource. Adverse event 
collection will begin after a subject signs the ICF. 
Medical terminology should be used for 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.  


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In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 8.8.3. Special attention 
should be paid to recording hospitalization and concomitant medications. 
Adverse event, start date, end date, seriousness, severity, relationship to trial treatment 
(IMP Causality), action taken with trial treatment and outcome will be recorded on the 
source documents and in eSource. 
8.8.3 
Immediately Reportable Events 
The investigator must immediately report (within 24 hours), using an IRE form, after 
he/she or site personnel become aware of any IRE (SAE, AE related to occupational 
exposure, AESI, potential serious hepatotoxicity, or confirmed pregnancy), by telephone, 
fax, or e-mail to the sponsor or designee using the contact information on the cover page 
of this protocol (Please note that the IRE form is NOT the AE page in eSource.). 
8.8.4 
Medical Device Incidents (Including Malfunctions) 
Not applicable. 
8.8.5 
Adverse Events of Special Interest 
The new onset or exacerbation of “Pathological Gambling and Other Compulsive 
Behaviors” will be analyzed as an AESI. 
8.8.6 
Potential Serious Hepatotoxicity 
For a subject who experiences an elevation in AST or ALT that is ≥ 3 times the ULN, a 
total bilirubin level should also be evaluated. If the total bilirubin is ≥ 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE in eSource. 
8.8.7 
Procedure for Breaking the Blind 
This trial will not use blinding procedures. 
8.8.8 
Follow-up of Adverse Events 
8.8.8.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE page in eSource with the current status (ongoing or resolved/recovered) noted. All 
nonserious events (that are not IREs) that are ongoing at the last scheduled contact will 
be recorded as ongoing in eSource. For any AE having been identified throughout the 
trial, during analysis, additional relevant medical history information may be requested 
by the sponsor to further ascertain causality (including, but not limited to, information 
such as risk-related behavior, family history and occupation). 


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8.8.8.2 
Follow-up of Immediately Reportable Events 
This trial requires that subjects be actively monitored for IREs up to 21 (± 3) days after 
the last dose of IMP is administered. 
Immediately reportable events that are identified or ongoing at the last scheduled contact 
must be recorded as such on the AE page in eSource and the IRE form. If updated 
information (eg, resolved status) on IRE status becomes available after a subject’s last 
scheduled contact (up to last in-clinic visit for the entire trial), this must be reported to the 
sponsor and recorded on the AE page in eSource and the IRE form, according to the 
appropriate reporting procedures described in Section 8.8.3. 
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. The 
investigator will follow IREs until the events are: 
• resolved, 
• stabilized, 
• the subject is lost to follow-up, or 
• has died. 
 
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 resolved or 
stabilized, or the subject is lost to follow-up, or has died. 
Refer to Section 10.3 for additional information regarding the follow-up period for 
subjects that become pregnant or for pregnant partners of male subjects. 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact 
Any new IREs reported to the investigator which 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 according to the procedures outlined in 
Section 8.8.3. This may include IREs that are captured on follow-up telephone contact or 
at any other time point after the defined trial period and continue to report any significant 
follow-up information to the sponsor until the events are resolved or stabilized, or the 
subject is lost to follow-up or has died. 


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8.9 
Treatment of Overdose 
For treatment of overdose, please refer to the current IB section for overdose.10 
8.10 
Subject Assessment Recording 
8.11 
Other Assessments 
Not applicable. 
CCI


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9 
Statistical Considerations 
9.1 
Sample Size 
The sample size is not based on statistical power considerations but on the number of 
subjects rolling over from the lead-in trials. The trial population will be derived from 
eligible subjects who completed the previous double-blind brexpiprazole BPD trials. The 
number of eligible subjects will be limited by the number of subjects enrolled into the 
double-blind trials. 
9.2 
Datasets for Analysis 
The following datasets are defined for this trial: 
x Enrolled Sample, which comprises all subjects who sign an ICF for the trial and are 
enrolled into the trial. 
x Safety Sample, which comprises all subjects who will receive at least 1 dose of IMP. 
 
9.3 
Handling of Missing Data for Primary and Secondary Endpoint 
Analysis 
In order to assess the sensitivity of results due to missing data, 2 types of analyses will be 
performed: last observation carried forward (LOCF) and observed cases (OC). The OC 
dataset will consist of the actual observations recorded at each visit. The LOCF dataset 
will include data recorded at a scheduled visit, ie, all OC data, or, if no observation is 
recorded at that visit, data will be carried forward from the previously scheduled visit. 
Baseline data will not be carried forward to impute missing values for the LOCF dataset. 
The OC dataset will be used for analyses at each trial visit and the LOCF dataset will be 
used for analyses at the last visit. 
9.4 
Statistical Analyses 
9.4.1 
Efficacy Analyses 
. 
9.4.2 
Safety Analysis 
The primary safety endpoint analysis is the frequency and severity of AEs in the 
open-label treatment phase. 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. 
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9.4.2.1 
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities preferred term. The incidence of the following events will be summarized by 
the prior treatment group: 
• Treatment-emergent AEs (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  
• AESI 
 
A TEAE is defined as an AE that starts after the first dose of IMP or an AE that is 
reported at baseline and increases in intensity or becomes serious or IMP-related or 
results in death, discontinuation, interruption or reduction of IMP. Information about new 
onset or exacerbation of “Pathological Gambling and Other Compulsive Behaviors” will 
be collected and analyzed as an AE of special interest. 
9.4.2.2 
Clinical Laboratory Data 
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements will be provided. In addition, the incidence of potentially clinically 
relevant values identified using prospectively defined in the statistical analysis plan 
(SAP) criteria for laboratory tests will be summarized. 
9.4.2.3 
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. 
9.4.2.4 
Electrocardiogram Data 
Mean change from baseline will be summarized by visit. 
The incidence of clinically relevant changes will be calculated for ECG parameters and 
summarized by visit. 


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For the analysis of QT and corrected QT interval (QTc) data from 3 consecutive 
complexes (representing 3 consecutive heart beats) will be measured to determine 
average values. The following QT corrections will be used: 
1) QTcB is the length of the QT interval corrected for heart rate using Bazett’s formula: 
QTcB=QT/(RR)0.5, and 
2) QTcF is the length of the QT interval corrected for heart rate using Fridericia’s 
formula: 
QTcF=QT/(RR)0.33 
3) QTcN is the length of the QT interval corrected for heart rate using the Food and Drug 
Administration (FDA) Neuropharm Division formula:  
QTcN=QT/(RR)0.37 
Results will be summarized by visit. 
9.4.2.5 
Other Safety Data 
Change from baseline in scores for EPS (eg, SAS, AIMS, and BARS) will be evaluated 
using descriptive statistics. The analyses will be based on the OC and LOCF datasets of 
the Safety Sample. 
Suicidality (eg, C-SSRS) will be summarized by the prior treatment group by descriptive 
statistics. Details will be described in SAP. 
9.4.3 
Other Analyses 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics 
Baseline demographic characteristics including age, race, ethnicity, sex, weight, height, 
and body mass index will be summarized by descriptive statistics (frequency, mean, 
median, standard deviation, maximum, minimum, and percentage when applicable). 
9.4.3.2 
Pharmacokinetic Analysis 
No PK analysis is planned. 
9.4.3.3 
Pharmacodynamic Analysis 
No pharmacodynamic (PD) analysis is planned. 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis 
No PK/PD analysis is planned. 


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9.4.3.5 
Pharmacogenomic Analysis 
No pharmacogenomic analysis is planned. 
9.5 
Interim Analysis and Adaptive Design 
No interim analysis or adaptive design are planned. 
9.5.1 
Data Monitoring Committee 
Not applicable. 
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10 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations 
10.1.1 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, FDA regulations, 
International Council for Harmonisation (ICH) GCP: Consolidated Guideline (E6[R2]), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science guidelines, and applicable local laws and 
regulations. Each trial site will seek approval/favorable opinion by an IRB or IEC 
according to regional requirements, and the investigator will provide that documentation 
to the sponsor. The IRB/IEC will evaluate the ethical, scientific and medical 
appropriateness of the trial. Further, in preparing and handling eSource, the investigator, 
subinvestigator and their staff will take measures to ensure adequate care in protecting 
subject privacy. To this end, a subject ID 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. 
10.1.2 
Informed Consent 
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The ICF will be approved by the 
same IRB/IEC that approves this protocol. 
Each ICF will comply with the ICH GCP: Consolidated Guideline E6(R2)27 and local 
regulatory requirements. The investigator will ensure that the sponsor reviews and 
authorizes any written site-specific ICF used in the trial before submission to the 
IRB/IEC. In support of the site’s standard process for administering informed consent, 
this trial will also allow for electronic informed consent (eICF) as a tool within applicable 
regions and trial sites. The eICF utilizes the IRB/IEC-approved site-specific ICF to offer 
subjects an enhanced platform to review and understand their rights as a research subject 
as well as required trial procedures. When possible, trial sites will have subjects review 
and sign the eICF prior to starting any trial procedures; however if local regulations does 
not allow for use of the electronic format, subjects may continue in the trial utilizing the 
standard paper and wet ink signature process. 


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Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented 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 subjects will be provided with controlled access to the eICF application 
by trial site staff. When the trial site staff and the subject agree that the subject has 
enough information to make an informed decision to participate, the subject will 
electronically sign in the eICF application and an electronic date and timestamp will be 
applied to the signature. The subject will be given a printed, signed copy of the ICF. 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 eICF in accordance with the ICH GCP Guideline and local regulatory 
requirements/guidelines. These signatures cannot be altered, removed, or copied. 
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator (or a qualified designee), and it has 
been documented that the subject has had the opportunity to ask questions, the 
IRB/IEC-approved written ICF will be signed and dated by both the subject and the 
person obtaining consent (investigator or designee), as well as by any other parties 
required by the IRB/IEC. The subject will receive a copy of the signed ICF; the original 
shall be kept on file by the investigator. 
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 continued trial 
participation. Female partners of male subjects who become pregnant during the course 
of the trial may be asked to sign additional ICFs in order to collect additional information 
regarding the nonsubject partner and fetus. 
10.1.3 
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 


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collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 
Subjects will be identified only by unique subject ID in eSource. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations. 
10.1.4 
Quality Control and Quality Assurance 
10.1.4.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH GCP: Consolidated Guideline (E6[R2]), 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 trial 
site personnel will undergo initial and ongoing training for this particular trial, and this 
training will be clearly documented. 
10.1.4.2 
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 a review of eSource with source documents, as 
applicable. 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. 
10.1.5 
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, subject enrolled in violation of eligibility criteria or concomitant medication 
criteria), the investigator or designee will contact the sponsor or designee at the earliest 
possible time by telephone or via e-mail. The investigator and sponsor (or designee) will 
come as quickly as possible to a joint decision regarding the subject’s continuation in the 
trial. This decision will be documented by the investigator and the sponsor (or designee) 
and reviewed by the site monitor. 
Any major protocol deviation will be recorded in eSource along with the start date and 
details of the deviation. 


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10.1.6 
Records Management 
10.1.6.1 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, screening/baseline 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. 
10.1.6.2 
Data Collection 
During each subject’s visit to the site or remote visit, an investigator or their designee 
participating in the trial will record information to document all significant observations. 
At a minimum, these notes will contain: 
• Documentation of the informed consent process, including any revised consents; 
• Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial; 
• The date of the visit and the corresponding Visit or Day in the trial schedule; 
• General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator’s assessment of relationship to IMP must also be recorded; 
• Any changes in concomitant medications or dosages; 
• A general reference to the procedures completed;  
• The signature (or initials) and date of the investigator (or designee) who made an 
entry in the medical record. 
 
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 (where permitted by 
local regulation) in this trial and will meet the same fundamental elements of data quality 
(eg, attributable, legible, contemporaneous, original, and accurate) as paper records. 
These data will be collected into a system that is fully validated according to 21 Code of 


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Federal Regulations Part 11. Changes to the data will be captured by an automatic audit 
trail. 
Designated trial site staff will not be given access to the electronic source 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 per the monitoring 
plan 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 
investigator or their designee. 
Another exception will be safety laboratory [or central ECG data], where the official 
source documentation will be considered the report issued by the analyzing laboratory. 
Remote monitoring of the original electronic source records 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. 
10.1.6.3 
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: Consolidated Guideline (E6[R2]) and as required by 
applicable local regulations. The investigator/institution will take measures to prevent 
accidental or premature destruction of these documents. 


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10.1.6.4 
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. 
10.1.6.5 
Publication Authorship Requirements 
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 


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Investigators or other trial subjects 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 subjects consent to such acknowledgement in any 
publications resulting from its conduct. 


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10.2 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10.2-1 will be performed. 
Table 10.2-1 
Clinical Laboratory Assessments 
Hematology: 
HbA1c 
Hemoglobin 
Hematocrit 
MCH 
MCHC 
MCV 
Platelet count  
RBC count 
RBC morphology 
RDW 
WBC count with differential  
 
Urinalysis: 
Specimen Appearance 
Color  
Occult Blood 
Glucose 
Microscopic analysis, WBC/RBC counts per high 
powered field 
pH 
Protein 
Specific Gravity 
Ketones 
 
Urine Drug Screens: 
Amphetamines/MDMA 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
Methadone 
Opiates 
Phencyclidine 
Propoxyphene 
 
Drug and Alcohol Screening: 
Blood alcohol 
Serum Chemistry: 
ALP 
ALT 
AST 
Bilirubin, total  
BUN 
Calcium 
Cholesterol (total, LDL, and HDL) 
CPK 
Creatinine 
GGT 
Glucose 
LDH 
Magnesium 
Potassium 
Prolactin 
Protein, total  
Sodium 
Triglycerides 
Uric acid 
 
Additional Tests: 
Urine and serum pregnancy for FOCBPa 
 
ALP = alkaline phosphatase; BUN = blood urea nitrogen; GGT = gamma glutamyl transferase; 
HDL = high-density lipoprotein; LDH = lactic dehydrogenase; LDL = low-density lipoprotein; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume; MDMA = methylenedioxymethamphetamine; RBC = red blood 
cell; RDW = red cell distribution width; WBC = white blood cell. 
aAll positive urine pregnancy test results must be confirmed by a serum test. Subjects with a positive 
serum pregnancy test result at screening/baseline must not be enrolled and subjects with a positive 
serum pregnancy test result during the trial must discontinue treatment and be withdrawn from the 
trial. 


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10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information 
Females of childbearing potential are females whose menstruation has started and who 
are not documented as sterile (eg, have had a bilateral oophorectomy, or hysterectomy, or 
who have been postmenopausal for at least 12 months). 
For males and FOCBP, who are sexually active, there must be a documented agreement 
that the subject and their partner will take effective measures (ie, 2 different approved 
methods of birth control or remains abstinent) to prevent pregnancy during the course of 
the trial and for 30 days after the last dose of IMP. Unless the subject is sterile (ie, 
females who have had a bilateral oophorectomy, have had a hysterectomy, or have been 
postmenopausal for at least 12 consecutive months; or males who have had a bilateral 
orchiectomy) or remains abstinent during the trial and for 30 days after the last dose of 
IMP, 2 of the following approved methods of birth control must be used: vasectomy, 
tubal ligation, intrauterine device, birth control pills, birth control implant, birth control 
depot injection, condom with spermicide, sponge with spermicide, or occlusive cap 
(vaginal diaphragm or cervical/vault cap) with spermicide. Any single method of birth 
control, including vasectomy and tubal ligation, may fail, leading to pregnancy. The 
contraceptive method will be documented in eSource. Abstinence is defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the trial 
treatments. The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
Consensual sexual activity that cannot biologically result in pregnancy may not be 
subject to required birth control methods, following discussion with the medical monitor. 
Male subjects must also agree not to donate sperm from trial screening/baseline through 
30 days after the last dose of IMP. 
Before enrolling males and females in this clinical trial, investigators must review the 
below information about trial participation as part of the ICF process. The topics should 
generally include: 
• General information 
• Informed consent form 
• Pregnancy prevention information 
• Drug interactions with hormonal contraceptives 
• Contraceptives in current use 
• Follow-up of a reported pregnancy 
 


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Before trial enrollment, males and FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. Subjects must sign the ICF confirming that the above-mentioned risk factors 
and the consequences were discussed. 
A urine or serum pregnancy test for human chorionic gonadotropin will be performed at 
screening/baseline and at each check-in to the inpatient facility on all FOCBP. If a urine 
test is performed and is positive, the investigator will follow-up with a confirmatory 
serum test. 
During the trial, all FOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle). Male subjects 
must be instructed to contact the investigator immediately, during the trial, if their partner 
suspects that they might be pregnant (eg, missed or late menstrual cycle). 
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. Exceptions to trial 
discontinuation may be considered for life-threatening conditions only after consultations 
with the IRE contact (see the title page of this protocol for contact information). 
The investigator must immediately notify the sponsor (within 24 hours) of any pregnancy 
associated with IMP exposure during the trial and for at least 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 the Pregnancy Surveillance Form(s) to the investigator 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 the 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.  


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10.4 
Appendix 4: Abbreviations 
Abbreviation 
Definition 
5-HT 
Serotonin 
AAD 
Agitation in Alzheimer’s dementia 
ADHD 
Attention-deficit/hyperactivity disorder 
ADT 
Antidepressant therapy 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIMS 
Abnormal Involuntary Movement Scale 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic-pyruvic transaminase) 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic 
transaminase) 
BARS 
Barnes Akathisia Rating Scale 
BPD 
Borderline personality disorder 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
 
 
 
 
 
 
COVID-19 
Coronavirus disease of 2019 
CPK 
Creatine phosphatase 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
D 
Dopamine 
DBP 
Diastolic blood pressure 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition 
ECG 
Electrocardiogram 
eICF 
Electronic informed consent 
EPS 
Extrapyramidal symptoms 
ET 
Early termination 
FDA 
Food and Drug Administration 
FOCBP 
Females of childbearing potential 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
 
 
HbA1c 
Glycosylated hemoglobin 
HDL 
High-density lipoprotein 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identifier 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
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Abbreviation 
Definition 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
Ki 
Inhibition constant 
LDH 
Lactic dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDD 
Major depressive disorder 
MDMA 
Methylenedioxymethamphetamine 
OC 
Observed cases 
PD 
Pharmacodynamic 
 
 
 
PK 
Pharmacokinetic 
PQC 
Product quality complaint 
PTSD 
Post-traumatic stress disorder 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QTcN 
QT interval corrected for heart rate using the Food and Drug 
Administration Neuropharm Division formula 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Simpson Angus Scale 
SBP 
Systolic blood pressure 
SYE 
Subject years of exposure 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US  
United States  
WBC 
White blood cell 
 
  
 
 
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10.5 
Appendix 5: Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance 
Laboratory Tests 
Criteria 
Chemistry 
 
AST (SGOT) 
≥ 3 x ULN 
ALT (SGPT) 
≥ 3 x ULN 
Alkaline phosphatase 
≥ 3 x ULN 
Lactate dehydrogenase 
≥ 3 x ULN 
Blood urea nitrogen 
≥ 30 mg/dL 
Creatinine 
≥ 2.0 mg/dL 
Uric acid 
 
Men 
≥ 10.5 mg/dL 
Women 
≥ 8.5 mg/dL 
Bilirubin (total) 
≥ 2.0 mg/dL 
Creatine phosphokinase 
> 3 x ULN 
Prolactin 
> ULN 
Hematology 
 
Hematocrit 
 
Men 
≤ 37 % and decrease of ≥ 3 percentage points from baseline 
Women 
≤ 32 % and decrease of ≥ 3 percentage points from baseline 
Hemoglobin 
 
Men 
≤ 11.5 g/dL 
Women 
≤ 9.5 g/dL 
WBC count 
≤ 2,800 mm3 or ≥ 16,000 mm3 
Eosinophils 
≥ 10% 
Neutrophils 
≤ 15% 
Absolute neutrophil count 
≤ 1,500/mm3 
Platelet count 
≤ 75,000/mm3 or ≥ 700,000/mm3 
Urinalysis 
 
Protein 
Increase of ≥ 2 units 
Glucose 
Increase of ≥ 2 units 
Casts 
Increase of ≥ 2 units 
Additional Criteria 
 
Chloride 
≤ 90 mEq/L or ≥ 118 mEq/L 
Potassium 
≤ 2.5 mEq/L or ≥ 6.5 mEq/L 
Sodium 
≤ 126 mEq/L or ≥ 156 mEq/L 
Calcium 
≤ 8.2 mg/dL or ≥ 12 mg/dL 
Glucose 
 
Fasting 
≥ 100 mg/dL 
Nonfasting 
≥ 200 mg/dL 
Total cholesterol, fasting 
≥ 240 mg/dL 
LDL cholesterol, fasting 
≥ 160 mg/dL 
HDL cholesterol, fasting 
 
Men 
< 40 mg/dL 
Women 
< 50 mg/dL 
Triglycerides, fasting 
≥ 150 mg/dL 


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10.6 
Appendix 6: Criteria for Identifying Vital Signs of Potential Clinical 
Relevance 
 
Variable 
Criterion Valuea 
Change Relative to 
Baselinea 
Heart rateb 
> 100 bpm 
< 50 bpm 
≥ 10 bpm increase 
≥ 10 bpm decrease 
Systolic blood pressureb 
≥ 140 mmHg Supine 
< 90 mmHg 
≥ 20 mmHg increase 
≥ 20 mmHg decrease 
Diastolic blood pressureb 
≥ 90 mmHg Supine 
< 60 mmHg 
≥ 10 mmHg increase 
≥ 10 mmHg decrease 
Orthostatic hypotension 
≥ 30 mmHg decrease in systolic blood 
pressure and/or a decrease of ≥ 20 mmHg 
in diastolic blood pressure after at least 
3 minutes of standing compared to the 
previous supine blood pressure. 
Not applicable 
(baseline status not 
considered) 
Orthostatic tachycardia 
≥ 25 bpm increase in heart rate from 
supine to standing 
Not applicable 
(baseline status not 
considered) 
Weight 
− 
≥ 7% increase 
≥ 7% decrease 
bpm = beats per minute. 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information in 
an Original New Drug Application Submission and for Organizing Information in Periodic Safety 
Updates,” FDA Division of Neuropharmacological Drug Products draft (2/27/87). 


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10.7 
Appendix 7: Criteria for Identifying ECG Measurements of 
Potential Clinical Relevance 
Variable 
Criterion Valuea 
Change Relative to 
Baselinea 
Rate 
 
 
Tachycardia 
≥ 120 bpm 
increase of ≥ 15 bpm 
Bradycardia 
≤ 50 bpm 
decrease of ≥ 15 bpm 
Rhythm 
 
 
Sinus tachycardiab 
≥ 120 bpm 
increase of ≥ 15 bpm 
Sinus bradycardiac 
≤ 50 bpm 
decrease of ≥ 15 bpm 
Supraventricular premature beat 
all 
not present → present 
Ventricular premature beat 
all 
not present → present 
Supraventricular tachycardia 
all 
not present → present 
Ventricular tachycardia 
all 
not present → present 
Atrial fibrillation 
all 
not present → present 
Atrial flutter 
all 
not present → present 
Conduction 
 
 
1 atrioventricular block 
PR ≥ 200 msec 
increase of ≥ 50 msec 
2 atrioventricular block 
all 
not present → present 
3 atrioventricular block 
all 
not present → present 
Left bundle-branch block 
all 
not present → present 
Right bundle-branch block 
all 
not present → present 
Pre-excitation syndrome 
all 
not present → present 
Other intraventricular conduction blockd 
QRS ≥ 120 msec 
increase of ≥ 20 msec 
Infarction 
 
 
Acute or subacute 
all 
not present → present 
Old 
all 
not present → present 
 
 
≥ 12 weeks post trial entry 
ST/T Morphological 
 
 
Myocardial ischemia 
all 
not present → present 
Symmetrical T-wave inversion 
all 
not present → present 
Increase in QTc 
QTcF > 450 msec 
(males) 
QTcF > 470 msec 
(females) 
 
QTc = corrected QT interval; QTcF = QT interval corrected for heart rate using Fridericia’s formula. 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality. 
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality. 
dNo current diagnosis of left bundle branch block or right bundle branch block. 
 


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10.8 
Appendix 8: Protocol Amendments 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB/IEC. Any 
permanent change to the protocol, whether an overall change or a change for specific trial 
site(s), must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB/IEC, as required by local 
regulations. Except for “administrative” or “nonsubstantial” 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. 


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10.8.1 
Protocol Amendment(s)/Administrative Change(s) 
10.8.1.1 
Protocol Amendment 1 
 
Amendment 1 Approval Date: 
01 Jul 2020 
 
PURPOSE: 
The purpose of this protocol amendment is to introduce an addendum for COVID-19 for 
any protocol-specified activities that are not able to be performed or cannot be performed 
due to COVID-19 considerations. Refer to the COVID-19 Addendum (dated 01 Jul 2020) 
for the appropriate measures to be followed. Additional administrative changes were 
made to the protocol and are documented below. Finally, minor editorial revisions were 
made for consistency with Otsuka style and for internal consistency. 
 
BACKGROUND: 
These changes to clinical trial protocol 331-201-00195, originally issued on 
21 Aug 2019, were made to introduce a COVID-19 addendum. In addition, 
administrative changes were incorporated as described in the protocol clarification 
memos (dated 20 Nov 2019 and 12 Feb 2020). 
 
MODIFICATIONS TO PROTOCOL: 
General Revisions: 
• Clarified in the trial design sections, for consistency with the schedule of 
assessments, that an optional telephone call or other form of communication will 
be made with the subject approximately 1 week (± 2 days) after the visit (eg, at 
Weeks 3, 5, 7, 9, and 11) to check on status. 
• Modified exclusion criterion #1 to indicate that consensual sexual activity that 
cannot biologically result in pregnancy may not be subject to required birth 
control methods (following discussion with the medical monitor). 
• Added to exclusion criterion #6 that if the major protocol deviation is due to 
COVID-19, eligibility for the subject to continue can be discussed with medical 
monitor. 
• Added that rescreening of subjects is not permitted. 
• For medications prohibited during the trial, added an exception for gabapentin 
when used to treat anxiety or pain (after discussion with the medical monitor). 
• Added trazodone to the list of medications prohibited during the trial (unless it is 
being used for sleep management, in which case further discussion with the 
medical monitor is required). 


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x 
 
x Added that the investigator (or their designee participating in the trial) will record 
information to document all significant observations at remote visits (in addition 
to site visits). 
x Incorporated the following items from the protocol clarification memos: 
 Revised the following text: “Note: assessments from the last scheduled 
treatment visit in the previous double-blind trial that are going to be used as 
the baseline measures for Trial 331-201-00195 will not need to be repeated if 
the subject enters Trial 331-201-00195 within 3 days 
 
 Revised the following text: “Weight should be recorded before a subject’s 
meal and at approximately the same time at each visit 
 
 
 Added a definition of abstinence: “Abstinence is defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the 
trial treatments. The reliability of sexual abstinence should be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle 
of the subject.” 
 Removed insulin and added HbA1c to the list of laboratory tests. 
 
ADDITIONAL RISK TO THE SUBJECT: 
There is no additional risk to the subjects. 
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11 
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E6/E6_R2__Step_4_2016_1109.pdf. 
 
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Amendment 1 Approval: 01 Jul 2020 
Agreement 
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement. 
 
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, OPC-34712, the concurrent medications, 
the efficacy and safety parameters and the conduct of the trial in general. I am aware that this protocol 
must be approved by the Institutional Review Board (IRB) or receive a favorable opinion by the 
Independent Ethics Committee (IEC) responsible for such matters in the clinical trial facility where 
OPC-34712 will be tested prior to commencement of this trial. I agree to adhere strictly to the attached 
protocol (unless amended in the manner set forth in the sponsor's Clinical Trial Agreement, at which 
time I agree to adhere strictly to the protocol as amended). 
 
I understand that this IRB/IEC-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered in eSource 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 subinvestigators 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 
 

SAP_001.pdf: 
NCT Number: 
Document Date: 
A Multicenter, Open-label Trial to Evaluate the Safety and 
Tolerability of Brexpiprazole in the Treatment of Adult Subjects 
With Borderline Personality Disorder
NCT04186403
Statistical Analysis Plan Final Version: 20 September 2021
Official Title: 


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Otsuka Pharmaceutical Development & Commercialization, Inc. 
Investigational New Drug 
Brexpiprazole (OPC-34712) 
A Multicenter, Open-label Trial to Evaluate the Safety and Tolerability of Brexpiprazole in 
the Treatment of Adult Subjects With Borderline Personality Disorder 
Open-label Trial of Brexpiprazole in the Treatment of Borderline Personality Disorder 
Protocol No. 331-201-00195 
IND No. 141091 
EudraCT No. 2019-002897-30 
Statistical Analysis Plan 
Version: Final 
Date: September 20, 2021 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc. 


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Table of Contents 
Table of Contents .......................................................................................... 2
List of In-text Tables ..................................................................................... 4
List of In-text Figures ................................................................................... 5
1 
Introduction .......................................................................................... 6
2 
Study Objectives .................................................................................. 6
3 
Trial Details .......................................................................................... 6
3.1 
Study Design ...................................................................................................... 6 
3.2 
Trial Treatments ................................................................................................. 9 
4 
Sample Size and Power Justification ................................................. 9
5 
Data Sets for Analysis and Missing Data......................................... 10
5.1 
Data Sets for Analysis ...................................................................................... 10 
5.2 
Handling of Missing Data................................................................................. 10 
6 
Study Conduct .................................................................................... 10
6.1 
Subject Disposition, Completion Rate and Reasons for Discontinuation ........ 10 
6.2 
Treatment Compliance ..................................................................................... 10 
6.3 
Protocol Deviation ............................................................................................ 11 
7 
Baseline Characteristics .................................................................... 11
7.1 
Baseline Definition ........................................................................................... 11 
7.2 
Demographic Characteristics ............................................................................ 11 
7.3 
Medical and Psychiatric History....................................................................... 11 
7.4 
Baseline Psychiatric Evaluation ....................................................................... 11 
8 
Efficacy Analysis ................................................................................ 11
8.1 
COVID-19 Related Supplementary Analyses .................................................. 12 
9 
Safety Analysis ................................................................................... 12
9.1 
Adverse Events ................................................................................................. 13 
9.2 
Clinical Laboratory Tests ................................................................................. 14 
9.2.1 
Drug Induced Liver Injury (DILI) ................................................................. 14 
9.2.2 
Metabolic Change .......................................................................................... 15 
9.3 
Physical Examination and Vital Signs.............................................................. 16 


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9.4 
12-Lead ECG .................................................................................................... 16 
9.5 
SAS, AIMS, and BARS .................................................................................... 17 
9.6 
Suicidality Data ................................................................................................ 17 
9.7 
Concomitant Medications ................................................................................. 18 
9.8 
Extent of Exposure ........................................................................................... 18 
10 
Conventions ........................................................................................ 18
10.1 
Study Visit Windows ........................................................................................ 18 
10.2 
Scales: Rules for Scoring and Handling of Missing Data ................................ 19 
 
 19 
 
 20 
 
 20 
 
. 20 
 
 20 
 
 21 
 
 21 
 
 21 
10.2.9 
SAS ................................................................................................................ 21 
10.2.10 
AIMS.............................................................................................................. 22 
10.2.11 
BARS ............................................................................................................. 22 
10.2.12 
C-SSRS .......................................................................................................... 22
11 
Potential Clinical Relevance Criteria from Protocol ..................... 23
12 
Proposed List of Summary Tables ................................................... 26
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List of In-text Tables 
Table 3.2-1 
Dosing Schedule ............................ Error! Bookmark not defined. 


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List of In-text Figures 
Figure 3.1-1 
Trial Design Schematic ................................................................... 8 


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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 331-201-00195.  All amendments and addendums to the protocol are 
taken into consideration in developing this SAP.  In addition, if the analyses described in the 
protocols differ from those in this SAP, the methods of the SAP prevail. 
2 
Study Objectives 
Primary Safety: To evaluate the safety and tolerability of brexpiprazole for the treatment of 
subjects with a diagnosis of BPD. 
3 
  Trial Details 
3.1 
Study Design 
This is a 12-week, multicenter, open-label trial designed to evaluate the safety and tolerability 
of brexpiprazole treatment in adult subjects diagnosed with BPD. Subjects will receive 2 to 3 
mg/day brexpiprazole. 
Enrollment into the trial will be drawn from eligible subjects who completed the last 
treatment visit of the previous double-blind brexpiprazole BPD trials (and took the 
investigational medicinal product [IMP] through the last scheduled treatment visit) and, in the 
investigator’s judgment, could potentially benefit from treatment with brexpiprazole for BPD. 
The trial will be organized as follows: 


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Screening/Baseline: Subjects will be screened for eligibility at the last scheduled treatment 
visit of the previous double-blind trial. Subjects will sign a separate informed consent form 
(ICF) at the last scheduled treatment visit of the previous double-blind trial for participation in 
this trial before any procedures specific to the open-label trial are performed. The assessments 
from the last scheduled treatment visit of the previous double-blind trial will serve as the 
baseline measures for this trial for any assessment that is not new (unique) to the open-label 
trial. Medical history will be updated, if necessary. Informed consent cannot be obtained after 
the last scheduled treatment visit of the previous double-blind trial without all 
screening/baseline assessments being repeated. If a subject is unable to rollover immediately, 
up to 3 days may be permitted between the end of the double-blind trial and the start of IMP 
in the open-label extension trial; however, this must be discussed with the medical monitor 
(Note: assessments from the last scheduled treatment visit in the previous double-blind trial 
that are going to be used as the baseline measures for Trial 331-201-00195 will not need to be 
repeated if the subject enters Trial 331-201-00195 within 3 days). 
Due to COVID-19, delayed entry subjects are permitted to be screened for Trial 331-201-
00195 up to 90 days after completing the last scheduled treatment visit of the previous 
double-blind BPD trial (discussion with the medical monitor is required if > 90 days have 
passed). These subjects will be screened for eligibility at a separate screening visit for 
Trial 331-201-00195, where they will undergo full assessments to determine eligibility. The 
screening period will be up to 21 days and may be extended upon discussion with the medical 
monitor. The delayed entry subjects will also undergo a separate baseline visit, and the 
assessments from that visit will serve as the baseline measures for Trial 331-201-00195. 
Delayed entry subjects will receive the first dose of IMP at the baseline visit.  
Treatment Phase: Eligible subjects will receive daily treatment with open-label brexpiprazole 
beginning at the screening/baseline visit. Visits will occur at the end of Weeks 2, 4, 8, and 12. 
Telephone contact will be made at Weeks 1, 6, and 10 to assess adverse events (AEs) and 
concomitant therapy. In addition, an optional telephone call or other form of communication 
will be made with the subject approximately 1 week (± 2 days) after the visit (e.g., at Weeks 
3, 5, 7, 9, and 11) to check on status. All subjects will receive up to 12 weeks of open-label 
treatment in this trial. 
Follow-up: Subjects will be followed for safety via telephone contact or clinic visit 21 (± 3) 
days after the last dose of open-label brexpiprazole. 
See Figure 3.1-1for a schematic of the trial design. 


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aThe last visit of the previous double-blind BPD trial will serve as the baseline measures for Trial 331-201-00195. If a subject is unable to rollover 
immediately, up to 3 days may be permitted between the end of the double-blind trial and the start of IMP in the open-label extension trial; however, this 
must be discussed with the medical monitor. 
bTelephone contact or clinic visit. 
cTelephone contact will be made at Weeks 1, 6, and 10 to assess AEs and concomitant therapy. 
 
Figure 3.1-1 
Trial Design Schematic    
Open- label Brexpiprazole (2 mg/day to 3 mg/day ) 
Treatment Phase 
Screening/ Baseline a 
Visits at end of Weeks 2, 4, 8, and 12 (unscheduled visits as necessary for IMP dose decreases) 
Safety Follow - Up 
Last visit of the previous
double - blind BPD trial 
b 
Week 1c 
Week 2 
Week 4 
Week 8 
Eligible subjects who 
completed a double-blind BPD 
trial and who, in the opinion of 
the investigator, could 
potentially benefit from the 
administration of brexpiprazole 
for the treatment of BPD  
Week 6c 
Week 10c 
Week 12/ET 
Week 15 
(21 [± 3] days after 
last dose) 


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3.2 
Trial Treatments 
The first dose of open-label brexpiprazole will be taken one day after the last dose of double-
blind IMP is taken for the previous double-blind, brexpiprazole BPD trial so that treatment 
continues without interruption. It is anticipated that the last dose of IMP of the double-blind 
trial will be taken the day of the treatment last visit of the previous double-blind brexpiprazole 
BPD trial (i.e., the day of the screening/baseline visit for the open-label trial). If a subject is 
unable to rollover immediately, up to 3 days may be permitted between the end of the double-
blind trial and the start of IMP in the open-label extension trial; however, this must be 
discussed with the medical monitor. Delayed entry subjects will receive the first dose of IMP 
at the baseline visit.All subjects will receive a starting dose of 1 mg/day at the 
screening/baseline visit, followed by an increase to 2 mg/day at the end of Week 1 (Table 3.2-
1). Subjects may increase their dose to 3 mg/day at the investigator’s discretion on or after the 
Week 2 visit, depending on treatment response and tolerability. Subjects taking 3 mg/day may 
down-titrate to 2 mg/day based on tolerability at any time during the course of the trial. 
Subjects unable to tolerate 2 mg/day will be discontinued from the trial. Dose adjustments to 
brexpiprazole must be made in increments of 1 mg/day. Dose decreases for brexpiprazole can 
occur at unscheduled visits and dose increases for brexpiprazole can only occur at scheduled 
visits. 
As applicable, dose changes of background antidepressant therapy (ADT) can be modified to 
achieve optimum efficacy and tolerability. Dose adjustments of ADT should not occur at the 
same visit as a dose adjustment of brexpiprazole and a recommended minimum of 5 days 
should occur between any dose adjustments of brexpiprazole or ADT at any point during the 
trial. 
Table 3.2-1 
Dosing Schedule 
IMP 
Screening/Baseline - Week 1 
Week 1 - Week 2 
Week 2 - Week 12a 
Brexpiprazole 
1 mg/day 
2 mg/day 
2 or 3 mg/dayb 
 
aDown titration can occur at any time due to tolerability after Week 2. The minimum dose allowed is 
2 mg/day. 
bOption to titrate to 2 or 3 mg/day (i.e., 2 mg, or 3 mg) based on clinical response and tolerability; changes 
must occur in 1 mg/day increments. 
 
4 
Sample Size and Power Justification 
The sample size is not based on statistical power considerations but on the number of subjects 
rolling over from the lead-in trials. The trial population will be derived from eligible subjects 


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who completed the previous double-blind brexpiprazole BPD trials. The number of eligible 
subjects will be limited by the number of subjects enrolled into the double-blind trials. 
5 
Data Sets for Analysis and Missing Data  
5.1 
Data Sets for Analysis 
The following datasets are defined for this trial: 
x Enrolled Sample, which comprises all subjects who sign an ICF for the trial and are 
enrolled into the trial. 
x Safety Sample, which comprises all subjects who will receive at least 1 dose of IMP. 
x 
 
 
5.2 
Handling of Missing Data 
In order to assess the sensitivity of results due to missing data, 2 types of analyses will be 
performed:  last observation carried forward (LOCF) and observed cases (OC). The OC 
dataset will consist of the actual observations recorded at each visit.  The LOCF dataset will 
include data recorded at a scheduled visit, i.e., all OC data, or, if no observation is recorded at 
that visit, data will be carried forward from the previously scheduled visit.  Baseline data will 
not be carried forward to impute missing values for the LOCF dataset. The OC dataset will be 
used for analyses at each trial visit and the LOCF dataset will be used for analyses at the last 
visit. 
6 
Study Conduct 
6.1 
Subject Disposition, Completion Rate and Reasons for Discontinuation 
Subject disposition will be summarized for the Enrolled Sample by parent study treatment 
group and overall.  
Subject completion rate and reasons for discontinuation will be summarized for the Enrolled 
Sample by parent study treatment group and overall.  
6.2 
Treatment Compliance 
Based on the Investigational medicinal product (IMP) panel of the CRF, compliance in taking 
IMP is calculated by dividing the number of tablets/capsules taken by the total number of 
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tablets/capsules the patients were scheduled to take during the study period. For lost-to-follow 
up patients, last IMP end date record will be used as the treatment end date.   
6.3 
Protocol Deviation 
Protocol deviations will be summarized by center and type of deviation for enrolled subjects by 
parent study treatment group. A listing of protocol deviations will be provided.  In addition, 
protocol deviations affected by the COVID-19 will be summarized. Listing of subjects with 
protocol deviations affected by the COVID-19 will also be provided. 
7 
Baseline Characteristics 
7.1 
Baseline Definition  
Baseline is defined as the last available measurement prior to the first dose of open-label IMP 
in the open-label treatment phase. 
7.2 
Demographic Characteristics 
Baseline demographic characteristics including age, race, ethnicity, gender, weight, height, and 
body mass index (BMI) will be summarized by descriptive statistics (frequency, mean, median, 
standard deviation, maximum, minimum, and percentage when applicable) for the Enrolled 
Sample by parent study treatment group and overall. 
7.3 
Medical and Psychiatric History  
A summary of medical, psychiatric, and borderline personality disorder history will be 
presented for the Enrolled Sample (by parent study treatment group and overall). 
7.4 
Baseline Psychiatric Evaluation  
For the Enrolled Sample, baseline psychiatric scale evaluation will be summarized by parent 
study treatment group and overall. The mean, median, range and standard deviation will be 
used to summarize the assessments of: 
 
 
.  
8 
Efficacy Analysis 
 
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8.1 
COVID-19 Related Supplementary Analyses  
Summary statistics for mean and mean change from baseline in 
, by 
trial visit and at the last visit (i.e., Week 12/ET) and by visit type (face-to-face vs. remote) 
based on the Efficacy Sample will be provided by parent study treatment group for rollover 
subjects and overall.  
9 
Safety Analysis 
The primary safety endpoint analysis is the frequency and severity of AEs in the open-label 
treatment phase (see Section 9.1). Other standard safety variables to be analyzed include 
clinical laboratory tests, vital signs, body weight, waist circumference, BMI, 12-lead 
electrocardiograms (ECGs), and physical examinations. In addition, data from the following 
safety scales will be evaluated: Abnormal Involuntary Movement Scale (AIMS), Simpson-
Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS) and Columbia-Suicide Severity 
Rating Scale (C-SSRS).   
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Safety analyses will be conducted based on the Safety Sample, and summary statistics will be 
provided by parent study treatment group and overall, unless otherwise indicated.  
Unless otherwise specified, in general, analysis of safety data will be performed on observed 
case and for last visit.  
9.1 
Adverse Events  
All adverse events will be coded by System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs that are sex-
specific, e.g., ovarian cancer, will have their incidence rates evaluated for the specific sex. 
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the first 
dose of IMP. In more detail, TEAEs are all adverse events which started after start of IMP; or 
if the event was continuous from baseline and was worsening, serious, study drug related, or 
resulted in death, discontinuation, interruption or reduction of study therapy. Adverse events 
occurring up to 30 days after the last day of IMP will be included in the summary tables.  
The incidence of the following events in the open-label treatment phase will be tabulated by 
treatment group and overall using the Safety Sample: 
a) TEAEs  
b) TEAEs by severity 
c) TEAEs potentially causally related to the IMP 
d) TEAEs with an outcome of death 
e) Serious TEAEs 
f) TEAEs leading to discontinuations of the IMP 
g) AESI 
The above summaries (b), (e) and (f) will also be prepared for TEAEs potentially causally 
related to the IMP. 
In addition, incidence of TEAE during the open-label treatment phase of at least 5% by SOC 
and PT will be provided. 
Incidence of TEAEs by SOC and PT will be summarized for sex, race, age and region 
subgroups. 
Extrapyramidal symptoms (EPS)-related AEs will be grouped into five categories. 


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1) Dystonic Events, which include cervical spasm, dystonia, emprosthotonos, muscle 
contractions involuntary, muscle rigidity, muscle spasms, muscle spasticity, myotonia, nuchal 
rigidity, oculogyration, opisthotonos, pleurothotonus, risus sardonicus, torticollis, and trismus; 
2) Parkinsonian Events, which include akinesia, asterixis, athetosis, bradykinesia, cogwheel 
rigidity, essential tremor, extrapyramidal disorder, freezing phenomenon, gait festinating, 
hypertonia, hypokinesia, hypokinesia neonatal, intention tremor, masked facies, parkinson’s 
disease, parkinsonian crisis, parkinsonian gait, parkinsonian rest tremor, parkinsonism, 
tremor, and tremor neonatal; 
3) Akathisia Events, which include akathisia, hyperkinesia, and psychomotor hyperactivity; 
4) Dyskinetic Events, which include ballismus, buccoglossal syndrome, choreoathetosis, 
clumsiness, dyskinesia, dyskinesia neonatal, dyskinesia oesophageal, fumbling, nodding of 
head, on and off phenomenon, and tardive dyskinesia; 
5) Residual Events, which include chorea, Huntington’s chorea, muscle twitching, and 
myoclonus. 
Adverse Events of Special Interest 
The new onset or exacerbation of “Pathological Gambling and Other Compulsive Behaviors” 
will be analyzed as an AESI. 
Unless otherwise specified, in general, analysis of safety data will be performed on observed 
case and for last visit. 
9.2 
Clinical Laboratory Tests 
Summary statistics for mean and mean change from baseline in the routine clinical laboratory 
measurements, prolactin concentrations, coagulation parameters (PT, aPTT, and INR), 
HbA1c, and TSH will be provided by parent study treatment group and by visit. 
Potentially clinically relevant laboratory measurement test results in the open-label treatment 
period will be identified for the Safety Sample and will be summarized by parent study 
treatment group and listed. Criteria for identifying laboratory values of potential clinical 
relevance are provided in Appendix 2. 
9.2.1 
Drug Induced Liver Injury (DILI) 
Total bilirubin level should be checked for any subject with increased ALT or AST levels ≥ 
three times the upper normal limits (ULN) or baseline.  


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• 
Reporting all DILI as SAE to the FDA based on Hy's Law:  
o AST or ALT > 3 x ULN or baseline and  
o T_Bili  > 2 x ULN or baseline 
A separate incidence table will be provided for DILI cases, and the corresponding listing will 
be provided for Safety Sample during the open-label treatment 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 
parent study treatment group using the following criteria. 
Criteria for Treatment-Emergent Significant Change in Lipids and Glucose 
LAB PARAMETER 
BASELINE¹ 
ANYTIME POST BASELINE      
LDL Direct, Fasting  
(MG/DL) 
Borderline 100-<160    
Normal/Borderline <160 
Normal <100            
Any Value              
High >=160             
High >=160             
Borderline/High >=100  
Increased >=30         
HDL Cholesterol, Fasting 
(MG/DL) 
Normal >=40   
Any Value     
Low <40             
Decreased >=20      
Triglycerides, Fasting  
(MG/DL)    
Normal <150            
Borderline 150-<200    
Normal/Borderline <200 
Normal <150            
Any Value     
High 200-<500              
High 200-<500              
High 200-<500              
Borderline/High/Very High >=150       
Increased >=50             
Glucose Fasting, Serum  
(MG/DL)    
Normal <100            
Impaired 100-<126      
Normal/Impaired <126   
Any Value              
High >=126        
High >=126        
High >=126        
Increased >=10    
    ¹ BASELINE IS DEFINED AS THE LAST AVAILABLE MEASUREMENT PRIOR TO THE FIRST DOSE OF OPEN-LABEL IMP IN THE OPEN-
LABEL TREATMENT PHASE. 
Criteria for Treatment-Emergent Metabolic Syndrome  
DESCRIPTION 
ANYTIME POST BASELINE¹      
Central Obesity         
                        
Dyslipidemia            
                        
Dyslipidemia            
                        
Supine Blood Pressure   
Waist Circumference >=102cm(MALE), >=88cm (FEMALE)     
                                                      
Triglycerides >= 150mg/dl                             
                                                      
HDL < 40mg/dl (MALE), <50mg/dl (FEMALE)               
                                                      
Systolic>=130mmHg and Diastolic>=85mmHg               


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Criteria for Treatment-Emergent Metabolic Syndrome  
DESCRIPTION 
ANYTIME POST BASELINE¹      
                        
Glucose Fasting, Serum 
                                                      
>=100mg/dl                                            
Metabolic Syndrome              Met 3 Or More of the Above Criteria at a Visit 
    ¹ BASELINE IS DEFINED AS THE LAST AVAILABLE MEASUREMENT PRIOR TO THE FIRST DOSE OF OPEN-LABEL IMP IN THE OPEN-
LABEL TREATMENT PHASE. 
9.3 
Physical Examination and Vital Signs  
Summary statistics for changes from baseline in vital signs will be provided for the Safety 
Sample. By-patient listings will be provided for physical examination. 
Potentially clinically relevant vital signs measurements identified in the open-label treatment 
phase for the Safety Sample will be listed and summarized. Criteria for identifying vital signs 
of potential clinical relevance are provided in Appendix 1. 
In addition, the change from baseline in weight, BMI, and waist circumference, and 
potentially clinically relevant abnormalities in weight, will also be summarized. 
9.4 
12-Lead ECG 
Summary statistics and incidence of potentially clinically relevant changes will be provided 
for ECG parameters. 
For the analysis of QT and QTc, data from three consecutive complexes (representing three 
consecutive heart beats) will be measured to determine average values.  The following QT 
corrections will be used for reporting purposes in the clinical study report: 
1)  QTcB is the length of the QT interval corrected for heart rate by the Bazett formula: 
QTcB=QT/(RR)0.5 and 
2)  QTcF is the length of the QT interval corrected for heart rate by the Fridericia formula: 
QTcF=QT/(RR)0.33 
3) QTcN is the length of the QT interval corrected for heart rate by the FDA Neuropharm 
Division formula:  QTcN=QT/(RR)0.37  
Potentially clinically relevant changes in the 12-lead ECG identified in the open-label 
treatment phase  for the Safety Sample will be listed and summarized by treatment group. 
Criteria for identifying ECG measurements of potential clinical relevance are provided in 
Appendix 3. 


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Categorical changes in ECG parameters during the open-label treatment phase will be 
summarized based on the following criteria: 
Categorical Change Criteria in QT/QTc Parameters 
Classification 
Category 
Criteria  
QT 
New Onset (> 450 Msec) 
New onset (>450 msec) in QT means a subject who 
attains a value > 450 msec during treatment period 
but not at baseline. 
QTc * 
New Onset ( 450 Msec 
IRUPHQDQG 470 Msec 
for women) 
 
New onset ( 450 Msec for men and ( 470 Msec 
for women) in QTc means a subject who attains a 
value  450 Msec IRUPHQRU 470 Msec for 
women during treatment period but not at baseline. 
 
New Onset ( 450 Msec 
IRUPHQDQG 470 Msec 
for women)  
And > 10% Increase 
New onset ( 450 Msec IRUPHQDQG 470 Msec for 
women) and  
> 10% increase in QTc means a subject who attains 
a value  450 Msec IRUPHQRU 470 Msec for 
women, and > 10% increase during treatment period 
but not at baseline 
 
New Onset (> 500 Msec) 
New onset (> 500 msec) in QTc means a subject 
who attains a value > 500 msec during treatment 
period but not at baseline. 
 
Increase 30 - 60 Msec 
Increase from baseline value > 30 and d 60 msec in 
QTc 
 
Increase > 60 Msec 
Increase from baseline value > 60 msec in QTc 
* QTc categorical change criteria apply to QTcB, QTcF and QTcN. 
9.5 
SAS, AIMS, and BARS 
 Change from baseline in SAS, AIMS, and BARS scales for trial visits during the open-label 
treatment phase using the Safety Sample will be summarized by descriptive statistics. In 
addition, incidence of BARS Global Clinical Assessment of Akathisia during the open-label 
treatment phase by severity category will be provided. Descriptive statistics will be 
summarized at each visit using the OC data set and at the last visit (Week 12/ET) using the 
LOCF data set.
9.6 
Suicidality Data 
Suicidality will also be monitored during the study using the C-SSRS 
 and will be summarized as number and 
percentage of subjects reporting any suicidal behavior, ideation, behavior by type (4 types), 
ideation by type (5 types) and treatment emergent suicidal behavior and ideation. Summary 
will be provided for the open-label treatment phase. 
Suicidality is defined as report of at least one occurrence of any type of suicidal ideation or at 
least one occurrence of any type of suicidal behavior during assessment period (count each 
person only once). 
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Treatment emergent suicidal behavior and ideation is summarized by four types: Emergence 
of suicidal ideation, Emergence of serious suicidal ideation, Worsening of suicidal ideation, 
Emergence of suicidal behavior.  
Emergence of suicidal behavior/ideation is defined as report of any type of suicidal 
behavior/ideation during treatment when there was no baseline suicidal behavior/ideation. 
Emergence of serious suicidal ideation is defined as observation of suicidal ideation severity 
rating of 4 or 5 during treatment when there was no baseline suicidal ideation.                                                   
Worsening of suicidal ideation is defined as a suicidal ideation severity rating that is more 
severe than it was at baseline. 
9.7 
Concomitant Medications 
Number and proportion of patients taking concomitant medications prior to the open-label 
treatment phase, during the open-label treatment phase, and after study therapy are tabulated by 
drug classification using the WHO drug dictionary  
9.8 
Extent of Exposure 
The start date of the open-label study therapy - brexpiprazole - will be the first day of dosing 
during the open-label treatment phase. The number and percentage of patients who receive 
study medication during the open-label treatment phase, will be presented by week. Each 
dosing week will be based on the actual week; i.e., Day 1-7 in Week 1, Day 8-14 in Week 2, 
etc. This summary will be performed on the Safety Sample.  
The mean daily dosage will be summarized by week using descriptive statistics. The mean 
daily dosage per patient per week will be determined for each week of the study. This will be 
calculated by dividing the sum of individual total doses by the number of days in the week 
interval. The summary will contain the number of patients receiving study medication during 
the open-label treatment phase, and the mean and range of the mean daily dose for each week. 
10 Conventions 
10.1 Study Visit Windows 
Study visit windows will be used to map visits using study day intervals. Observations at each 
scheduled visit and Early Termination will be assigned to Week 2, Week 4, Week 8 and Week 
12 visits based on their visit windows as shown in Table 10.1A. This visit window convention 
applies to tables and listings for all efficacy and safety scales (
 
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 SAS, AIMS and BARS). This 
derived study window variable will be named as DAY and will be footnoted. In listings, it 
will be listed along with the CRF study visit. 
Table 10.1A shows classifications for study day intervals in the open-label treatment phase. 
The variable “target day” is defined using the number of days since the start of open-label 
brexpiprazole dosing. The first day of open-label brexpiprazole dosing is defined as “Day 1”. 
If more than one observation falls within a particular study day interval, then the last 
observation within that interval is used. Evaluations occurring more than 7 days after the last 
open-label brexpiprazole dosing date will not be mapped into study visit windows, and will be 
excluded from the analysis. 
Table 10.1A: Study Day and Visit Windows in the Open-label Treatment Phase
Week 
Target Day a 
Study Day Interval a 
2 
14 
2-21 
4 
28 
22-42 
8 
56 
43-70 
12 
84 
71-91 b 
a Relative to the first day of open-label brexpiprazole in the open-label treatment phase. 
b Evaluations occurring more than seven days after the last dosing date of open-label brexpiprazole in the open-
label treatment phase will be excluded from the efficacy analyses. 
10.2 Scales: Rules for Scoring and Handling of Missing Data 
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10.2.9 
SAS 
The SAS will be used to evaluate extrapyramidal symptoms (EPS). It consists of a list of 10 
symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist 
rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). Each item will be rated 
on a 5-point scale, with a score of zero representing absence of symptoms, and a score of 4 
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representing a severe condition. The SAS Total score is the sum of ratings for all 10 items, 
with possible Total scores from 0 to 40. The SAS Total score will be un-evaluable if less than 
8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the Total score will be 
the mean of the recorded items multiplied by 10 and then rounded to the first decimal place. 
10.2.10 AIMS 
The AIMS is a 12-item scale. The first 10 items are rated from 0 to 4 (0=best, 4=worst). An 
item score of 0, depending on the item, either means: no abnormal involuntary movement 
(AIM), or no incapacitation due to AIM, or no awareness of AIM. An item score of 4 either 
means: severe AIM, or severe incapacitation due to AIM, or being aware of, and severe 
distress caused by AIM. Items 11 and 12, related to dental status, have dichotomous 
responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven 
items. The possible total scores are from 0 to 28. The AIMS Total Score will be un-evaluable 
if less than 6 of the first 7 items are recorded. If 6 of the items are recorded, then the total 
score will be the mean of the recorded items multiplied by 7 and then rounded to the first 
decimal place. 
10.2.11 BARS 
The BARS consists of 4 items related to akathisia: objective observation of akathisia by the 
investigator, subjective feelings of restlessness by the subject, subjective distress due to 
akathisia, and global clinical assessment of akathisia. The first 3 items will be rated on a 4-
point scale, with a score of zero representing absence of symptoms and a score of 3 
representing a severe condition. The global clinical evaluation will be made on a 6-point 
scale, with zero representing absence of symptoms and a score of 5 representing severe 
akathisia. 
10.2.12 C-SSRS 
Suicidality will be monitored during the trial using the C-SSRS. The “Since Last Visit” 
version of the scale will be completed at all visits for all subjects. Any subject with active 
suicidal ideation and intent at entry or who has engaged in prohibited suicidal behaviors, or 
who, in the clinical judgment of the investigator, presents a serious risk of suicide should be 
excluded from the trial. 
 
 
 
 


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11 Potential Clinical Relevance Criteria from Protocol 
Appendix 1 
Criteria for Identifying Vital Signs of Potential Clinical Relevance 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Heart Rateb 
 
> 120 bpm 
< 50 bpm 
≥ 15 bpm increase 
≥ 15 bpm decrease 
Systolic Blood Pressureb 
 
> 180 mmHg 
< 90 mmHg 
≥ 20 mmHg increase 
≥ 20 mmHg decrease 
Diastolic Blood Pressureb 
 
> 105 mmHg 
< 50 mmHg 
≥ 15 mmHg increase 
≥ 15 mmHg decrease 
Orthostatic Hypotension 
 
≥ 20 mmHg decrease in systolic blood 
pressure and a ≥ 25 bpm increase in 
heart rate from supine to 
sitting/standing 
Not Applicable 
(baseline status not considered) 
Weight 
- 
≥ 7% increase 
≥ 7% decrease 
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the “Criterion 
Value” and also represent a change from the subject’s baseline value of at least the magnitude shown in the 
“Change Relative to Baseline” column. 
b As defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information in 
an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA Division 
of Neuropharmacological Drug Products draft (2/27/87). 
 


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Appendix 2 
Criteria for Identifying Laboratory Values of Potential Clinical 
Relevance 
Laboratory Tests 
Criteria 
Chemistry 
 
 
AST (SGOT) 
≥ 3 x upper limit of normal (ULN) 
 
ALT (SGPT) 
≥ 3 x ULN 
 
Alkaline phosphatase 
≥ 3 x ULN 
 
Lactate dehydrogenase (LDH) 
≥ 3 x ULN 
 
Blood urea nitrogen (BUN) 
≥ 30 mg/dL 
 
Creatinine 
≥ 2.0 mg/dL 
 
Uric Acid 
 
 
 
Men 
≥ 10.5 mg/dL 
 
 
Women 
≥ 8.5 mg/dL 
 
Bilirubin (total) 
≥ 2.0 mg/dL 
 
Creatine phosphokinase (CPK) 
≥ 3 x ULN 
 
Prolactin 
> ULN 
Hematology 
 
 
Hematocrit 
 
 
 
Men 
≤ 37 % and decrease of ≥ 3 percentage points from Baseline 
 
 
Women 
≤ 32 % and decrease of ≥ 3 percentage points from Baseline 
 
Hemoglobin 
 
 
 
Men 
≤ 11.5 g/dL 
 
 
Women 
≤ 9.5 g/dL 
 
White blood count 
≤ 2,800/ mm3 or ≥ 16,000/ mm3 
 
Eosinophils 
≥ 10% 
 
Neutrophils 
≤ 15% 
 
Absolute neutrophil count 
≤ 1,500/ mm3 
 
Platelet count 
≤ 75,000/ mm3 or ≥ 700,000/ mm3 
Urinalysis 
 
 
Protein 
Increase of ≥ 2 units 
 
Glucose 
Increase of ≥ 2 units 
 
Casts 
Increase of ≥ 2 units 
Additional Criteria 
 
 
Chloride 
≤ 90 mEq/L or ≥ 118 mEq/L 
 
Potassium 
≤ 2.5 mEq/L or ≥ 6.5 mEq/L 
 
Sodium 
≤ 126 mEq/L or ≥ 156 mEq/L 
 
Calcium 
≤ 8.2 mg/dL or ≥ 12 mg/dL 
 
Glucose 
 
 
 
Fasting 
≥ 100 mg/dL  
 
 
Non-Fasting 
≥ 200 mg/dL 
 
Total Cholesterol, Fasting 
≥ 240 mg/dL  
 
LDL Cholesterol, Fasting 
≥ 160 mg/dL  
 
HDL Cholesterol, Fasting 
 
 
 
Men 
< 40 mg/dL 
 
 
Women 
< 50 mg/dL 
 
Triglycerides, Fasting 
≥ 150 mg/dL 
 


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Appendix 3 
Criteria for Identifying ECG Measurements of Potential Clinical 
Relevance 
 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Rate 
 
 
 
Tachycardia 
≥ 120 bpm 
increase of  ≥ 15 bpm 
 
Bradycardia 
≤ 50 bpm 
decrease of ≥ 15 bpm 
Rhythm 
 
 
 
Sinus tachycardiab 
≥ 120 bpm 
increase of ≥ 15 bpm 
 
Sinus bradycardiac 
≤ 50 bpm 
decrease of ≥ 15 bpm 
 
Supraventricular premature beat 
all 
not present  present 
 
Ventricular premature beat 
all 
not present  present 
 
Supraventricular tachycardia 
all 
not present  present 
 
Ventricular tachycardia 
all 
not present  present 
 
Atrial fibrillation 
all 
not present  present 
 
Atrial flutter 
all 
not present  present 
Conduction 
 
 
 
1° atrioventricular block 
PR ≥ 200 msec 
increase of  ≥ 50 msec 
 
2° atrioventricular block 
all 
not present  present 
 
3° atrioventricular block 
all 
not present  present 
 
Left bundle-branch block 
all 
not present  present 
 
Right bundle-branch block 
all 
not present  present 
 
Pre-excitation syndrome 
all 
not present  present 
 
Other intraventricular conduction blockd 
QRS ≥ 120 msec 
increase of ≥ 20 msec 
Infarction 
 
 
 
Acute or subacute 
all 
not present  present 
 
Old 
 
all 
 
not present  present 
≥ 12 weeks post study entry 
ST/T Morphological 
 
 
 
Myocardial Ischemia 
all 
not present  present 
 
Symmetrical T-wave inversion 
all 
not present  present 
 
Increase in QTc 
QTcF ≥ 450 msec 
(men) 
QTcF ≥ 470 msec 
(women) 
 
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the “Criterion 
Value” and also represent a change from the subject’s baseline value of at least the magnitude shown in the 
“Change Relative to Baseline” column. 
b No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial flutter, 
or other rhythm abnormality. 
c No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality. 
d No current diagnosis of left bundle branch block or right bundle branch block. 


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12 
Proposed List of Summary Tables 
CT-1.1   Subject Disposition (Enrolled Sample) 
CT-1.2   Subject Disposition by Center (Enrolled Sample) 
CT-1.3   Subject Completion Rates by Week (Enrolled Sample) 
CT-1.4   Enrollment by Country (Enrolled Sample) 
CT-1.5   Enrollment by Country by Age Group (Enrolled Sample) 
CT-1.6 Summary of Proportion of the Face-to-Face and Virtual Visits by Study Week (Enrolled Sample) 
CT-2      Reasons for Discontinuation (Enrolled Sample)  
CT-3.1   Demographic Characteristics (Enrolled Sample) 
CT-3.2.1   Medical History (Enrolled Sample) 
CT-3.2.2   Psychiatric History (Enrolled Sample)  
CT-3.2.3 Borderline Personality Disorder Disease History (Enrolled Sample)   
CT-3.3   Baseline Psychiatric Scale Evaluation (Enrolled Sample) 
CT-4.1.1   Concomitant Medications: Medications Taken Prior to Start of Study Therapy (Safety Sample) 
CT-4.1.2   Concomitant Medications: Medications Taken During Study Therapy Period (Safety Sample) 
CT-4.1.3   Concomitant Medications: Medications Taken Post Study Therapy Period (Safety Sample) 
CT-4.2.1   Psychiatric Concomitant Medications: Medications Taken Prior to Start of Study Therapy (Safety 
Sample) 
CT-4.2.2   Psychiatric Concomitant Medications: Medications Taken During Study Therapy Period (Safety 
Sample) 
CT-4.2.3   Psychiatric Concomitant Medications: Medications Taken Post Study Therapy (Safety Sample) 
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CT-6.1   Summary of Mean Change from Baseline in Simpson-Angus Scale (SAS) Total Score (Safety Sample)  
CT-6.2   Summary of Mean Change from Baseline in Abnormal Involuntary Movement Scale (AIMS) Total 
Score and Item Scores 8, 9 and 10 (Safety Sample)  
CT-6.3.1   Summary of Mean Change from Baseline in Barnes Akathisia Rating Scale (BARS) Global Clinical 
Assessment of Akathisia (Safety Sample)  
CT-6.3.2   Incidence of Barnes Akathisia Rating Scale (BARS) Global Clinical Assessment of Akathisia (Safety 
Sample)  
CT-6.4.1   Columbia-Suicide Severity Rating Scale(C-SSRS), Suicidality (Safety Sample) 
CT-6.4.2   Columbia-Suicide Severity Rating Scale(C-SSRS), Suicidal Behavior by Type (Safety Sample) 
CT-6.4.3   Columbia-Suicide Severity Rating Scale(C-SSRS), Suicidal Ideation by Type (Safety Sample) 
CT-6.4.4   Columbia-Suicide Severity Rating Scale(C-SSRS), Treatment Emergent Suicidal Behavior and 
Ideation (Safety Sample)  
CT-6.4.5   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Suicidal Ideation 
(Safety Sample) 
CT-6.4.6   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Suicidal 
Behavior (Safety Sample) 
CT-6.4.7   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Serious Suicidal 
Ideation (Safety Sample) 
CT-6.4.8   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Worsening Suicidal Ideation (Safety 
Sample)  
 
CT-7.1   Extent of Exposure to Study Medication (Safety Sample) 
CT-7.2   Number and Percentage of Subjects Receiving Study Medication and Mean and Range of Average 
Daily Dose (Safety Sample) 
CT-8.1   Adverse Events (All Causalities) (Safety Sample) 
CT-8.2.1   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term (Safety Sample) 
CT-8.2.2   Incidence of TEAEs by System Organ Class, MedDRA Preferred Term and Severity (Safety Sample) 
CT-8.2.3   Incidence of TEAE of at Least 5% by System Organ Class and MedDRA Preferred Term (Safety 
Sample) 
CT-8.2.4   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Sex (Safety Sample) 
CT-8.2.5   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Race (Safety Sample) 
CT-8.2.6   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Age (Safety Sample)  
CT-8.2.7   Incidence of TEAEs by System Organ Class and MedDRA Preferred Term, by Region (Safety 
Sample) 
CT-8.2.8   Incidence of Non-Serious TEAE of at Least 5% by System Organ Class and MedDRA Preferred 
Term (Safety Sample) 
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CT-8.2.9   Occurrence (Number of Events) of Serious Treatment-Emergent Adverse Events by System Organ 
Class and MedDRA Preferred Term (Safety Sample) 
CT-8.2.10   Occurrence (Number of Events) of Potentially Drug-Related Serious Treatment-Emergent Adverse 
Events by System Organ Class and MedDRA Preferred Term (Safety Sample) 
CT-8.2.11   Occurrence (Number of Events) of Non-Serious Treatment-Emergent Adverse Events by System 
Organ Class and MedDRA Preferred Term (Safety Sample) 
CT-8.3.1   Incidence of Potentially Drug-Related TEAEs by System Organ Class and MedDRA Preferred Term 
(Safety Sample) 
CT-8.3.2   Incidence of Potentially Drug-Related TEAEs by System Organ Class, MedDRA Preferred Term and 
Severity (Safety Sample) 
CT-8.4   Incidence of Deaths Due to TEAEs by System Organ Class and MedDRA Preferred Term (Safety 
Sample) 
CT-8.5.1   Incidence of Serious TEAEs by System Organ Class and MedDRA Preferred Term (Safety Sample) 
CT-8.5.2   Incidence of Serious TEAEs by System Organ Class, MedDRA Preferred Term and Severity (Safety 
Sample) 
CT-8.6.1   Incidence of TEAEs Resulting in Discontinuation from Study by System Organ Class and MedDRA 
Preferred Term (Safety Sample) 
CT-8.6.2   Incidence of TEAEs Resulting in Discontinuation from Study by System Organ Class, MedDRA 
Preferred Term and Severity (Safety Sample) 
CT-8.7.1   Incidence of TE EPS-related AEs by EPS Category and MedDRA Preferred Term (Safety Sample) 
CT-8.7.2   Incidence of Onset of Akathisia Adverse Event by Week (Safety Sample) 
CT-8.8.1 Listing of TEAEs that Are Related or Probably Related to COVID-19 (Safety Sample) 
CT-8.8.2 Listing of Serious TEAEs or Deaths that Are Related or Probably Related to COVID-19 (Safety  
 
 
 Sample) 
CT-8.9 Incidence of Treatment-Emergent Adverse Events of Special Interests (AESIs) by System Organ Class 
and MedDRA Preferred Term (Safety Sample) 
CT-9.1   Listing of Deaths  
CT-9.2   Listing of Serious Adverse Events  
CT-9.3 Listing of Discontinuations Due to Adverse Events  
CT-10.1   Criteria for Laboratory Test Values with Potential Clinical Relevance 
CT-10.2.1   Listing of Laboratory Test Values with Potential Clinical Relevance by Subject (Safety Sample) 
CT-10.2.2   Listing of Laboratory Test Values with Potential Clinical Relevance by Test (Safety Sample) 
CT-10.2.3   Incidence of Laboratory Test Values with Potential Clinical Relevance (Safety Sample) 
CT-10.3.1   Mean Change from Baseline in Clinical Laboratory Test Results - Serum Chemistry (Safety Sample) 
CT-10.3.2   Mean Change from Baseline in Clinical Laboratory Test Results - Hematology (Safety Sample) 
CT-10.3.3   Mean Change from Baseline in Clinical Laboratory Test Results - Urinalysis (Safety Sample) 
CT-10.3.4   Mean Change from Baseline in Clinical Laboratory Test Results - Prolactin, by Sex (Safety Sample) 
CT-10.3.5   Mean Change from Baseline in Clinical Laboratory Test Results - Other Tests (Safety Sample) 
CT-10.4.1   Incidence of Laboratory Test Values with Potential Clinical Relevance - Prolactin (Safety Sample) 
CT-10.4.2   Listing of Laboratory Test Values with Potential Clinical Relevance - Prolactin (Safety Sample) 
CT-10.5.1.1 Incidence of Treatment-Emergent Significant Change in Lipids (Safety Sample) 
CT-10.5.1.2   Listing of Treatment-Emergent Significant Change in Lipids (Safety Sample) 
CT-10.5.2.1   Incidence of Treatment-Emergent Significant Change in Glucose (Safety Sample) 
CT-10.5.2.2   Listing of Treatment-Emergent Significant Change in Glucose (Safety Sample) 
CT-10.5.3.1   Incidence of Treatment-Emergent Metabolic Syndrome (Safety Sample) 


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CT-10.5.3.2   Listing of Treatment-Emergent Metabolic Syndrome (Safety Sample) 
CT-10.6   Incidence of Potentially Liver Injury Related Laboratory Test Abnormalities (Safety Sample) 
CT-10.7   Listing of Potentially Liver Injury Related Laboratory Test Abnormalities (Safety Sample) 
CT-11.1   Criteria for Potentially Clinically Relevant Abnormalities in Vital Signs 
CT-11.2.1   Listing of Potentially Clinically Relevant Abnormalities in Vital Signs (Safety Sample) 
CT-11.2.2   Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs (Safety Sample) 
CT-11.2.3   Mean Change from Baseline in Vital Signs (Safety Sample)  
CT-11.3   Mean Change from Baseline in Body Weight (kg) (Safety Sample) 
CT-11.4   Mean Change from Baseline in Waist Circumference (cm) (Safety Sample)  
CT-11.5   Mean Change from Baseline in BMI (kg/m2) (Safety Sample)  
CT-12.1   Criteria for Potentially Clinically Relevant Abnormalities in ECG Evaluations 
CT-12.2.1   Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations (Safety Sample) 
CT-12.2.2   Incidence of Potentially Clinically Relevant Changes in ECG Evaluations (Safety Sample) 
CT-12.2.3   Mean Change from Baseline in Electrocardiogram Results (Safety Sample) 
CT-12.3.1   Listing of Categorical Changes in QT/QTc (Safety Sample) 
CT-12.3.2   Incidence of Categorical Changes in QT/QTc (Safety Sample)