Clinical trial NCT03538691
Conditions: Major Depressive Disorder
Keywords: Brexpiprazole MDD
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2018-07-13; Completion date: 2022-07-29
Enrollment: 1149 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Major depressive disorder (MDD) is a serious medical illness associated with significant suicidal risk and marked disability. Despite the availability of numerous treatments, achievement of consistent and favorable long-term outcomes remains challenging.

This study will assess the safety, efficacy and tolerability of brexpiprazole as adjunctive therapy to protocol-specific open-label antidepressant therapy.

Detailed description:

Arms: arm 1: Participants received brexpiprazole 2 or 3 milligrams per day (mg/day) along with protocol-specified antidepressant therapy (ADT), orally, for 6 to 8 weeks during Phase A. Participants were initially titrated to a target dose of brexpiprazole 2 mg over a 2 to 4-week period. Thereafter, participants who had not met response criteria as defined in the blinded addendum, did not have potentially dose-related adverse events (AEs), and had not achieved the maximum dose of medication had their dose increased up to 3 mg. arm 2: Eligible participants completing Phase A were enrolled in Phase B to receive brexpiprazole 2 or 3 mg/day along with protocol-specified ADT, orally, for 12 weeks. arm 3: Eligible participants completing Phase B received brexpiprazole 2 or 3 mg/day (dose of brexpiprazole that they were receiving at Week 20 of the Stabilization Phase) along with protocol-specified ADT, orally, for up to 26 weeks during Phase C. arm 4: Eligible participants completing Phase B received brexpiprazole-matching placebo along with protocol-specified ADT, orally, for up to 26 weeks during Phase C.
Interventions: intervention 1: Brexpiprazole intervention 2: Antidepressant therapy
Intervention descriptions: intervention 1: Administered as tablets. intervention 2: Protocol-specified oral ADTs included:

citalopram hydrobromide (Celexa®) tablets, escitalopram (Lexapro®) tablets, fluoxetine (Prozac®) capsules, paroxetine (Paxil CR®) controlled-release tablets, sertraline (Zoloft®) tablets, duloxetine (Cymbalta®) delayed-release capsules, venlafaxine XR (Effexor XR®) extended-release (XR) capsules.

Protocol documents:
Prot_000.pdf: 
Table of Contents
Table of Contents..........................................................................................................
1
Study 331-201-00079 Protocol Amendment 2; 08 Jul 2020.........................................
2
Study 331-201-00079 Protocol Addendum; 16 Jul 2020..............................................
107
Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
1




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
3
Protocol 331-201-00079
Confidential - Proprietary Information
2
08 Jul 2020
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 related 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.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
4
Protocol 331-201-00079
Confidential - Proprietary Information
3
08 Jul 2020
Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Name of Investigational Medicinal Product:  
Brexpiprazole (OPC-34712)
Protocol No.: 
331-201-00079
IND No.: 103,958
EudraCT No.:
2018-000601-22
Protocol Title:
A Phase 3, multicenter, randomized, double-blind, 
placebo-controlled trial to evaluate the efficacy, safety, and 
tolerability of brexpiprazole as adjunctive therapy in the 
maintenance treatment of adults with major depressive 
disorder.
Clinical Phase/Trial 
Type:
3, Therapeutic confirmatory
Treatment Indication:
Major depressive disorder
Objectives:
Primary:  To compare the efficacy of brexpiprazole (2 to 
3 mg/day) to placebo as adjunctive therapy to antidepressant 
therapy (ADT) for the maintenance treatment in adults with 
major depressive disorder (MDD).
Secondary:
To evaluate the safety and tolerability of brexpiprazole (2 to 
3 mg/day) as adjunctive therapy to ADT in the proposed 
subject population with MDD.
Trial Design:
This is a phase 3, multicenter, randomized, double-blind, 
placebo-controlled trial designed to assess the safety, efficacy, 
and tolerability of brexpiprazole (2 to 3 mg/day) as adjunctive 
therapy to protocol-specified open-label ADT in subjects with 
a diagnosis of a current major depressive episode of at least 
8 weeks in duration with an inadequate response to 1 or 
2 adequate ADTs. The trial will be organized as follows:

Screening Period: The screening period will range from a 
minimum of 3 days to a maximum of 6 weeks and will 
begin when informed consent is signed. The purpose of the 
screening period is to assess eligibility criteria at 1 or more 
visits (as necessary to complete screening assessments)
and to allow subjects to continue their current ADT for an 
adequate duration, if needed. 

Acute Treatment Phase (Phase A): Subjects will be 
enrolled into a 6- to 8-week single-blind Acute Treatment 
Phase (Phase A) if they meet the entrance criteria. The 
purpose of this phase is to identify subjects who respond to 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
5
Protocol 331-201-00079
Confidential - Proprietary Information
4
08 Jul 2020
adjunctive brexpiprazole + protocol-specified ADT. 
Treatment will consist of single-blind brexpiprazole plus 
continuation of the ADT taken during the screening period. 
The investigator should titrate to the dose of brexpiprazole 
that optimizes efficacy with the protocol-specified ADT 
with minimum tolerability issues. Subjects will attend 
weekly visits during the Acute Treatment Phase and will 
be evaluated at Weeks 6 to 8 to determine whether they 
meet response criteria as defined in the blinded addendum 
to the protocol. Subjects not meeting response criteria by 
the Week 8 visit will be discontinued from the trial.

Stabilization Phase (Phase B): Subjects who meet 
response criteria at the end of the Phase A will continue to 
a 12-week Stabilization Phase (Phase B). The purpose of 
this phase is to ensure subjects are able to maintain 
stability of depression symptoms at the dose of 
brexpiprazole optimized during Phase A. To proceed to the 
Double-blind Randomized Withdrawal Phase (Phase C), 
subjects must meet the stability criteria as defined in the 
blinded addendum to the protocol. Subjects not meeting 
stability criteria will be discontinued from the trial.

Double-blind Randomized Withdrawal Phase (Phase C): 
Subjects eligible for the Double-blind Randomized 
Withdrawal Phase will be randomized 1:1 to double-blind 
treatment with brexpiprazole + ADT or placebo + ADT for 
up to 26 weeks. Transition from the Stabilization Phase to 
the Double-blind Randomized Withdrawal Phase should 
not be made evident to the subject. During the 
Double-blind Randomized Withdrawal Phase, subjects will 
be evaluated in the clinic at biweekly visits for the first 
2 visits and at monthly visits thereafter. Subjects meeting 
the criteria for relapse will be withdrawn due to lack of 
efficacy.

Follow-up: Subjects who are discontinued, withdrawn, or 
complete the trial will be followed up for safety 21 (+2) 
days after the last dose of investigational medicinal 
product (IMP) by telephone contact or clinic visit at the 
investigator’s discretion. Subjects should be prescribed 
appropriate depression treatment as per the investigator or 
the subject's psychiatrist or primary care physician.
Subject Population:
Male and female outpatients between 18 and 65 years, 
inclusive, with a diagnosis of recurrent MDD and a current 
major depressive episode of at least 8 weeks in duration with 
an inadequate response to 1 or 2 adequate ADTs, and currently 
taking protocol-mandated ADTs at an adequate dose. 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
6
Protocol 331-201-00079
Confidential - Proprietary Information
5
08 Jul 2020
Adequate treatment is defined as an ADT taken for at least 
6 weeks in duration at a minimum dose (or higher) as specified 
in the Massachusetts General Hospital Antidepressant 
Treatment Response Questionnaire (ATRQ). Inadequate 
response is defined as < 50% reduction in depressive symptom 
severity, as assessed by the ATRQ.
Inclusion/Exclusion 
Criteria:
Key inclusion criteria include the following:

Subjects with both a diagnosis of recurrent MDD, and in a 
current major depressive episode of ≥ 8 weeks in duration, 
as defined by Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria and confirmed 
by both the MINI and an adequate clinical psychiatric 
evaluation.

Subjects must have reported a history for the current major 
depressive episode of an inadequate response to 1 or 
2 adequate antidepressant treatments, and subjects must 
currently be taking a protocol-mandated antidepressant 
treatment at an adequate dose and duration, and must not 
have reported ≥ 50% improvement (as defined by the 
ATRQ). For subjects who are currently on an adequate 
dose of a protocol mandated ADT but for an inadequate 
duration, the screening period may be used to achieve 
adequate duration. At Phase A baseline, all subjects must 
have either 2 or 3 documented inadequate responses to 
antidepressant treatment for the current episode as defined 
by the ATRQ.

Subjects with a 17-item Hamilton Depression Rating Scale 
(HAM-D17) total score ≥ 18 at the screening and Phase A 
baseline visits.
Key exclusion criteria include the following:

Subjects with a primary DSM-5 diagnosis of:

Schizophrenia Spectrum and Other Psychotic 
Disorders

Bipolar and Related Disorders

Obsessive compulsive disorder

Feeding and Eating Disorders (including anorexia 
nervosa or bulimia)

Neurocognitive disorders (including but not limited to: 
Delirium, Major or Mild Neurocognitive Disorder due 
to: Alzheimer’s, Parkinson’s, Traumatic Brain Injury)

Panic disorder

Post-traumatic stress disorder


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
7
Protocol 331-201-00079
Confidential - Proprietary Information
6
08 Jul 2020

Subjects with a current DSM-5 diagnosis of borderline, 
antisocial, paranoid, schizoid, schizotypal or histrionic 
personality disorder or intellectual disability
Please see the complete list of inclusion and exclusion criteria.
Trial Sites:
It is anticipated that approximately 2100 subjects will be 
screened from approximately 75 sites to enroll approximately 
1450 subjects into Phase A in order to enroll approximately 
700 in Phase B and randomize 450 subjects in Phase C.
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
Treatment will consist of oral brexpiprazole plus 1 of 
7 protocol-specified oral ADTs: citalopram hydrobromide 
(Celexa®), escitalopram (Lexapro®), fluoxetine (Prozac®), 
paroxetine (Paxil CR®) controlled-release tablets, sertraline 
(Zoloft®) tablets, duloxetine (Cymbalta®) delayed-release 
capsules, venlafaxine XR (Effexor XR®) extended-release 
(XR) capsules. Subjects will be on an adequate treatment as 
specified in the ATRQ. Brexpiprazole doses will be 2 to 
3 mg/day depending on tolerability assessed during dose 
titration in Phase A. Doses of each ADT are listed in the 
protocol.
Trial Assessments:
Efficacy: Montgomery Asberg Depression Rating Scale
(MADRS), Clinical Global Impression - Severity of Illness 
Scale (CGI-S), and Sheehan Disability Scale (SDS)
Pharmacokinetic, Pharmacogenomics,
 
plasma concentrations of brexpiprazole,
cytochrome P450 (CYP) 2D6 metabolizer activity,
 
Safety: Adverse event (AE) reporting, clinical laboratory tests, 
12-lead electrocardiogram, 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: HAM-D17, Mini International 
Neuropsychiatric Interview (MINI), ATRQ, medical and 
medication history, psychiatric history, urine drug screening, 
urine pregnancy test
Criteria for 
Evaluation:
Primary Endpoint: The primary endpoint is time-to-relapse by 
any criteria as defined in the blinded addendum to this 
protocol.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
8
Protocol 331-201-00079
Confidential - Proprietary Information
7
08 Jul 2020
Key Secondary Endpoints:

Change from randomization in the SDS mean total score at 
Week 46 (last observation carried forward)

Time-to-functional relapse based on SDS criteria
Statistical Methods:
The objective of the primary analysis is to compare the 
efficacy of brexpiprazole (2 to 3 mg/day) + ADT with that of 
placebo + ADT with regard to time-to-relapse. The statistical 
comparison will be performed by the log-rank test comparing 
the 2 treatment groups (brexpiprazole + ADT versus 
placebo + ADT) at an overall nominal significance level of 
0.05 (2-sided) using the Double-blind Randomized 
Withdrawal (Phase C) Efficacy Sample.  
Assuming that each subject will be followed for up to 
26 weeks after randomization (Week 20) or until relapse, and 
allowing for a 20% loss to follow-up, the projected total 
number of subjects to be randomized into the trial (Phase C) is 
450. Using a 1:1 randomization ratio, the number of subjects 
to be randomized into each treatment group is 225. Assuming 
approximately 68% of subjects will progress from 
Stabilization Phase to Double-blind Randomized Withdrawal
Phase, it is expected that approximately 700 subjects will be 
enrolled into Stabilization Phase of the trial to allow 
450 subjects to be randomized. Assuming approximately 55% 
subjects will progress from the Acute Treatment Phase to the 
Stabilization Phase, it is expected that approximately 
1450 subjects will be enrolled into the Acute Treatment Phase. 
However, only the number of relapse events (ie, 104 events) is 
the hard sample size in this protocol. The other estimates, such 
as number of randomized subjects and number of subjects 
entering the Acute Treatment Phase and the Stabilization 
Phase, are only based on projections using assumptions that 
may or may not hold in this trial. Therefore, the actual number 
of subjects enrolled into the Acute Treatment Phase, the 
Stabilization Phase, or Double-blind Randomized Withdrawal 
Phase may vary from the projected values.
Trial Duration:
The duration of this trial from first subject enrolled to last 
subject completed is estimated to be approximately 39 months, 
of which approximately 22 months are allotted for recruitment 
of subjects. Individual participation for subjects who complete 
the trial without early withdrawal will range from 47 to 
55 weeks, consisting of a 3-day up to 6-week screening period, 
a 6- to 8-week single-blind Acute Treatment Phase, a 12-week 
single-blind Stabilization Phase, and up to 26-week 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
9
Protocol 331-201-00079
Confidential - Proprietary Information
8
08 Jul 2020
Double-Blind Randomized Withdrawal Phase, and a 
21 (+ 2)-day follow-up.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
10
Protocol 331-201-00079
Confidential - Proprietary Information
9
08 Jul 2020
Table of Contents
Protocol Synopsis...........................................................................................2
Table of Contents...........................................................................................9
List of In-text Tables ...................................................................................14
List of In-text Figures..................................................................................15
List of Appendices........................................................................................16
List of Abbreviations and Definitions of Terms .......................................17
1
Introduction ........................................................................................19
1.1
Nonclinical Data................................................................................................20
1.1.1
Efficacy Pharmacology...................................................................................20
1.1.2
Safety Pharmacology......................................................................................20
1.2
Clinical Data......................................................................................................20
1.2.1
Pharmacokinetics/Pharmacodynamics ...........................................................21
1.2.2
Major Depressive Disorder.............................................................................22
1.3
Known and Potential Risks and Benefits ..........................................................22
2
Trial Rationale and Objectives..........................................................22
2.1
Trial Rationale...................................................................................................22
2.2
Dosing Rationale...............................................................................................23
2.3
Trial Objectives.................................................................................................23
3
Trial Design.........................................................................................24
3.1
Type/Design of Trial .........................................................................................24
3.2
Trial Treatments ................................................................................................27
3.2.1
Protocol-specified Antidepressant Therapy....................................................27
3.2.2
Brexpiprazole + Antidepressant Treatment Dosing Regimen........................28
3.3
Trial Population.................................................................................................29
3.3.1
Number of Subjects and Description of Population .......................................29
3.3.2
Subject Selection and Numbering ..................................................................29
3.4
Eligibility Criteria..............................................................................................29
3.4.1
Informed Consent ...........................................................................................29
3.4.2
Inclusion Criteria ............................................................................................31
3.4.3
Exclusion Criteria...........................................................................................31


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
11
Protocol 331-201-00079
Confidential - Proprietary Information
10
08 Jul 2020
3.5
Endpoints...........................................................................................................36
3.5.1
Primary Endpoint............................................................................................36
3.5.2
Secondary Endpoints ......................................................................................36
3.6
Measures to Minimize/Avoid Bias....................................................................37
3.6.1
Randomization................................................................................................37
3.7
Trial Procedures ................................................................................................38
3.7.1
Schedule of Assessments................................................................................49
3.7.1.1
Screening (Day −42 to Day −3) ..................................................................49
3.7.1.2
Acute Treatment Phase ...............................................................................50
3.7.1.2.1
Baseline (Day 1)......................................................................................50
3.7.1.2.2
Weeks 1 through 7 (Phase A)..................................................................51
3.7.1.2.3
End of Phase A (Weeks 6, 7, or 8) or Early Termination .......................52
3.7.1.3
Stabilization Phase, Week 9 through Week 20/Randomization (Phase B).53
3.7.1.4
Double-blind Randomized Withdrawal Phase (Week 21 through Week 
46/End of Phase C/Relapse) (Phase C).......................................................54
3.7.1.5
Post-treatment Follow-up Safety Visit (21 + 2 days) .................................55
3.7.2
Efficacy Assessments .....................................................................................55
3.7.2.1
Montgomery Asberg Depression Rating Scale...........................................55
3.7.2.2
Clinical Global Impression - Severity of Illness Scale ...............................55
3.7.2.3
Sheehan Disability Scale.............................................................................55
3.7.2.4
Subject Assessment Recording ...................................................................56
3.7.2.4.1
Mini International Neuropsychiatric Interview.......................................56
3.7.2.4.2
Hamilton Depression Rating Scale 17-Item Version ..............................56
3.7.2.4.3
Antidepressant Treatment Response Questionnaire................................56
3.7.3
Safety Assessments.........................................................................................56
3.7.3.1
Adverse Events............................................................................................56
3.7.3.2
Clinical Laboratory Assessments................................................................56
3.7.3.3
Physical Examination and Vital Signs........................................................58
3.7.3.4
Electrocardiogram Assessments..................................................................60
3.7.3.5
Other Safety Assessments...........................................................................61
3.7.3.5.1
Simpson Angus Scale..............................................................................61
3.7.3.5.2
Abnormal Involuntary Movement Scale (AIMS)....................................61


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
12
Protocol 331-201-00079
Confidential - Proprietary Information
11
08 Jul 2020
3.7.3.5.3
Barnes Akathisia Rating Scale (BARS) ..................................................62
3.7.3.5.4
Columbia-Suicide Severity Rating Scale ................................................62
3.7.4
Prior and Concomitant Medications...............................................................62
3.7.5
Pharmacokinetic/Pharmacogenomic Assessments .........................................63
3.7.6
End of Trial.....................................................................................................63
3.7.7
Interim Analysis Review Committee..............................................................63
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................63
3.8.1
Entire Trial......................................................................................................63
3.8.2
Individual Site.................................................................................................64
3.8.3
Individual Subject Discontinuation ................................................................64
3.8.3.1
Treatment Interruption ................................................................................64
3.8.3.2
Treatment Discontinuation..........................................................................64
3.8.3.3
Documenting Reasons for Treatment Discontinuation...............................64
3.8.3.4
Withdrawal of Consent ...............................................................................65
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................66
3.9
Screen Failures ..................................................................................................67
3.10
Definition of Completed Subjects.....................................................................67
3.11
Definition of Subjects Lost to Follow-up..........................................................67
3.12
Subject Compliance...........................................................................................67
3.13
Protocol Deviations...........................................................................................68
4
Restrictions..........................................................................................68
4.1
Prohibited Medications......................................................................................68
4.2
Other Restrictions..............................................................................................71
5
Reporting of Adverse Events.............................................................72
5.1
Definitions.........................................................................................................72
5.2
Eliciting and Reporting Adverse Events ...........................................................74
5.3
Immediately Reportable Events ........................................................................74
5.4
Potential Serious Hepatotoxicity.......................................................................74
5.5
Pregnancy..........................................................................................................75
5.6
Procedure for Breaking the Blind......................................................................76
5.7
Follow-up of Adverse Events............................................................................77
5.7.1
Follow-up of Nonserious Adverse Events......................................................77


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
13
Protocol 331-201-00079
Confidential - Proprietary Information
12
08 Jul 2020
5.7.2
Follow-up of Serious Adverse Events and Immediately Reportable Events..77
5.7.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring after Last Scheduled Contact ..........................77
6
Pharmacokinetic/Pharmacogenomic Analysis ................................78
7
Statistical Analysis..............................................................................78
7.1
Sample Size.......................................................................................................78
7.2
Datasets for Analysis.........................................................................................79
7.3
Handling of Missing Data .................................................................................80
7.4
Primary and Secondary Endpoint Analyses ......................................................80
7.4.1
Primary Endpoint Analysis.............................................................................80
7.4.2
Secondary Endpoint Analysis.........................................................................81
7.4.2.1
Key Secondary Efficacy Endpoint..............................................................81
7.4.2.2
Other Secondary Efficacy Endpoints..........................................................81
7.4.3
Exploratory Endpoint Analysis.......................................................................82
7.4.4
Interim Analysis..............................................................................................82
7.5
Analysis of Demographic and Baseline Characteristics....................................83
7.6
Safety Analysis..................................................................................................83
7.6.1
Adverse Events ...............................................................................................84
7.6.1.1
Phase A .......................................................................................................84
7.6.1.2
Phase B........................................................................................................84
7.6.1.3
Phase C........................................................................................................84
7.6.2
Clinical Laboratory Data ................................................................................84
7.6.3
Physical Examination and Vital Signs Data ...................................................85
7.6.4
Electrocardiogram Data..................................................................................85
7.6.5
Other Safety Data ...........................................................................................85
8
Management of Investigational Medicinal Product........................85
8.1
Packaging and Labeling ....................................................................................86
8.2
Storage...............................................................................................................86
8.3
Accountability ...................................................................................................86
8.4
Returns and Destruction....................................................................................86
8.5
Reporting of Product Quality Complaints.........................................................87
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................87


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
14
Protocol 331-201-00079
Confidential - Proprietary Information
13
08 Jul 2020
8.5.2
Information Required for Reporting Purposes ...............................................87
8.5.3
Return Process ................................................................................................88
8.5.4
Assessment/Evaluation...................................................................................88
9
Records Management.........................................................................88
9.1
Source Documents.............................................................................................88
9.2
Data Collection..................................................................................................89
9.3
File Management at the Trial Site.....................................................................90
9.4
Records Retention at the Trial Site....................................................................90
10
Quality Control and Quality Assurance...........................................91
10.1
Monitoring.........................................................................................................91
10.2
Auditing.............................................................................................................91
11
Ethics and Responsibility...................................................................91
12
Confidentiality ....................................................................................92
13
Amendment Policy..............................................................................92
14
Publication Authorship Requirements.............................................93
15
References............................................................................................94
16
Appendices ..........................................................................................96


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
15
Protocol 331-201-00079
Confidential - Proprietary Information
14
08 Jul 2020
List of In-text Tables
Table 3.2.2-1
Dosing Schedule - Acute Treatment Phase (Phase A)...................28
Table 3.4.2-1
Inclusion Criteria ...........................................................................31
Table 3.4.3-1
Exclusion Criteria ..........................................................................31
Table 3.7-1
Schedule of Assessments - Screening and Acute Treatment Phase 
(Phase A)
................................................................................39
Table 3.7-2
Schedule of Assessment - Stabilization Phase (Phase B)..............43
Table 3.7-3
Double-blind Randomized Withdrawal Phase (Phase C)..............46
Table 3.7.3.2-1
Clinical Laboratory Assessments...................................................57
Table 4.1-1
List of Medications Prohibited Before the Trial............................68
Table 4.1-2
List of Medications Prohibited During the Trial............................69
Table 4.1-3
Oral Benzodiazepine Rescue Therapy During the Trial................70
Table 4.1-4
List of Medications Prohibited During the Trial: CYP2D6 
Inhibitors and CYP3A4 Inhibitors and Inducers ...........................71
Table 7.4.4-1
Boundaries for Rejection of Null Hypothesis for Interim and Final 
Analyses
................................................................................83


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
16
Protocol 331-201-00079
Confidential - Proprietary Information
15
08 Jul 2020
List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................26


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
17
Protocol 331-201-00079
Confidential - Proprietary Information
16
08 Jul 2020
List of Appendices
Appendix 1
Criteria for Identifying Laboratory Values of Potential Clinical 
Relevance
................................................................................96
Appendix 2
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance
................................................................................97
Appendix 3
Criteria for Identifying Electrocardiogram Measurements of 
Potential Clinical Relevance..........................................................98
Appendix 4
Handling and Shipment of Bioanalytical Samples ........................99
Appendix 5
Protocol Amendment(s)/Administrative Change(s) ....................101


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
18
Protocol 331-201-00079
Confidential - Proprietary Information
17
08 Jul 2020
List of Abbreviations and Definitions of Terms
Abbreviation
Definition
5-HT
Serotonin, 5-hydroxytryptamine
ADHD
Attention deficit/hyperactivity disorder
ADT
Antidepressant therapy
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
aPTT
activated prothromplastin time
AST
Aspartate aminotransferase
ATRQ
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire
BARS
Barnes Akathisia Rating Scale
BUN
Blood urea nitrogen
CGI-S
Clinical Global Impression - Severity of Illness
CR
Controlled release
CRA
Clinical research associate
CRO
Clinical Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CST
Clinical Surveillance Team
CYP
Cytochrome P450
D
Dopamine
DBP
Diastolic blood pressure
DILI
Drug Induced Liver Injury
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition
ECG
Electrocardiogram
ECT
Electroconvulsive therapy
EPS
Extrapyramidal symptoms
ET
Early termination
EudraCT
European Clinical Trial Data Base
FDA
(United States) Food and Drug Administration
GCP
Good Clinical Practice
HAM-D17
Hamilton Depression Rating Scale 17-Item
HbA1c
Glycosylated hemoglobin
HIV
Human immunodeficiency virus
IARC
Interim Analysis Review Committee
IB
Investigator’s Brochure
ICF, eICF
Informed consent form, electronic informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IEC
Independent ethics committee


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
19
Protocol 331-201-00079
Confidential - Proprietary Information
18
08 Jul 2020
IMP
Investigational medicinal product
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional review board
IRE
Immediately reportable event
IRT
Interactive response technology
Ki
Inhibition constant
LDH
Lactic dehydrogenase
LOCF
Last observation carried forward
MADRS
Montgomery Asberg Depression Rating Scale
MDD
Major depressive disorder
MINI
Mini International Neuropsychiatric Interview
OC
Observed case
OPC
Otsuka Pharmaceutical Co.
OTC
Over-the-counter
PE
Physical examination
PK
Pharmacokinetic
PQC
Product quality complaint
PT
Prothrombin time
PTSD
Post-traumatic stress disorder
QTcF
QT interval ,corrected for heart rate by Fridericia’s formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Simpson Angus Scale
SBP
Systolic blood pressure
SDS
Sheehan Disability Scale
SIGH-D
Structured Interview Guide for the Hamilton Depression Rating 
Scale
T4
Thyroxine
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
US 
United States 
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
Women of childbearing potential
XR
Extended release


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
20
Protocol 331-201-00079
Confidential - Proprietary Information
19
08 Jul 2020
1
Introduction
Major depressive disorder (MDD) is a serious medical illness associated with significant 
suicide risk and marked disability. Despite the availability of numerous treatments 
(eg, pharmacotherapy, cognitive behavioral psychotherapy, electroconvulsive therapy), 
achievement of consistent and favorable long-term outcomes remains challenging. 
Although there are different classes of antidepressants, most patients with MDD do not 
achieve adequate response or remission. Most patients with MDD will experience 
relapses and recurrences, and the risk of recurrence increases with every successive major 
depressive episode.1,2
In the STAR*D trial, 51.4% and 71.5% of patients did not respond adequately to first-
and second-line treatment, respectively, with 83.7% still not achieving response after 
4 courses of treatment. One-third of patients did not achieve remission after as many as 
4 different treatment strategies.3,4,5,6 Patients who fail to achieve a full remission have a 
more recurrent and chronic course, increased medical and psychiatric comorbidities, and 
greater functional burden.7
Practice guidelines emphasize the importance of adequate treatment for MDD, including 
continuation of pharmacotherapy after an initial response is achieved to prevent relapse 
and maintenance treatment in individuals at risk of recurrence.2 Second-generation 
antipsychotics such as aripiprazole and quetiapine have been shown to be associated with 
significant clinical improvements in patients who had not experienced an adequate 
response to prior antidepressant medications8,9,10,11; however, the side effect profiles of 
currently approved products may be unacceptable to many patients, subsequently limiting 
their use in clinical practice.12 Consequently, there has been an ongoing medical need to 
identify adjunctive strategies that offer the efficacy of second-generation antipsychotics, 
while reducing the frequency and burden of side effects.
Brexpiprazole (OPC-34712 and Lu AF41156) is a novel atypical antipsychotic 
synthesized by Otsuka that is being codeveloped by Otsuka and Lundbeck. Brexpiprazole 
is currently approved in the United States (US), Canada, and Australia as monotherapy 
for the treatment of schizophrenia and in the US for use as an adjunctive therapy to 
antidepressants for the treatment of MDD. Brexpiprazole is a serotonin
(5-hydroxytryptamine [5-HT]) –dopamine (D) activity modulator which is a partial 
agonist at serotonin 5-HT1A and dopamine D2 receptors, and an antagonist at serotonin
5-HT2A and noradrenaline α1B/2C receptors, all with subnanomolar potencies.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
21
Protocol 331-201-00079
Confidential - Proprietary Information
20
08 Jul 2020
1.1
Nonclinical Data
Efficacy and safety pharmacology of brexpiprazole are summarized in Section 1.1.1 and 
Section 1.1.2. A complete description of the available data from nonclinical studies, 
including pharmacokinetic and toxicology studies in different animal species can be 
found in the Investigator’s Brochure (IB).13
1.1.1
Efficacy Pharmacology
While the precise mechanism of action of brexpiprazole in treating psychiatric conditions 
is unknown, the pharmacology of brexpiprazole is believed to be mediated by a 
combination of high binding affinity and functional activities at multiple monoaminergic 
receptors. It has modulatory activity at the serotonin and dopamine systems that 
combines partial agonist activity at serotonergic 5-HT1A and at dopaminergic D2
receptors with antagonist activity at serotonergic 5-HT2A receptors, with similar high 
affinities at all of these receptors (inhibition constant [Ki]: 0.1 - 0.5 nM).  Brexpiprazole 
also shows antagonist activity at noradrenergic α1B/2C with affinity in the same 
subnanomolar Ki range (Ki: 0.2 - 0.6 nM). The 5 HT1A/D2 receptor partial agonist activity 
in combination with 5 HT2A and α1B/2C receptors antagonism of brexpiprazole may 
correlate with antipsychotic and antidepressant efficacy. These mechanisms of actions 
have previously shown activity in preclinical models for MDD.
Please refer to the IB13 for more detailed information.
1.1.2
Safety Pharmacology
Please refer to the IB13 for information.
1.2
Clinical Data
As of 17 Apr 2017, the brexpiprazole clinical development program consisted of a total
of 68 clinical trials conducted in North America, Latin America, Europe, and Asia 
(60 completed and 8 ongoing). This total includes 61 trials conducted under United States 
(US) Investigational New Drug Applications (INDs) (54 completed and 7 ongoing) for 
schizophrenia, adjunctive treatment of MDD, adjunctive treatment of attention-
deficit/hyperactivity disorder (ADHD), agitation associated with dementia of the 
Alzheimer’s type, or post-traumatic stress disorder (PTSD); and 7 non-US IND trials 
(6 completed and 1 ongoing in either South Korea or Japan) conducted in healthy 
subjects and subjects with schizophrenia.
Please refer to the IB13 for more detailed information.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
22
Protocol 331-201-00079
Confidential - Proprietary Information
21
08 Jul 2020
1.2.1
Pharmacokinetics/Pharmacodynamics
The pharmacokinetics (PK) of single and multiple doses of brexpiprazole was studied in 
healthy subjects and in subjects with MDD, ADHD, and schizophrenia or schizoaffective 
disorder. Based on preclinical data and human clinical trials, brexpiprazole and 
1 metabolite, DM-3411, were identified as the major analytes that are present in human 
plasma.  In vitro, the activity of DM-3411 is 17 times lower than that of brexpiprazole 
and thus is considered a minimally active metabolite. Both brexpiprazole and DM-3411 
pharmacokinetics were linear in healthy subjects following single oral doses of 
brexpiprazole 0.2 to 6.0 mg. In healthy subjects, administration of single-dose 
brexpiprazole with a high-fat meal did not affect its rate and extent of absorption.
Steady state PK was linear following multiple daily doses of brexpiprazole in the range of 
0.5 to 2.0 mg to healthy subjects. The accumulation factor based on maximum (peak) 
plasma concentration (Cmax) and area under the concentration time curve calculated to the 
last observable concentration at time t (AUCt) was approximately 4 times. After multiple 
dose administration of brexpiprazole (1.0 to 12.0 mg/day) to subjects with schizophrenia 
or schizoaffective disorder, brexpiprazole and DM-3411 mean terminal elimination 
half-life at steady state was 95.4 and 89.3 hours, respectively; median tmax was 3.0 and 
8.0 hours, respectively.
In drug interaction trials in healthy subjects, brexpiprazole was shown to be metabolized 
by cytochrome P450 (CYP) 3A4 and CYP2D6 isozymes and was not an inhibitor of 
CYP3A4, CYP2B6, CYP2D6, or P-glycoprotein. Coadministration of potent CYP3A4 or 
CYP2D6 inhibitors with brexpiprazole resulted in about a 2-fold higher exposure and 
about a 1.5-fold increase in the terminal elimination half-life of brexpiprazole. Of note, 
administration of brexpiprazole with fluoxetine, paroxetine, and duloxetine (medications 
for treatment of MDD coadministered in this trial) may potentially increase brexpiprazole 
plasma concentrations by up to 2-fold. Pharmacokinetic interactions with ADTs that are 
strong inhibitors of CYP2D6 are described in Section 2.2.  
In a single-dose trial in healthy subjects, approximately 46.0% and 24.6% of 
administered radioactivity following an oral dose of 14C-brexpiprazole was excreted in 
feces and urine, respectively. In this same trial, brexpiprazole did not preferentially bind 
to red blood cells. Brexpiprazole showed high protein binding in human serum (≥99.8%) 
in vitro.
The binding of brexpiprazole to dopamine receptors was assessed using positron 
emission tomography. The mean D2/D3 receptor occupancies at 4 and 24 hours postdose 
after 0.25, 0.5, 1.0, 2.0, 4.0, 5.0, and 6.0 mg single-dose administration of brexpiprazole 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
23
Protocol 331-201-00079
Confidential - Proprietary Information
22
08 Jul 2020
to healthy subjects were 11.4% to 17.4%, 36.5% to 46.3%, 45.6% to 60.2%, 52.7% to 
68.6%, 67.9% to 79.5%, 71.9% to 88.2%, and 69.5% to 92.6%, respectively 
(Trial 331-07-202). Based on the single-dose D2/D3 receptor occupancy data and 
steady-state PK/pharmacodynamic (PD) modeling, it was predicted that the D2/D3
receptor occupancy after multiple daily dose administration of 1.0 to 2.0 mg and higher 
doses of brexpiprazole will result in at least 80% to 90% D2/D3 receptor occupancy.
Population PK analysis of phase 1 through phase 3 trials demonstrated no differences in 
the PK of brexpiprazole between healthy subjects, subjects with MDD, and subjects with 
either schizophrenia or schizoaffective disorder (in phase 1 trials).  
Please refer to the IB for more detailed information.13
1.2.2
Major Depressive Disorder
The data derived from 6 adequate and well-controlled short-term trials provides evidence 
that brexpiprazole 2 mg/day and 3 mg/day is efficacious as adjunctive treatment in adults
with MDD who had a persistent inadequate response to antidepressant therapy (ADT).
Please refer to the IB13 for more detailed information.
1.3
Known and Potential Risks and Benefits
Phase 1 data indicated that brexpiprazole demonstrated good safety and tolerability when 
administered to healthy volunteers at single doses of 0.2 to 6 mg and at a repeated dose of 
2 mg/day. Data from completed repeated dosing trials in the US indicate that 
brexpiprazole demonstrated good tolerability when administered to subjects with 
schizophrenia or schizoaffective disorder at doses of up to 12 mg/day; when administered 
to subjects with MDD at doses of up to 4 mg/day in combination with a marketed 
antidepressant; up to 3 mg/day as adjunctive therapy in elderly subjects (70 - 85 years of 
age) with MDD; and when administered to subjects with ADHD at doses of up to 
4 mg/day in combination with a marketed stimulant.
Please refer to the current IB13 for a summary of available nonclinical and clinical safety 
data.
2
Trial Rationale and Objectives
2.1
Trial Rationale
This trial is a phase 3, double-blind, placebo-controlled, randomized withdrawal 
maintenance trial of brexpiprazole in subjects who require adjunctive treatment of MDD 
designed to fulfill a post-marketing commitment to the US Food and Drug 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
24
Protocol 331-201-00079
Confidential - Proprietary Information
23
08 Jul 2020
Administration (FDA). There is a paucity of data on long-term use of the combination of 
ADT and an antipsychotic drug; only 2 studies have been published.14,15 The trial will 
assess long-term benefit of continuation of adjunctive therapy in subjects who achieve a 
level of clinical stabilization. The design is similar to that used in other trials for the 
evaluation of antipsychotic drugs in long-term management of MDD.14
Efficacy and safety of brexpiprazole 2 mg/day and 3 mg/day have been demonstrated in 
subjects with MDD who had an inadequate response to ADT in four phase 3, short-term 
fixed- and flexible-dose clinical trials with a 6-week double-blind placebo-controlled 
treatment phase. A single long-term trial with a 24-week double-blind, placebo-controlled
treatment phase was conducted in inadequate responders and failed to demonstrate 
efficacy in terms of full remission with adjunctive brexpiprazole at flexible doses of 1 to 
3 mg/day; however, safety and tolerability were seen over this long-term period.
2.2
Dosing Rationale
The dosing paradigm of brexpiprazole to be used in this trial is based on the current 
approved dosing for MDD (2 mg/day to 3 mg/day) in product labeling. Subjects will 
receive
a target 
dosage of 2 mg/day up to the maximum recommended daily dosage of 3 mg/day.
The ADTs and dosages approved for use in this trial, are listed in Section 3.2.1. Dose 
adjustments will be made for those ADTs that are strong inhibitors of CYP2D6 (ie, 
duloxetine, fluoxetine, and paroxetine). Brexpriprazole labeling states that there is a 
2-fold increase in exposure to brexpiprazole in the typical patient when strong CYP2D6 
inhibitors are administered. In order to limit the potential higher exposure of 
brexpiprazole when coadministered with such inhibitors, the upper limit of the 
therapeutic ADT dose is set at 60 mg for duloxetine, 40 mg for fluoxetine, and 50 mg for 
paroxetine controlled-release (CR) in the current trial (see Section 3.2.1).
2.3
Trial Objectives
Primary:
To compare the efficacy of brexpiprazole (2 to 3 mg/day) to placebo as 
adjunctive therapy to ADT for the maintenance treatment in adults with 
MDD.
Secondary:
To evaluate the safety and tolerability of brexpiprazole (2 to 3 mg/day) as 
adjunctive therapy to ADT in the proposed subject population with MDD.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
25
Protocol 331-201-00079
Confidential - Proprietary Information
24
08 Jul 2020
3
Trial Design
3.1
Type/Design of Trial
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial 
designed to assess the efficacy, safety, and tolerability of brexpiprazole as adjunctive 
therapy to a protocol-specified single-blind ADT in the maintenance treatment of adult 
subjects with a diagnosis of recurrent MDD. This trial consists of a screening period of 
up to 6 weeks, a 6- to 8-week open-label Acute Treatment Phase, a 12-week Stabilization 
Phase, an up to 26-week Double-Blind Randomized Withdrawal Phase, and a 21-day 
safety follow-up.
The trial phases are described below:
Screening Phase: The screening period will range from a minimum of 3 days up to 
6 weeks and will begin when informed consent is signed. The purpose of the screening 
period is to assess eligibility criteria at 1 or more visits (as necessary to complete 
screening assessments), and to allow subjects to continue their current ADT for an 
adequate duration as needed.
Acute Treatment Phase (Phase A):  At Phase A baseline, all subjects must have either 2 
or 3 documented inadequate responses to ADT in total for the current episode as defined 
by the ATRQ. Subjects will be enrolled into the 6- to 8-week, single-blind, Acute 
Treatment Phase (Phase A) if they meet the entrance criteria. The purpose of the Acute 
Treatment Phase is to identify subjects who respond to adjunctive 
brexpiprazole + protocol-specified ADT. Treatment will consist of single-blind 
brexpiprazole plus continuation of the ADT taken during the screening period 
(Section 3.2.1). The investigator should titrate to the dose of brexpiprazole that optimizes 
efficacy with the protocol-specified ADT with minimum tolerability issues. Subjects will 
attend weekly visits during the Acute Treatment Phase and will be evaluated at Weeks 6
to 8 to determine whether they meet response criteria as defined in the blinded addendum 
to the protocol. Subjects not meeting response criteria by the Week 8 visit will be 
discontinued from the trial.
Stabilization Phase (Phase B): Subjects who meet response criteria at the end of the 
Acute Treatment Phase will continue to a 12-week Stabilization Phase (Phase B). The
purpose of the Stabilization Phase is to ensure subjects are able to maintain stability of 
depression symptoms at the dose of brexpiprazole optimized during Phase A. To proceed 
to the Double-blind Randomized Withdrawal Phase (Phase C), subjects must meet the 
stability criteria as defined in the blinded addendum to the protocol. Subjects not meeting 
stability criteria will be discontinued from the trial.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
26
Protocol 331-201-00079
Confidential - Proprietary Information
25
08 Jul 2020
Double-blind Randomized Withdrawal Phase (Phase C): Subjects eligible for the 
Double-blind Randomized Withdrawal Phase will be randomized 1:1 to double-blind 
treatment with brexpiprazole + ADT or placebo + ADT for up to 26 weeks. Transition 
from the Stabilization Phase to the Double-blind Randomized Withdrawal Phase should 
not be made evident to the subject. During the Double-blind Randomized Withdrawal 
Phase, subjects will be evaluated in the clinic at biweekly visits for the first 2 visits and 
monthly visits thereafter. Subjects meeting the criteria for relapse as defined in the 
blinded addendum to the protocol will be withdrawn due to lack of efficacy.
Follow-up: Subjects who are discontinued, withdrawn, or complete the trial will be 
followed up for safety 21 (+2) days after the last dose of investigational medicinal 
product (IMP) by telephone contact or clinic visit at the investigator’s discretion. 
Subjects should be prescribed appropriate depression treatment as per the investigator or 
the subject's psychiatrist or primary care physician.




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
28
Protocol 331-201-00079
Confidential - Proprietary Information
27
Version 2.0, 15 Jun 2018
3.2
Trial Treatments
Treatment will consist of single-blind brexpiprazole plus an open-label, 
protocol-specified ADT (Section 3.2.1).  Investigational medicinal product will be 
provided to the investigator(s) by the sponsor (or designated agent) and will consist of 
active brexpiprazole tablets, matching placebo tablets, and open-label ADTs. A list of 
ADTs to be used in this trial, including dosages, is provided in Section 3.2.1.
All doses of IMP should be taken orally at the same time each day. All doses of IMP can 
be taken without regard to meals. If tolerability issues arise, the timing of administration 
of the IMP may be adjusted at the investigator’s discretion in order to achieve optimum 
tolerability and compliance.
3.2.1
Protocol-specified Antidepressant Therapy
At screening, subjects must be taking 1 of the 7 ADTs at one of the approved doses listed 
below for their current major depressive episode. At the Phase A baseline visit, subjects 
will be allowed to switch from their current/pre-trial generic ADT to the matching trial-
provided branded ADT. Subjects will not be permitted to switch to another ADT during 
the trial.  If it is determined that a subject must switch to a different ADT during the 
course of the trial, the subject must be discontinued.

Selective Serotonin Reuptake Inhibitors

Citalopram hydrobromide (Celexa®), tablets, 20 or 40 mg/day

Escitalopram (Lexapro®) tablets, 10 or 20 mg/day

Fluoxetine (Prozac®) capsules, 20 or 40 mg/day

Paroxetine (Paxil CR®) controlled-release tablets, 37.5 or 50 mg/day

Sertraline (Zoloft®) tablets, 100, 150 or 200 mg/day
Note:  Fluoxetine 20 mg is dosed once daily. Fluoxetine 40 mg can be dosed once daily 
or in divided doses twice daily. All doses should be taken at the same time each day. All 
other treatments are dosed once daily at the same time each day.

Serotonin-norepinephrine Reuptake Inhibitors

Duloxetine (Cymbalta®) delayed-release capsules, 40 or 60 mg/day

Venlafaxine XR (Effexor XR®) extended-release (XR) capsules, 75, 150 or
225 mg/day
The sponsor may limit and/or discontinue assignment to any single ADT based on the 
overall distribution of antidepressants in the trial.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
29
Protocol 331-201-00079
Confidential - Proprietary Information
28
08 Jul 2020
3.2.2
Brexpiprazole + Antidepressant Treatment Dosing Regimen
Acute Treatment Phase (Phase A): Subjects will receive single-blind brexpiprazole + 
open-label ADT for 6 to 8 weeks. Subjects will be titrated to a target dose of 
brexpiprazole over a 2- to 4-week period. Thereafter, subjects who had not met response 
criteria as defined in the blinded addendum, did not have potentially dose-related adverse 
events (AEs), and had not achieved the maximum dose of medication can have their dose
increased up to 3 mg. Dose decreases can occur at scheduled or unscheduled visits once 
a dose of 3 mg is achieved.  Subjects not able to tolerate the minimum specified target 
dose of 2 mg/day will be discontinued.  The intention of this dosing paradigm is to have 
subjects treated at a maximum tolerated dose of brexpiprazole during the Acute 
Treatment Phase to optimize an efficacious response. 
No adjustments to ADT doses are allowed in Phase A without approval from the medical 
monitor and changes may not be made within 5 days of a change in brexpiprazole dose.
The Acute Treatment Phase dosing schedule for brexpiprazole (flexible dosing with 
lead-in titration) is presented in Table 3.2.2-1.
Stabilization Phase (Phase B): Eligible subjects who have completed Phase A and enroll 
in the Stabilization Phase will receive single-blind brexpiprazole + open-label ADT for 
12 weeks. Brexpiprazole dose decreases can occur at scheduled or unscheduled visits, but 
dose increases can occur only at scheduled visits. The dose of brexpiprazole must be 
stable for the last 4 weeks of the Stabilization Phase. Subjects not meeting stability 
criteria will be discontinued from the trial.  
No adjustments to ADT doses are allowed in Phase B without approval from the medical 
monitor and changes may not be made within 5 days of a change in brexpiprazole dose.
No dose adjustments to the ADT are allowed in the last 4 weeks of Phase B.
Double-blind Randomized Withdrawal Phase (Phase C): Eligible subjects who have 
completed the Stabilization Phase will be randomized into the Double-blind Randomized 
Withdrawal Phase to brexpiprazole or placebo + open-label ADT in a 1:1 ratio for up to 
26 weeks. Subjects randomized to brexpiprazole +ADT should maintain the doses of 
brexpiprazole that they were receiving at Week 20 of the Stabilization Phase. A one-time 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
30
Protocol 331-201-00079
Confidential - Proprietary Information
29
08 Jul 2020
change (ie, increase or decrease) in the dose of brexpiprazole or placebo may be
permitted after discussion with the medical monitor. If a dose modification for 
brexpiprazole is implemented during Phase C, a one-time return to the original dose from 
the start of Phase C is permitted with approval from the medical monitor.
No doses adjustments to the ADT are allowed in Phase C. 
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
The trial population will include male and female outpatients between 18 and 65 years of 
age at the time of consent, inclusive, with a Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) diagnosis of recurrent MDD and a current major 
depressive episode confirmed by both the Mini International Neuropsychiatric Interview 
(MINI) and an adequate clinical psychiatric evaluation.  The current episode must be at 
least 8 weeks in duration.
Subjects must meet all eligibility criteria specified in Section 3.4.2 (inclusion criteria) and 
Section 3.4.3 (exclusion criteria).
The sponsor reserves the right to utilize external quality oversight methods to ensure the 
validity of diagnosis, severity of illness, and other factors determining appropriateness of 
subject selection.
It is anticipated that approximately 1450 subjects will be enrolled into Phase A in order to 
enroll approximately 700 in Phase B and randomize 450 subjects in Phase C.
3.3.2
Subject Selection and Numbering
At screening, subjects will be assigned a unique subject identification (ID) number upon 
completion of the consent process.
3.4
Eligibility Criteria
3.4.1
Informed Consent
Informed consent will be freely obtained from all subjects.  The informed consent form 
(ICF) will be approved by the same institutional review board or independent ethics 
committee (IRB/IEC) that approves this protocol.  
Each ICF will comply with the International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline 11 and local regulatory requirements.  The investigator 
will ensure that the sponsor or its designee reviews and authorizes any written site-
specific ICF used in the trial before submission to the IRB/IEC. 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
31
Protocol 331-201-00079
Confidential - Proprietary Information
30
08 Jul 2020
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Prospective trial participants will be provided with controlled access to the electronic 
informed consent application by site staff. When the site staff and the participant agree 
that the participant has enough information to make an informed decision to participate, 
the participant will electronically sign the electronic ICF (eICF) application and an 
electronic date and time stamp will be applied to the signature. The eICF utilizes the IRB 
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, 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.
All reference to ICF throughout this document will be inclusive of both consent 
modalities to ensure all circumstances are covered.
The participant will be given a printed, signed copy of the eICF. 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.
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol results in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on trial participation.
 
 
 
 
 
 
 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
32
Protocol 331-201-00079
Confidential - Proprietary Information
31
08 Jul 2020
3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
1.
Informed consent prior to the initiation of any protocol-required procedures.  In addition, the 
subject must provide informed consent at screening and must be able to understand that he or she 
can withdraw from the trial at any time. All informed consent procedures must be in accordance 
with the trial site’s IRB/IEC and local regulatory requirements.
2.
Ability, in the opinion of the principal investigator, to understand the nature of the trial and 
follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and 
discontinuation of prohibited concomitant medications, to read and understand the written word 
in order to complete subject-reported outcomes measures, and to be reliably rated on assessment 
scales.
3.
Male and female outpatient subjects 18 to 65 years of age, inclusive, at the time of informed 
consent.
4.
Subjects with both a diagnosis of recurrent MDD, and in a current major depressive episode of 
≥8 weeks in duration, as defined by DSM-5 criteria and confirmed by both the MINI and an 
adequate clinical psychiatric evaluation.
5.
Subjects must have reported a history for the current major depressive episode of an inadequate
response to 1 or 2 adequate ADTs (as defined by the ATRQ). In addition, subjects must 
currently be taking a protocol-mandated antidepressant treatment at a dose defined in 
Section 3.2.1 and adequate duration (as defined by the ATRQ), and must not have reported ≥ 
50% improvement (as defined by the ATRQ). For subjects who are currently on an adequate 
dose of a protocol-mandated ADT but for an inadequate duration, the screening period may be 
used to achieve adequate duration. At Phase A baseline, all subjects must have either 2 or 3 
documented inadequate responses to ADT in total for the current episode as defined by the 
ATRQ.
6.
Subjects with a HAM-D17 total score ≥ 18 at the screening and Phase A baseline visits.
7.
Subjects willing to discontinue all prohibited psychotropic medications to meet protocol-
required washouts prior to and during the trial period.
ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; 
HAM-D17 = 17-item Hamilton Depression Rating Scale.
NOTE: An inadequate response is defined as < 50% reduction in depressive symptom severity, as 
assessed by the ATRQ. Adequate treatment is defined as an antidepressant treatment for at least 
6 weeks in duration at a minimum dose (or higher) as specified in the ATRQ.
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
Sex and Reproductive Status
1.
Females who are breast-feeding and/or who have a positive pregnancy test result prior to 
receiving IMP.  
2.
Sexually active males or WOCBP who do not agree to practice 2 different methods of birth 
control or remain abstinent during the trial and for 30 days after the last dose of IMP. If 
employing birth control, 2 of the following precautions must be used:  vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device, birth control pill, birth control implant, birth control 
depot injection, condom with spermicide, or sponge with spermicide.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
33
Protocol 331-201-00079
Confidential - Proprietary Information
32
08 Jul 2020
Table 3.4.3-1
Exclusion Criteria
Target disease
3.
Subjects who report treatment with adjunctive antipsychotic medication with an antidepressant 
for a minimum of 3 weeks during the current major depressive episode.
4.
Subjects who report allergies or an intolerability (lifetime treatment history) to trial-provided 
ADTs that have not been prescribed to the subject during the current major depressive episode.
5.
Subjects who have received ECT for the current major depressive episode.
6.
Subjects who have had an inadequate response to ECT at any time in the past or who have had a 
vagus nerve stimulation or deep brain stimulation device implanted at any time for the 
management of treatment-resistant depression. Subjects who have had transcranial magnetic 
stimulation during the current major depressive episode.
7.
Subjects with a current need for involuntary commitment or who have been hospitalized within 4 
weeks of screening for the current major depressive episode.
8.
Subjects with a primary DSM-5 diagnosis of:

Schizophrenia Spectrum and Other Psychotic Disorders

Bipolar and Related Disorders

Obsessive compulsive disorder

Feeding and Eating Disorders (including anorexia nervosa or bulimia)

Neurocognitive disorders (including but not limited to: Delirium, Major or Mild 
Neurocognitive Disorder due to: Alzheimer’s, Parkinson’s, Traumatic Brain Injury)

Panic disorder

PTSD
9.
Subjects with a current DSM-5 diagnosis of borderline, antisocial, paranoid, schizoid, 
schizotypal or histrionic personality disorder or intellectual disability
10.
Subjects experiencing hallucinations, delusions, or any psychotic symptomatology in the current 
major depressive episode
11.
Subjects receiving new onset psychotherapy (individual, group, marriage, or family therapy) 
within 42 days of screening or at any time during participation in the trial.
Medical History and Concurrent diseases
12.
Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal Ideation 
with Some Intent to Act, Without Specific Plan) and whose most recent episode meeting criteria 
for this C-SSRS Item 4 occurred within the last 6 months,
OR Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal 
Ideation with Specific Plan and Intent) and whose most recent episode meeting criteria for this 
C-SSRS Item 5 occurred within the last 6 months 
OR Subjects who answer “Yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual 
attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most 
recent episode meeting criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred 
within the last 2 years, 
OR Subjects who, in the opinion of the investigator, present a serious risk of suicide.
13.
Subjects who have met DSM-5 criteria for substance use disorder (moderate or severe) within 
the past 60 days; including alcohol and benzodiazepines, but excluding nicotine.
14.
Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with 
medications for at least the past 90 days) and/or an abnormal result for free T4 at screening, 
unless discussed with and approved by the medical monitor.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
34
Protocol 331-201-00079
Confidential - Proprietary Information
33
08 Jul 2020
Table 3.4.3-1
Exclusion Criteria
15.
Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, 
hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders such as 
any history of myocardial infarction, congestive heart failure, HIV seropositive status/acquired 
immunodeficiency syndrome, chronic hepatitis B or C. Medical conditions that are minor or well 
controlled may be considered acceptable if the condition does not expose the subject to an undue 
risk of a significant AE or interfere with assessments of safety or efficacy during the course of 
the trial. The medical monitor should be contacted in any instance where the investigator is 
uncertain regarding the stability of a subject’s medical condition(s) and the potential impact of 
the condition(s) on trial participation.  Subjects who are severely obese, as confirmed by a 
corresponding high body mass index, need to be reviewed and discussed with the medical 
monitor.
16.
Subjects with diabetes mellitus (IDDM and non-IDDM) are ineligible for the trial unless their 
condition is stable and well-controlled as determined by satisfying ALL of the following criteria 
at screening and Phase A baseline:

Screening HbA1c < 7.0%, AND

Screening glucose must be ≤ 125 mg/dL (fasting) or < 200 mg/dL (nonfasting). If the 
nonfasting screening glucose is ≥ 200 mg/dL, subjects must be retested in a fasted state and 
the retest value must be ≤ 125 mg/dL, AND

Subject has not had any hospitalizations within the 3 months prior to screening due to 
diabetes or complications related to diabetes.
Subjects with non-IDDM (ie, any subjects not using insulin) must also satisfy the following 
criterion:

Subject has been maintained on a stable regimen of oral antidiabetic medication(s) for at 
least 28 days prior to screening or diabetes has been well-controlled by diet for at least 
28 days prior to screening.
Subjects with newly diagnosed diabetes during screening will be excluded.
17.
Subjects with uncontrolled hypertension (DBP > 95 mmHg) or symptomatic hypotension, or 
orthostatic hypotension which is defined as a decrease of ≥ 30 mmHg in SBP and/or a decrease 
of ≥ 20 mmHg in DBP after at least 3 minutes standing compared to the previous supine blood 
pressure, OR development of symptoms.
NOTE:  Blood pressure measurements may be repeated once to ensure reproducibility of the 
exclusionary result(s) before excluding a subject based on the criteria noted above.
18.
Subjects with known ischemic heart disease or history of myocardial infarction- or congestive 
heart failure (whether controlled or uncontrolled).
19.
Subjects with epilepsy or a history of seizures, except for a single seizure episode; for instance 
childhood febrile seizure, post traumatic, or alcohol withdrawal.
Physical and Laboratory Results
20.
Subjects with a positive drug screen for cocaine or other drugs of abuse (excluding known 
prescription stimulants and other prescribed medications and marijuana). Detectable levels of 
alcohol, marijuana, barbiturates, or opiates in the drug screen are not exclusionary if, in the 
investigator’s documented opinion, the subject does not meet DSM-5 criteria for moderate to 
severe substance use disorder and the positive test does not signal a clinical condition that would 
impact the safety of the subject or interpretation of the trial results, and participation is agreed to 
by the medical monitor prior to treatment.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
35
Protocol 331-201-00079
Confidential - Proprietary Information
34
08 Jul 2020
Table 3.4.3-1
Exclusion Criteria
21.
The following laboratory test and ECG results are exclusionary:
1) Platelets ≤ 75000/mm3
2) Hemoglobin ≤ 9 g/dL
3) Neutrophils, absolute ≤ 1000/mm3
4) WBC count ≤ 2800/mm3
5) AST > 2 × ULN
6) ALT > 2 × ULN
7) Creatinine ≥ 2 mg/dL
8) HbA1c ≥ 7.0%
9) Abnormal free T4, unless discussed with and approved by the medical monitor.  (Note:  Free 
T4 is measured only if result for TSH is abnormal.)
10) CPK > 3 × ULN, unless discussed with and approved by the medical monitor
11) QTcF ≥ 450 msec for males and ≥ 470 for females
NOTE:  In addition, subjects should be excluded if they have any other abnormal laboratory 
tests, vital sign results, or ECG findings which in the investigator’s judgment is medically 
significant and would impact the safety of the subject or the interpretation of the trial results.  
Criteria are provided to assist investigators in their assessments of results that may be potentially 
medically significant, depending on the subject’s medical history and clinical presentation.  
Abnormal results for laboratory parameters or vital signs should be repeated 1 time to ensure 
reproducibility of the abnormality before excluding a subject based on the criteria noted above.  
Based on the QTcF corrections reported by the central service, a subject will be excluded if the
correction equals or exceeds 450 msec for males and 470 msec for females for 2 or more of the 3 
time points of the ECGs conducted.  If only 1 ECG time point has a corrected QTc of equal to or 
greater than 450 msec for males or 470 msec for females for either correction factor and it is not 
reproduced at either of the other 2 time points, the subject meets the inclusion criteria.
Prohibited Therapies or Medications
22.
Treatment with a MAOI (eg, Nardi® [phenelzine] or EMSAM® [selegiline]) within the 14 days 
prior to the first dose of IMP in Phase A.
23.
Use of benzodiazepines and/or hypnotics (including non-benzodiazepine sleep aids) within 7 
days prior to the first dose of IMP in Phase A.
24.
Use of varenicline within 5 days prior to the first dose of IMP in Phase A.
25.
Use of oral (or immediate release intramuscular) neuroleptics within 7 days prior or long-acting 
approved neuroleptics ≤1 full cycle plus 1/2 cycle (length of 1 cycle based on the prescribing 
label) prior to the first dose of IMP in Phase A.
26.
Subjects who would be likely to require prohibited concomitant therapy during the trial.
27.
Subjects who have been exposed to brexpiprazole in any prior clinical trial or have received
commercial brexpiprazole (Rexulti).
Allergies and Adverse Drug Reactions
28.
Subjects with a history of neuroleptic malignant syndrome or serotonin syndrome.
29.
Subjects with a history of true allergic response (ie, not intolerance) to more than one class of 
medications.
Other
30.
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (eg, infectious disease) illness must not be enrolled into this trial.
31.
Inability to tolerate oral medication or swallow tablets.
32.
Subjects who participated in any clinical trial within the last 60 days or who participated in more 
than 2 clinical trials within the past year.
33.
Any subject who, in the opinion of the investigator, should not participate in the trial.
Exclusion Criteria Assessed at the Week 6 through 8 Visits
34.
Subjects who do not meet predetermined blinded criteria for response.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
36
Protocol 331-201-00079
Confidential - Proprietary Information
35
08 Jul 2020
Table 3.4.3-1
Exclusion Criteria
35.
Subjects with a positive result for cocaine or other illicit drugs at any scheduled visit during 
Phase A. Subjects with a positive urine drug screen due to marijuana, prescription or OTC 
medications or products and/or a positive blood alcohol result may continue to Phase B only 
after consultation and approval by the medical monitor.  
36.
Subjects who, in the opinion of the principal investigator or medical monitor, developed any 
clinically significant safety concerns during participation in Phase A (eg, laboratory values, ECG 
findings, or medical conditions).
Exclusion Criteria Assessed at the Week 20 Visit
37.
Subjects who do not meet predetermined blinded stabilization criteria.
38.
Subjects with a positive result for cocaine or other illicit drugs at any scheduled visit during 
Phase B. Subjects with a positive urine drug screen due to marijuana, prescription or OTC 
medications or products and/or a positive blood alcohol result may continue to Phase C only 
after consultation and approval by the medical monitor.  
39.
Subjects who, in the opinion of the principal investigator or medical monitor, developed any
clinically significant safety concerns during participation in Phase B (eg, laboratory values, ECG
findings, or medical conditions).
40.
Subjects who, in the opinion of the investigator, medical monitor or clinical surveillance team, 
are not suitable for randomization for other reasons.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = Creatine phosphokinase;
C-SSRS = Columbia-Suicide Severity Rating Scale; DBP = diastolic blood pressure; ECG = 
electrocardiogram; ECT = electroconvulsive therapy; HbA1c = glycosylated hemoglobin; 
HIV = human immunodeficiency virus; IDDM = insulin-dependent diabetes mellitus; IRT = 
interactive response technology; MAOI = monoamine oxidase inhibitor; QTcF = QT interval as 
corrected for heart rate by Fridericia’s formula; SBP = systolic blood pressure; T4 = thyroxine; TSH = 
thyroid stimulating hormone; ULN = upper limit of normal; WBC = white blood cells; WOCBP = 
women of childbearing potential.
Nonchildbearing potential is defined as male and female subjects who are surgically 
sterile (ie, male subjects who have undergone bilateral orchidectomy and female subjects 
who have undergone bilateral oophorectomy and/or hysterectomy) and female subjects 
who have been postmenopausal for at least 12 consecutive months.
Subjects must agree to restrictions to medications as described in Section 4.
During screening, subjects with a positive blood alcohol screen should be reassessed for 
alcohol abuse and dependence before consultation with medical monitor about approval 
for inclusion.  Subjects with a positive drug screen that, in the judgment of the 
investigator with concurrence of the medical monitor, could compromise the subject’s 
safety or ability to comply with the trial procedures that could interfere with the 
interpretation of trial results should be excluded from the trial.  Subjects with a positive 
drug screen for cocaine or other illicit drugs are excluded and may not be retested or 
rescreened.  Subjects with a positive urine drug screen resulting from use of marijuana, 
opiates, barbiturates, prescription or over-the-counter (OTC) medications, or products 
that in the investigator’s documented opinion do not signal a clinical condition that would 
impact the safety of the subject or interpretation of the trial results, or the subject does not 




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
38
Protocol 331-201-00079
Confidential - Proprietary Information
37
08 Jul 2020
3.6
Measures to Minimize/Avoid Bias
During the entire trial, treatment with ADT will be open-label. The investigator and the 
subject will have knowledge of the ADT treatment. 
During the Acute Treatment Phase (Phase A) and the Stabilization Phase (Phase B), 
treatment will be single-blind, meaning that the investigator, but not the subject, will have 
knowledge of brexpiprazole administration.  Both the investigator and subject will be 
blinded to response and stabilization/randomization criteria. The investigator, but not 
subject, will be informed if a subject meets response criteria between Weeks 6 and 8 in 
Phase A and if the subject meets stabilization/randomization criteria in Phase B. Subjects 
will not know when they transition between phases.
During the Double-Blind Randomized Withdrawal Phase (Phase C), IMP other than ADT 
will be double-blind.  In other words, neither the investigator nor the subject will have 
knowledge of the treatment assignment (ie, placebo or brexpiprazole).  Subjects will be 
randomly assigned by the interactive response technology (IRT) to receive brexpiprazole 
+ ADT or matching placebo + ADT. The randomization will be stratified by trial centers.
Treatment assignments will be based on a computer-generated randomization code 
provided by the Otsuka Pharmaceutical Development & Commercialization, Inc (OPDC) 
Biometrics Department. Sponsor and Clinical Research Organization (CRO) personnel, 
including those involved in monitoring, data management, and data analysis, will not 
have access to the treatment code during the trial. Access to the treatment codes will be 
restricted to personnel charged with generating and maintaining randomization files, 
packaging IMP, operating the IRT, and reporting serious adverse events (SAEs) to
regulatory agencies.
3.6.1
Randomization
Personnel at the trial sites will be blinded to the details of the randomization criteria. The
scale scores will be entered into the eSource system at Weeks 6, 7, and 8 during the 
Acute Treatment Phase. The investigator will be informed by eSource if the subject 
meets score-based criteria for response (ie, whether a subject is a “Phase A Responder” 
or a “Phase A Inadequate Responder”). The score-based criteria for response are 
identified in a blinded addendum to this protocol. At the end of the Stabilization Phase
(Week 20), the investigator will be informed by eSource if the subject meets 
randomization criteria.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
39
Protocol 331-201-00079
Confidential - Proprietary Information
38
08 Jul 2020
3.7
Trial Procedures
The duration of this trial from first subject enrolled to last subject completed is estimated 
to be approximately 39 months, of which approximately 22 months are allotted for 
recruitment of subjects. Individual participation for subjects who complete the trial 
without early withdrawal will range from 47 to 55 weeks, consisting of a 3-day to 6-week
screening period, a 6- to 8-week single-blind acute treatment phase, a 12-week 
single-blind stabilization phase, an up to a 26-week double-blind treatment phase, and a 
21 (+ 2)-day follow-up.
External quality oversight methods will be used by the Clinical Surveillance Team (CST)
at Syneos Health to promote appropriate subject enrollment and randomization. Such 
methods will require sites to communicate certain aspects of subject data (collected in the 
course of the protocol and per the Schedule of Assessments) to the CST. Subjects cannot 
be enrolled until the CST review process has been completed and the site has received the 
final notification from the Medical Director or Clinical Scientist. Sites can expect that 
CST review and feedback to site on screening data will occur within 2 business days of 
receipt of full data set.  Decisions regarding inclusion of subjects at 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.
Trial assessment time points are summarized in Table 3.7-1 (Screening and Phase A), 
Table 3.7-2 (Phase B), and Table 3.7-3 (Phase C).


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
40
Protocol 331-201-00079
Confidential - Proprietary Information
39
08 Jul 2020
Table 3.7-1
Schedule of Assessments - Screening and Acute Treatment Phase (Phase A)
Assessment
Screening
Day −42 
to −3
Acute Treatment Phase
Phase 
A Base-
line
Week 1
(± 2 
days)
Week 2
(± 2 
days)
Week 3
(± 2 
days)
Week 4
(± 2 
days)
Week 5
(± 2 
days)
Week 6
(± 2 
days)
Week 7
(± 2 
days)
Week 8/
End-of 
Phase A
or ETa
(± 2 
days)
Entrance criteria and subject history
Informed Consent
X
Inclusion/exclusion criteria
X
X
Demography
X
Medical history
X
Psychiatric history
X
MINI
X
HAM-D17
X
X
Antidepressant history (ATRQ)
X
Prior medication washoutb
X
HIV, HBsAg, and anti-HCVc
X
Efficacy
MADRS
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
SDS
X
X
Safety
Physical examinationd
X
X
Vital signse
X
X
X
X
X
X
X
X
X
X
12-lead ECGf
X
X
X
Clinical laboratory tests (hematology, 
serum chemistry, urinalysis)c
X
X
X
Prolactinc
X
X
HbA1cc
X
X




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
42
Protocol 331-201-00079
Confidential - Proprietary Information
41
08 Jul 2020
be confirmed by eSource based on the score-based criteria defined in the blinded addendum to this protocol. The site will be notified of the subject’s 
response status during the Weeks 6, 7, or 8 visits. Any subject who does not meet the criteria for adequate response will be discontinued from the trial. If a 
subject meets response criteria at Week 6 or 7 they will complete the Week 8 procedures and any remaining visits in Phase A will not be completed.
bWashout of prohibited medications begins after signing the ICF and must comply with the required washout periods in Table 4.1-1  Prohibited and restricted 
medications requiring a washout of at least 24 hours before the first dose of protocol-specified ADT in Phase A are listed in Table 4.1-2 and Table 4.1-4.
cBlood samples for clinical laboratory tests must be drawn after a minimum 8-hour fast at the baseline visit and should be drawn after a minimum 8-hour fast 
at all other visits. If fasting blood samples are not feasible at visits other than the baseline visit, nonfasting blood samples may be collected.  Vital sign and 
ECG assessments should be completed before any blood samples are collected.
dTo include measurement of height and waist circumference at screening and waist circumference at all other time points.
eVital signs include body weight, body temperature, SBP, DBP, and heart rate. Blood pressure and heart rate will be measured in the following order:  supine, 
sitting, and standing after the subject has been in each position for at least 3 minutes. Vital signs scheduled for the same visit as blood samples are to be 
completed before blood is drawn.
fStandard 12-lead ECGs will be performed after the subject has been supine and at rest for ≥5 minutes prior to the ECG. The ECG results will be evaluated at 
the investigational site to determine the subject’s eligibility and to monitor safety. A QTcF ≥ 450 msec for males and ≥ 470 msec for females at screening is 
exclusionary. Any screening ECG with abnormal result(s) considered to be clinically significant should be repeated to confirm the finding(s) before 
excluding the subject from the trial. A central ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety analysis.  
Subjects will continue in the trial based on Week 8 ECG results from the trial site. ECGs scheduled for the same visit as blood samples are to be completed 
before blood is drawn.
gA 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.
hEligibility for continuation in the trial beyond the Week 8 visit is based in part on the Week 4 urine drug screen and blood alcohol results. Subjects whose 
Week 4 urine drug screen is positive for cocaine or other illicit drugs must be withdrawn from the trial.  Subjects with a positive urine drug screen at 
Week 4 due to prescription or OTC medications or products may continue evaluation in the trial only after consultation and approval by the medical 
monitor.
iAll positive urine pregnancy test results must be confirmed by a serum test. Subjects with a positive serum pregnancy test result at screening 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. Pregnancy 
tests can be performed at any point during the trial if pregnancy is suspected.
jThe “baseline/screening” C-SSRS form will be completed for all subjects at screening to determine eligibility and the “Since Last Visit” C-SSRS form will 
be completed at the baseline visit to assure that the subject continues to qualify for the trial. Any subject with suicidal ideation within the last 6 months,
suicidal behaviors within the last 2 years, or who in the clinical judgment of the investigator presents a serious risk of suicide should be excluded from the 
trial (see Table 3.4.3-1). The “Since Last Visit” C-SSRS form will also be completed at all visits after the baseline visit.
kAll medications taken within 30 days of informed consent will be recorded. In addition, all prescription and non-prescription medications taken during the 
trial will be recorded as concomitant medications. Details of prohibited and restricted medications are provided in Section 4.1.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
43
Protocol 331-201-00079
Confidential - Proprietary Information
42
08 Jul 2020
 
 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
44
Protocol 331-201-00079
Confidential - Proprietary Information
43
08 Jul 2020
Table 3.7-2
Schedule of Assessment - Stabilization Phase (Phase B)
Assessment
Week
9
(± 2 
days)
Week 
10
(± 2 
days)
Week 
11
(± 2 
days)
Week 
12
(± 2 
days)
Week 
13
(± 2 
days)
Week 
14
(± 2 
days)
Week 
15
(± 2 
days)
Week 
16
(± 2 
days)
Week 
17
(± 2 
days)
Week 
18
(± 2 
days)
Week 
19
(± 2 
days)
Week 20/
Random-
ization/ 
ETa,b
(± 2 days)
Efficacy
MADRS
X
X
X
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
X
X
X
SDS
X
X
X
Safety
Physical examinationc
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGe
X
Clinical laboratory tests 
(hematology, serum chemistry, 
urinalysis)f
X
Prolactinf
X
HbA1cf
X
Urine drug screeng
X
Urine pregnancy test
(WOCBP only)h
X
X
X
SAS
X
X
AIMS
X
X
BARS
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
Other
Randomization
X
IMP dispensing
X
X
X
X
X
X
X
X
X
X
X
X




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
46
Protocol 331-201-00079
Confidential - Proprietary Information
45
08 Jul 2020
iPharmacogenomic sample is only to be collected during randomization.  If a subject early terminates at Week 20, no sample will be collected.
 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
47
Protocol 331-201-00079
Confidential - Proprietary Information
46
08 Jul 2020
Table 3.7-3
Double-blind Randomized Withdrawal Phase (Phase C)
Assessments
Week 
21
(± 2 
days)
Week 
23
(± 2 
days)
Week
25
(± 2 
days)
Week
29
(± 2
days)
Week 
33
(± 2 
days)
Week 
37
(± 2 
days)
Week 
41
(± 2 
days)
Week 
45
(± 2 
days)
Week 46/
ETa/ 
End of 
Phase C
or MDD 
Relapse
(± 2 
days)
Follow-up 
Safety visit 
(21 + 2 
days)
Efficacy
MADRS
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
SDS
X
X
X
X
X
X
X
X
X
Safety
Physical examinationb
X
Vital signsc
X
X
X
X
X
X
X
X
X
12-lead ECGd
X
X
Clinical laboratory tests (hematology, 
serum chemistry, urinalysis)e
X
Prolactine
X
Blood alcoholf
X
Urine drug screenf
X
X
Urine pregnancy test  (WOCBP only)g
X
X
SAS
X
X
X
X
AIMS
X
X
X
X
BARS
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
49
Protocol 331-201-00079
Confidential - Proprietary Information
48
08 Jul 2020
gAll positive urine pregnancy test results must be confirmed by a serum test. Subjects with a positive serum pregnancy test result during the trial must
discontinue treatment and be withdrawn from the trial. Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.
 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
50
Protocol 331-201-00079
Confidential - Proprietary Information
49
08 Jul 2020
3.7.1
Schedule of Assessments
3.7.1.1
Screening (Day −42 to Day −3)
The screening period begins after consent has been obtained. Although the screening 
period takes place between Day −42 and Day −3, subjects will participate in screening 
activities for 3 days. After the subject has provided consent, a subject number will be 
assigned. Screening evaluations will include the following:

An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial. Subjects cannot be enrolled until the CST review 
process has been completed and the site has received the final notification from the 
Medical Director or Clinical Scientist.  Sites can expect that CST review and 
feedback to site on screening data will occur within 2 business days of receipt of full 
data set.

Demographic data will be recorded.

A general clinical evaluation will be performed, including concurrent medical 
conditions, medical history over the past 2 years, and medical history beyond 2 years 
which is considered to be clinically relevant per the investigator’s judgment.

Psychiatric history will be recorded, including the DSM-5 diagnosis of MDD that will 
be made by an adequately trained and experienced clinician and will be confirmed by 
the administration of the MINI (Section 3.7.2.4.1).

Antidepressant history will be assessed by the Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire (ATRQ; Section 3.7.2.4.3). If the 
subject is on their current antidepressant for an inadequate duration at the time of the 
administration of the ATRQ, the subject may be contacted via telephone to collect 
their response to the current ADT once the subject is on this treatment for an adequate 
duration.

Medications (including those that were taken within 30 days of screening) will be 
recorded. In addition, all prescription and non-prescription medications taken during 
the trial will be recorded as concomitant medications. Details of prohibited/restricted 
medications are provided in Table 4.1-1, Table 4.1-2, and Table 4.1-4.

Washout from prohibited concomitant medications, if applicable (Table 4.1-1).

The investigator (or qualified designee) who is adequately trained will complete the 
17-item Hamilton Depression Rating Scale (HAM-D17) (Table 3.4.2-1; 
Section 3.7.2.4.2).

The investigator (or qualified designee) who is adequately trained will complete the 
“Baseline/Screening” Columbia-Suicide Severity Rating Scale (C-SSRS) form to 
exclude subjects with a significant risk of suicidal behavior (Table 3.4.3-1; 
Section 3.7.3.5.4).

A complete physical examination (including height and waist circumference) will be 
performed.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded. Blood pressure and heart rate are to be measured in the 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
51
Protocol 331-201-00079
Confidential - Proprietary Information
50
08 Jul 2020
following order: supine, sitting, and standing after the subject has been in each 
position at least 3 minutes. See Table 3.4.3-1 for exclusions based on outcome of 
screening vital sign measurements.  Vital signs will be completed before any blood is 
collected.

A standard 12-lead electrocardiogram (ECG) will be performed after the subject has 
been supine and at rest for at least 5 minutes. See Table 3.4.3-1 for exclusions based 
on ECG results.  The ECG is to be completed before any blood sample is collected.

Blood samples will be drawn for clinical laboratory tests (hematology, coagulation 
parameters, and serum chemistry, including glycosylated hemoglobin [HbA1c], and 
thyroid-stimulating hormone [TSH] with reflex to free thyroxine [T4] if the result for 
TSH is abnormal and for infectious diseases) after a minimum 8-hour fast at 
screening. If fasting blood samples are not feasible, nonfasting blood samples may be 
collected.  See Table 3.4.3-1 for exclusions based on outcome of screening clinical 
laboratory tests.

Samples will be obtained for blood alcohol testing. See Section 3.4.3 for details 
regarding subjects with a positive blood alcohol test.

Urine will be collected from all potential subjects for urinalysis and urine screen(s) 
for drugs of abuse. See Section 3.4.3 for exclusions based on outcome of screening 
urinalysis and urine screen(s) for drugs of abuse.

A urine pregnancy test will be performed for all women of childbearing potential
(WOCBP). All positive results must be confirmed by a serum pregnancy test. 
Subjects with a positive serum pregnancy test result will be excluded from the trial.

Adverse events will be recorded beginning with the completion of the consent 
process.


3.7.1.2
Acute Treatment Phase
3.7.1.2.1
Baseline (Day 1)
If the subject continues to be eligible for the trial after the screening period, the following 
procedures will be performed:

Inclusion/exclusion criteria will be verified.

A qualified and certified rater will administer MADRS and HAM-D17.

The investigator (or qualified designee) will administer the CGI-S.

The subject will complete the SDS.

Vital sign measurements (body temperature, blood pressure, and heart rate) and body 
weight will be recorded. Blood pressure and heart rate are to be measured in the 
following order:  supine, sitting, and standing after the subject has been in each 
position at least 3 minutes.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
52
Protocol 331-201-00079
Confidential - Proprietary Information
51
08 Jul 2020

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood sample is 
collected.

Blood samples for clinical laboratory tests (hematology and serum chemistry), 
including HbA1c and prolactin, must be drawn after a minimum 8-hour fast.

A urine sample will be collected for urinalysis.

If the subject has signed a separate consent form, blood may be drawn for FBR (or at 
any other visit).

A urine pregnancy test will be performed for all WOCBP. All positive results must 
be confirmed by a serum pregnancy test. Subjects with a positive serum pregnancy 
test result will be excluded from the trial.

An adequately trained and experienced clinician will administer the Simpson Angus 
Scale (SAS; Section 3.7.3.5.1), Abnormal Involuntary Movement Scale (AIMS; 
Section 3.7.3.5.2), and Barnes Akathisia Rating Scale (BARS; Section 3.7.3.5.3) to 
assess extrapyramidal symptoms (EPS).

The investigator (or qualified designee) who is adequately trained will complete the 
“Since Last Visit” C-SSRS (Section 3.7.3.5.4) form.

Adverse events and concomitant medications will be recorded.

IMP will be dispensed to the subject.
3.7.1.2.2
Weeks 1 through 7 (Phase A)
The following evaluations will be performed at the designated visits in Phase A:

A qualified and certified rater will administer MADRS at Weeks 1 through 7.

The investigator (or qualified designee) will administer the CGI-S at Weeks 1 through 
7.

The subject will complete the SDS only at Week 6.

Criteria will be assessed for the Stabilization Phase (Phase B) by a qualified rater at
Weeks 4 through 7.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded. Blood pressure and heart rate are to be measured in the 
following order: supine, sitting, and standing after the subject has been in each 
position at least 3 minutes, at Weeks 1 through 7. Vital signs are to be completed 
before any blood is drawn.

Blood alcohol will be tested and a urine drug screen performed at Week 4.

A urinary pregnancy test (WOCBP only) will be performed at Weeks 1, and 4. Any 
positive result must be confirmed by a serum pregnancy test. WOCBP with a 
positive serum pregnancy test result must discontinue the IMP and be withdrawn 
from the trial.

An adequately trained and experienced clinician will administer the SAS, AIMS, and 
BARS to assess EPS only at Week 6.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
53
Protocol 331-201-00079
Confidential - Proprietary Information
52
08 Jul 2020

The investigator (or qualified designee) who is adequately trained will complete the 
“Since Last Visit” C-SSRS form at Weeks 1 through 7.

Adverse events and concomitant medications will be recorded at Weeks 1 through 7.

IMP will be dispensed to the subject at Weeks 1 through 7.

Any need for dose modification will be assessed at Weeks 1 through 4.

Drug accountability will be performed at Weeks 1 through 7.
3.7.1.2.3
End of Phase A (Weeks 6, 7, or 8) or Early Termination
Subjects who meet the response criteria, as defined in the blinded addendum to this 
protocol, either at Week 6, Week 7, or Week 8 will have the following assessments 
performed. For subjects who meet these criteria at Week 6 or Week 7, these assessments 
will replace the Week 6 and Week 7 assessments described in Section 3.7.1.2.2. For 
subjects who do not meet response criteria at Visit 8, this will be an ET visit and the 
following procedures will be performed.

A qualified and certified rater will administer the MADRS.

The investigator (or qualified designee) will administer the CGI-S.

The investigator (or qualified designee) who is adequately trained will complete the 
“Since Last Visit” C-SSRS form.

A complete physical examination (including waist circumference) will be performed.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded. Blood pressure and heart rate are to be measured in the 
following order: supine, sitting, and standing after the subject has been in each 
position at least 3 minutes. Vital signs are to be completed before any blood is 
drawn.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes. The ECG is to be completed before any blood sample is 
collected.

Blood alcohol will be tested and a urine drug screen performed.

A blood draw will be collected for clinical laboratory tests and urine will be collected 
for urinalysis. Vital sign and ECG assessments should be completed before any 
blood samples are collected.

A urinary pregnancy test (WOCBP only) will be performed. Any positive result must 
be confirmed by a serum pregnancy test. WOCBP with a positive serum pregnancy 
test result must discontinue the IMP and be withdrawn from the trial.

Adverse events and concomitant medications will be recorded.

IMP will be dispensed to the subject.

Drug accountability will be performed.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
54
Protocol 331-201-00079
Confidential - Proprietary Information
53
08 Jul 2020
3.7.1.3
Stabilization Phase, Week 9 through Week 20/Randomization
(Phase B)
The following assessments will occur during the Stabilization Phase:

A qualified and certified rater will administer the MADRS at Weeks 9 through 20.

The investigator (or qualified designee) will administer the CGI-S at Weeks 9 through 
20.

The subject will complete the SDS at Weeks 9, 14, and 20.

A complete physical examination (including waist circumference) will be performed 
at Week 20 only.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded at Weeks 9 through 20. Blood pressure and heart rate are to be 
measured in the following order: supine, sitting, and standing after the subject has 
been in each position at least 3 minutes. Vital signs are to be completed before any 
blood is drawn.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes at Week 16. The ECG is to be completed before any blood 
sample is collected.

A fasting blood draw must be collected for clinical laboratory tests (hematology and 
serum chemistry) and urine will be collected for urinalysis at Week 20. The 
laboratory tests will include prolactin. Vital sign and ECG assessments should be 
completed before any blood samples are collected.

Blood samples will be drawn for PK analysis at Weeks 16 and 20.

A urine drug screen will be performed at Week 16.

A urinary pregnancy test (WOCBP only) will be performed at Weeks 12, 16, and 20. 
Any positive result must be confirmed by a serum pregnancy test. WOCBP with a 
positive serum pregnancy test result must discontinue the IMP and be withdrawn 
from the trial.

A qualified and certified rater will administer the SAS, AIMS, and BARS at
Weeks 12 and 20.

The investigator (or qualified designee) who is adequately trained will complete the 
“Since Last Visit” C-SSRS form at Weeks 9 through 20.

Adverse events and concomitant medications will be recorded at Weeks 9 through 20.

IMP will be dispensed to the subject at Weeks 9 through 20.

Drug accountability will be performed at Weeks 9 through 20.

Subjects will be randomized at the Week 20/Randomization visit.


Blood sample will be drawn for pharmacogenomic analysis at the 
Week 20/Randomization visit.  If a subject early terminates at Week 20, no sample 
will be collected.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
55
Protocol 331-201-00079
Confidential - Proprietary Information
54
08 Jul 2020
3.7.1.4
Double-blind Randomized Withdrawal Phase (Week 21 through
Week 46/End of Phase C/Relapse) (Phase C)
The following assessments will occur during the Double-blind Randomized Withdrawal 
Phase:

A qualified and certified rater will administer the MADRS at Weeks 21 through 46.

The investigator (or qualified designee) will administer the CGI-S at Weeks 21
through 46.

The subject will complete the SDS at Weeks 21 through 46.

For subjects who discontinue early, attempts should be made to complete ALL 
evaluations, particularly efficacy assessments (ie, MADRS, CGI-S, and SDS), for the 
Week 46/ET visit prior to the administration of any new antidepressant medications. 
However, if the subject receives a new antidepressant prior to ET procedures, no 
efficacy assessments should be done.

A complete physical examination (including waist circumference) will be performed 
at Week 46 only.

Vital sign measurements (body weight, body temperature, blood pressure, and heart 
rate) will be recorded at Weeks 21 through 46. Blood pressure and heart rate are to be 
measured in the following order: supine, sitting, and standing after the subject has 
been in each position at least 3 minutes. Vital signs are to be completed before any 
blood is drawn.

A standard 12-lead ECG will be performed after the subject has been supine and at 
rest for at least 5 minutes at Weeks 29 and 46. The ECG is to be completed before 
any blood sample is collected.

A fasting blood draw should be collected for clinical laboratory tests (hematology and 
serum chemistry) and urine will be collected for urinalysis at Week 46. If fasting 
blood samples are not feasible, nonfasting blood samples may be collected.  The 
laboratory tests will also include prolactin at Week 46. Vital sign and ECG 
assessments should be completed before any blood samples are collected.

Blood alcohol will be tested at Week 46.

Blood samples will be drawn for PK analysis at Weeks 37 and 46.

A urine drug screen will be performed at Weeks 33 and 46.

A urinary pregnancy test (WOCBP only) will be performed at Weeks 33 and 46.  Any 
positive result must be confirmed by a serum pregnancy test. WOCBP with a 
positive serum pregnancy test result must discontinue the IMP and be withdrawn 
from the trial.

A qualified and certified rater will administer the SAS, AIMS, and BARS, at
Weeks 25, 33, 41, and 46. The investigator (or qualified designee) who is adequately 
trained will complete the “Since Last Visit” C-SSRS form at Weeks 21 through 46.

Adverse events and concomitant medications will be recorded at Weeks 21 through 
46.

IMP will be dispensed to the subject at Weeks 21 through 45.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
56
Protocol 331-201-00079
Confidential - Proprietary Information
55
08 Jul 2020

Drug accountability will be performed at Weeks 21 through 46.

3.7.1.5
Post-treatment Follow-up Safety Visit (21 + 2 days)
Adverse events and concomitant medications will be recorded at this Visit 21 (+2) days 
after the last dose of IMP via telephone contact or clinic visit at the investigator’s 
discretion.
3.7.2
Efficacy Assessments
It is required that trained and experienced clinicians administer the MADRS and CGI-S. 
In addition, the raters must be certified for this trial to administer the MADRS.  The 
number of raters within each trial center should be kept to a minimum. Notations in the 
subject’s trial records should substantiate the ratings. Training, certification, and 
materials for rating will be provided by Bracket (Wayne, PA).
3.7.2.1
Montgomery Asberg Depression Rating Scale 
The MADRS16 will be utilized as the primary efficacy assessment of a subject’s level of 
depressive symptoms and must be administered using a structured interview guide.
Detailed instructions for administration of the structured interview will be provided.  This 
scale consists of 10 items each with 7 defined grades of severity.
3.7.2.2
Clinical Global Impression - Severity of Illness Scale
The severity of illness for each subject will be rated using the CGI-S17.  To perform this 
assessment, the rater or investigator will answer the following question: “Considering 
your total clinical experience with this particular population, how mentally ill is the 
patient at this time?” Response choices include: 1 = normal, not at all ill; 2 = borderline 
mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = 
among the most extremely ill patients.  
3.7.2.3
Sheehan Disability Scale 
The SDS18,19 is a self-rated instrument used to measure the effect of the subject’s 
symptoms on work/school, social life, and family/home responsibilities. The SDS is a 
visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors 
simultaneously to assess disability across the 3 domains. The number most 
representative of how much each area was disrupted by symptoms is marked along the 
line from 0 = not at all, to 10 = extremely. Scores of 5 and above are associated with 
significant functional impairment. In addition to the visual scale, the SDS includes 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
57
Protocol 331-201-00079
Confidential - Proprietary Information
56
08 Jul 2020
2 questions related to productivity losses due to the psychiatric symptoms and 
impairment.
3.7.2.4
Subject Assessment Recording
3.7.2.4.1
Mini International Neuropsychiatric Interview 
The MINI20 will be conducted at the screening visit to confirm the subject’s diagnosis of 
MDD and to rule out exclusionary comorbid psychiatric diagnoses. Detailed instructions 
for administration of this structured interview will be provided.
3.7.2.4.2
Hamilton Depression Rating Scale 17-Item Version 
The HAM-D1721,22 will be utilized at screening as a secondary assessment of a subject’s 
level of depression and to determine eligibility, and must be administered utilizing the 
Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D).
Detailed instructions for administration of this structured interview will be provided in 
the SIGH-D. It is required that trained and experienced clinicians administer the 
HAM-D17.
3.7.2.4.3
Antidepressant Treatment Response Questionnaire
The ATRQ23 will be used to collect a subject’s history of pharmacologic treatment for 
their current major depressive episode, will be administered during screening as part of 
the collection of a subject’s psychiatric history and will be utilized to determine 
eligibility for entry into the trial.  If the subject is on their current antidepressant for an 
inadequate duration at the time of the administration of the ATRQ, the subject may be 
contacted via telephone to collect their response to the current ADT once the subject is on 
this treatment for an adequate duration to complete the ATRQ.
3.7.3
Safety Assessments
3.7.3.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
3.7.3.2
Clinical Laboratory Assessments
A central laboratory designated by the sponsor will be used for all laboratory testing 
required during the trial. The central laboratory should be used for all laboratory testing 
whenever possible (including unscheduled and follow-up, if needed). In cases where an 
immediate result is required for a particular laboratory test, the sample should be divided 
and sent to both a local laboratory and the designated central laboratory. Subjects should 
be fasting for a minimum of 8 hours prior to the blood draws, if possible. If fasting blood 
samples are not feasible at screening, nonfasting blood samples may be obtained initially 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
58
Protocol 331-201-00079
Confidential - Proprietary Information
57
08 Jul 2020
for determining eligibility for the trial. The results of these tests at screening must be 
reviewed by the investigator prior to initiation of the administration of the IMP.
Additional urine and blood samples may be collected for further evaluation of safety as 
warranted by the investigator’s judgment. 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. A list of clinical laboratory assessments 
is provided in Table 3.7.3.2-1.
Table 3.7.3.2-1
Clinical Laboratory Assessments
Hematology:
WBC count with differential
RBC count
Hematocrit
Hemoglobin
Platelet count
Urinalysis:
pH
Specific Gravity
Protein
Ketones
Glucose
Blood
Microscopic analysis (performed only if any part of
the urinalysis is not negative)
Urine Drug Screens:
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Marijuana
Methadone
Opiates
Phencyclidine
Propoxyphene
Other:
Blood Alcohol
Serum Chemistry:
ALP
ALT
Albumin
AST
Bicarbonate
Bilirubin, total 
BUN
CPK
Calcium
Chloride
Cholesterol (total, low density lipoprotein, and high 
density lipoprotein)
Creatinine
GGT
Glucose
Inorganic phosphorus
Insulin
LDH
Magnesium
Potassium
Protein, total
Sodium
TSH
T4 (if needed)
Uric acid
Triglycerides
Additional Tests:
Urine or serum pregnancy for WOCBP
PT
aPTT
INR
HbA1c
Prolactin
Additional Tests (screening only);
HIV
HbsAg
anti-HCV
ALP = alkaline phosphatase; BUN = blood urea nitrogen; GGT = gamma glutamyl transferase; LDH 
=lactic dehydrogenase; RBC = red blood cells.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
59
Protocol 331-201-00079
Confidential - Proprietary Information
58
08 Jul 2020
Any value outside the normal range will be flagged for the attention of the investigator 
who must indicate whether or not a flagged value is of clinical significance.  If one or 
more values are questionable, the test(s) may be repeated. If the result of any test (or 
repeat test, if done) is indicated as clinically significant in the samples taken during the 
screening period, the subject will NOT be enrolled into the trial without the permission of 
the medical monitor. In addition, follow-up unscheduled laboratory tests should be 
performed if clinically significant abnormalities are observed. Unscheduled laboratory 
tests may be repeated at any time at the discretion of the investigator for appropriate 
medical care. Refer to Appendix 1 for criteria for identifying laboratory values of
potential clinical relevance.
The following laboratory test results at screening are exclusionary:

Platelets ≤ 75000/mm3

Hemoglobin ≤ 9 g/dL

Neutrophils, absolute ≤ 1000/mm3

WBC count ≤ 2800/mm3

Aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN)

Alanine aminotransferase (ALT) > 2 × ULN

Creatinine ≥2 mg/dL

HbA1c ≥ 7.0%

Abnormal free T4, unless discussed with and approved by the medical monitor. (Note: 
Free T4 is measured only if result for TSH is abnormal.)

CPK > 3 × ULN, unless discussed with and approved by the medical monitor

QTcF ≥ 450 msec for males and ≥ 470 for females
The total volume of blood to be collected during the trial per subject is expected to be 
approximately 150 mL.
A pregnancy test will be conducted in WOCBP prior to trial intervention; results must be 
available prior to the administration of the IMP. Pregnancy tests can be performed at any 
point during the trial if pregnancy is suspected.
3.7.3.3
Physical Examination and Vital Signs
A complete physical examination will consist of measurement of height and waist 
circumference and a review of the following body systems:  head, eyes, ears, nose, and 
throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosae.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
60
Protocol 331-201-00079
Confidential - Proprietary Information
59
08 Jul 2020
Height will be measured with a stadiometer, measuring stick, or tape. Waist 
circumference will be measured with each physical examination. The following 
procedures will aid in the standardization of these measurements:

The subject should be minimally clothed (ie, lightweight clothing; no heavy 
overgarments).

Waist circumference should be recorded before a subject’s meal and at approximately 
the same time at each visit.

The waist circumference measurement will be accomplished by locating the upper hip 
bone and the top of the right iliac crest and placing a weighted measuring tape in a 
horizontal plane around the abdomen at the level of the crest. Before reading the tape 
measure, the assessor should assure that the tape is snug, but does not compress the 
skin, and is parallel to the floor. The measurement is to be made at the end of a 
normal exhalation.
The principal investigator or his/her appointed designee is primarily responsible to 
perform the physical examination. If the appointed designee is to perform the physical 
examination, he/she must be permitted by local regulations and his/her name must be 
included on the FDA Form 1572. Whenever possible, the same individual should 
perform all physical examinations. Any condition present at the post-treatment physical 
examination that was not present at the Phase A baseline examination should be 
documented as an AE and followed to a satisfactory conclusion.
The measurement of vital signs will include body weight, body temperature, systolic 
blood pressure (SBP), diastolic blood pressure (DBP), and heart rate. The following 
guidelines will aid in the standardization of body weight measurements:

The same scale should be used to weigh a given subject each time, if possible.

Scales should be calibrated and reliable; scales should be at zero just prior to each 
subject’s weigh-in session.

A subject should void prior to being weighed and be minimally clothed (ie, no shoes 
or heavy overgarments).

Weight should be recorded before a subject’s meal and at approximately the same 
time at each visit.
Blood pressure and heart rate measurements will be made in the supine, sitting, and 
standing positions after the subject has been in each position for at least 3 minutes. The 
supine measurements will be performed first followed by sitting.
Subjects with uncontrolled hypertension (screening DBP > 95 mmHg in any position) or 
symptomatic hypotension are excluded from the trial as are subjects with orthostatic 
hypotension defined as a decrease of ≥ 30 mmHg in SBP and/or a decrease of 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
61
Protocol 331-201-00079
Confidential - Proprietary Information
60
08 Jul 2020
≥20 mmHg in DBP after at least 3 minutes standing compared to the previous supine 
blood pressure OR development of symptoms (see Table 3.4.3-1). In addition, subjects 
should be excluded if they have any other vital sign measurement at screening that, in the 
investigator’s judgment, is medically significant in that it would impact the safety of the 
subject or the interpretation of the trial results. However, any abnormal screening vital 
sign result(s) considered to be clinically significant should be repeated to confirm the 
finding(s) before excluding the subject from the trial. Appendix 2 is included to assist
investigators in their assessments of results that may be potentially medically significant, 
depending on the subject’s medical history and clinical presentation.
3.7.3.4
Electrocardiogram Assessments
All ECG recordings will be obtained after the subject has been supine and at rest for at 
least 5 minutes. Additional 12-lead ECGs may be obtained at the investigator’s 
discretion and should always be obtained in the event of an electroconvulsive therapy 
(ECT). Electrocardiogram results will be evaluated at the investigational site to 
determine the subject’s eligibility and to monitor safety during the trial. The principal 
investigator or qualified designee will review, sign, and date each ECG reading, noting 
whether or not any abnormal results are of clinical significance. The ECG will be 
repeated if any results are considered to be clinically significant. A central ECG service 
will be utilized for reading all ECGs in order to standardize interpretations for the safety 
analysis.
If, according to the investigator's judgment, any abnormal ECG finding is deemed 
medically significant (impacting the safety of the subject and/or the interpretation of the 
trial results) or meets an exclusion criterion (see Table 3.4.3-1), the subject should be 
excluded from the trial. Abnormal results for ECGs should be repeated once at screening 
with 3 consecutive ECG recordings to ensure reproducibility of the abnormality before 
excluding a subject based on the criteria noted above. Each ECG recording should be 
taken approximately 5 minutes apart (the ECG result reported will be evaluated at each 
time point). The central ECG service will provide the corrections for the 3 ECGs 
performed. Based on the QT interval corrected for heart rate by Fridericia’s formula 
(QTcF) reported by the central service, a subject will be excluded if the corrections are 
≥450 msec in men and ≥ 470 msec in women for 2 of the 3 time points of the ECGs 
done, unless due to ventricular pacing. If only 1 ECG time point has a QTcF of ≥ 450 
msec in men and ≥ 470 msec in women, and this is not reproduced at either of the other 
2 time points, the subject can be included in the trial.
Refer to Appendix 3 for a list of potentially clinically relevant ECG abnormalities to
guide investigators for the assessment of potential ECG abnormalities for clinical 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
62
Protocol 331-201-00079
Confidential - Proprietary Information
61
08 Jul 2020
significance postrandomization. Exclusion criteria for screening do not apply as 
mandatory discontinuation criteria for subjects who are already randomized. Please 
consult the medical monitor in case of questions.  
3.7.3.5
Other Safety Assessments
3.7.3.5.1
Simpson Angus Scale 
The SAS24 consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, 
shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, 
salivation, and akathisia). Each item will be rated on a 5-point scale, with a score of zero 
representing absence of symptoms, and a score of 4 representing a severe condition. The 
SAS total score is the sum of the scores for all 10 items.
Anticholinergics, propranolol, benzodiazepines, and non-benzodiazepine sleep aids are 
not permitted within 12 hours of scale administration (Table 4.1-2 and Table 4.1-3). 
Investigators are encouraged to delay scale administration until 8 hours have elapsed, if at 
all possible.
However, if delaying administration of the scale is not feasible, the SAS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.
3.7.3.5.2
Abnormal Involuntary Movement Scale (AIMS)
The AIMS17,25,26 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/no questions that address the subject’s dental status. Anticholinergics, 
propranolol, benzodiazepines, and non-benzodiazepine sleep aids are not permitted 
within 12 hours of scale administration (Table 4.1-2 and Table 4.1-3). Investigators are 
encouraged to delay scale administration until 8 hours have elapsed, if at all possible. 
However, if delaying administration of the scale is not feasible, the AIMS should still be 
administered and the use of the medication documented, including a notation of the drug 
name, dose, and time of administration on the eSource.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
63
Protocol 331-201-00079
Confidential - Proprietary Information
62
08 Jul 2020
The AIMS Movement Rating Score is defined as the sum of items 1 through 7 (ie, items 
1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, 
trunk movements).
3.7.3.5.3
Barnes Akathisia Rating Scale (BARS)
The BARS26,27 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 12 hours of scale administration (Table 4.1-2 and Table 4.1-3). 
Investigators are encouraged to delay scale administration until 8 hours have elapsed, if at 
all possible. However, if delaying administration of the scale is not feasible, the BARS 
should still be administered and the use of the medication documented, including a 
notation of the drug name, dose, and time of administration on the eSource.
3.7.3.5.4
Columbia-Suicide Severity Rating Scale
Suicidality will be monitored during the trial using the C-SSRS27. This trial will use the 
“Baseline/Screening” and “Since Last Visit” versions of the scale. The 
“Baseline/Screening” version, which assesses the lifetime experience of the subject with 
suicide events and suicidal ideation and the occurrence of suicide events or ideation 
within a specified time period prior to entry into the trial, will be completed for all 
subjects at screening to determine eligibility. Any subject with active suicidal ideation 
within the last 6 months, suicidal behaviors within the last 2 years, or who in the clinical 
judgment of the investigator presents a serious risk of suicide should be excluded from 
the trial (Table 3.4.3-1). The “Since Last Visit” C-SSRS form will also be completed at 
all visits after screening.
3.7.4
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject from 
30 days prior to signing of informed consent through the end of the evaluation period 
(defined as the time period during which subjects are evaluated for primary or secondary 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
64
Protocol 331-201-00079
Confidential - Proprietary Information
63
08 Jul 2020
objectives) on the eSource.  Details of prohibited and restricted medications are provided 
in Section 4.1.  The investigator will record all medications and therapies taken by the 
subject for treatment of an AE or which caused an AE until the end of the trial (defined as 
the last date of contact or date of final contact attempt) on the eSource.
3.7.5
Pharmacokinetic/Pharmacogenomic Assessments
 At the 
Week 20/Randomization visit, a blood sample will be collected for assessments of 
CYP 2D6 metabolizer activity for subjects randomized in to Phase C. Blood sampling 
for plasma concentrations of brexpiprazole will be collected in the Stabilization Phase 
(Phase B) during the Week 16 and Week 20 visits and in the Double-blind Randomized 
Withdrawal Phase (Phase C) during the Week 37 and Week 46/ET visits.
All blood samples for PK assessments will be shipped to the testing facility for analysis. 
All blood samples for pharmacogenomic assessments will be shipped to the 
pharmacogenomics laboratory. Detailed handling and shipping instructions are provided 
in Appendix 4.
3.7.6
End of Trial
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up eSource page for the last subject completing or 
withdrawing from the trial.
3.7.7
Interim Analysis Review Committee
This trial is planned to be monitored for efficacy under the supervision of an independent 
Interim Analysis Review Committee (IARC). In particular, for assessment of efficacy,
2 interim analyses are planned to be performed, with the second interim analysis
performed only if the first is not positive (see Section 7.4.4). The details of the IARC 
structure and its roles and responsibilities will be documented in an IARC charter.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs/IECs, and regulatory authorities in accordance with 
regulatory requirements.
Two interim analyses are planned so that the trial can be terminated once the primary 
objective of the trial is met in order to minimize exposure of subjects to placebo in 
Phase C. The first interim analysis will be performed after 50% of events have been 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
65
Protocol 331-201-00079
Confidential - Proprietary Information
64
08 Jul 2020
achieved. If the result of this interim analysis is positive, the trial will be terminated and 
investigators will be notified. If the interim analysis is negative, a second interim analysis 
will be performed after 75% of events have been achieved.
3.8.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC if judged to be necessary for medical, safety, regulatory, ethical or other 
reasons consistent with applicable laws, regulations, and GCP. The investigator will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB/IEC at 
the site.
3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Interruption
No treatment interruptions are permitted in this trial.
3.8.3.2
Treatment Discontinuation
After randomization, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 3.8.3.5.
3.8.3.3
Documenting Reasons for Treatment Discontinuation
A subject may discontinue IMP for a number of reasons including those listed below:

Reasons related to AE:

Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard

Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP)

SAEs

Other potentially IMP-related safety concerns or AEs

Death

Reasons unrelated to medical condition (provide detail and review AE history with 
subject)

Withdrawal of informed consent (complete written withdrawal of consent form)

Lost to follow-up


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
66
Protocol 331-201-00079
Confidential - Proprietary Information
65
08 Jul 2020

Pregnancy (see Section 5.5)

Termination of all or part of the trial by the sponsor
In addition, subjects meeting the following criteria must be withdrawn from the trial:

Occurrence of any AE, intercurrent illness or abnormality in a laboratory assessment 
which, in the opinion of the investigator, warrants the subject's permanent withdrawal 
from the trial

Treatment with a prohibited concomitant medication other than the use of appropriate 
medications for the treatment of AEs under direction of the investigator; 

Subject noncompliance, defined as refusal or inability to adhere to the trial schedule 
or procedures (Section 3.12)

At the request of the subject, investigator, OPDC or designee, or regulatory authority;

Subject becomes pregnant

Subject cannot tolerate the minimum dose of brexpiprazole (ie, 2 mg/day or matching 
placebo)

Subject does not fulfill the response criteria by Week 8 of Phase A.

Subject does not fulfill stability criteria by Week 12 of Phase B. In addition, subjects 
who have more than 3 excursions (ie, do not meet stability criteria at a scheduled 
visit) during Phase B and subjects with 3 consecutive excursions or an excursion on 
the last visit of the Phase B are to be withdrawn. A missed visit during Phase B will 
be considered an excursion.

Subjects that do not maintain a stable dose of IMP or ADT for the last 4 weeks of 
Phase B

Subject meets criteria for relapse in Phase C

Subject is lost to follow-up
If the subject discontinues IMP due to an AE, the investigator, or other trial personnel, 
will make every effort to follow the event until it has resolved or stabilized. Follow up 
procedures in Section 3.8.3.2 must be followed.
3.8.3.4
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
67
Protocol 331-201-00079
Confidential - Proprietary Information
66
08 Jul 2020
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial ICF):

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).

Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources).  
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.8.3.2).  A subject may, however, indicate that further trial participation is 
creating a burden on their work or social schedule. Therefore, the investigator should 
follow the procedures outlined in Section 3.8.3.3 to determine if the subject can continue 
participation in the trial if modifications to his/her treatment and/or schedule of 
assessments can be accommodated. Only subjects who withdraw their permission for all 
of the above degrees of follow-up are considered to have completely withdrawn their 
consent to participate in the trial.
3.8.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be given instructions to meet and discuss with the subject their options of continuing in 
the trial, preferably on therapy. The investigator should ensure understanding and 
documentation of the reasons for the subject’s desire to withdraw consent.  


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
68
Protocol 331-201-00079
Confidential - Proprietary Information
67
08 Jul 2020
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject completes the consent process), but who is not 
randomized or assigned trial treatment.
Screen failures due to exclusionary criteria may be rescreened at any time if the exclusion 
characteristic has changed. 
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP. Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers. For purposes of this 
trial, subjects who complete Visit 46 will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Visit 46 during the treatment period, who 
do not have a known reason for discontinuation (eg, withdrew consent or AE), and for 
whom a survival status at the end of the trial cannot be determined will be classified as 
“lost to follow-up” as the reason for discontinuation. Survival status can be determined 
from a variety of sources, either by obtaining acceptable documentation for death (ie, 
death certificate, medical records, public records, statement by a family member or 
primary care physician) or acceptable documentation for life (ie, direct contact with the 
subject, medical records, successful telephone contact with the subject, statement by a 
family member or primary care physician, or public records).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.12
Subject Compliance
Responsible trial personnel will dispense the IMP. Accountability and compliance 
verification should be documented in the subject’s trial records. Subjects must be 
counseled on the importance of taking the IMP as directed at all trial visits. If poor 
compliance continues (eg, multiple missed doses resulting in less than 80% overall 
compliance at any point in the trial), discontinuation of the subject from the trial should 
be considered. Subjects who habitually miss visits or habitually attend visits outside of 
the protocol-defined visit window are also noncompliant and should be considered for 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
69
Protocol 331-201-00079
Confidential - Proprietary Information
68
08 Jul 2020
discontinuation. The medical monitor should be contacted if the investigator is uncertain 
whether a subject's lack of compliance merits discontinuation from the trial.
3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor at 
the earliest possible time by telephone. The investigator and sponsor will come as quickly 
as possible to a joint decision regarding the subject’s continuation in the trial. This 
decision will be documented by the investigator and the sponsor, and reviewed by the site 
monitor.
4
Restrictions
4.1
Prohibited Medications
All subjects must agree to discontinue all prohibited medications during the screening 
period in order to meet the protocol-specified washout periods.  Table 4.1-1 provides the 
required duration of washout for selected prohibited medications.  All other prohibited 
medications must be discontinued at least 24 hours before the first dose of IMP in 
Phase A.
Table 4.1-1
List of Medications Prohibited Before the Trial
Medication
Required Duration of Washout 
1.
Antipsychotics (depot or long-acting injectable)
One full cycle plus 1/2 cycle
2.
Monoamine oxidase inhibitors
14 days
3.
Antipsychotics (oral)
7 days
4.
Benzodiazepines
7 days
5..
Hypnotics, including non-benzodiazepine sleep aids
7 days


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
70
Protocol 331-201-00079
Confidential - Proprietary Information
69
08 Jul 2020
Table 4.1-2 lists all medications prohibited during the trial, including exceptions, where 
appropriate.
Table 4.1-2
List of Medications Prohibited During the Trial
1.
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including depot or long-acting injectable formulations
b) Anticonvulsants
c) Antidepressants other than those prescribed as IMP
d) Mood stabilizers (ie, lithium)
e) Benzodiazepines, except when used to manage treatment-emergent AEs such as agitation
and anxiety (See Table 4.1-3)
f)
Hypnotics, including ramelteon and other non-benzodiazepine sleep aids, except for specific 
medications when used to manage treatment-emergent AEs related to insomniaa
g) Stimulants
h) Opioid analgesics, unless permission is obtained from the medical monitor.  Permission for 
opioid use may be considered for a documented and clinically appropriate indication 
(eg, episodic pain condition, tooth extraction) if prescribed at a medically appropriate dose 
and frequency.
i)
Nutritional supplements and non-prescription herbal preparations with central nervous 
system effects (eg, St. John’s Wort, omega-3 fatty acids, kava extracts, gamma-aminobutyric 
acid supplements, etc)
2.
Investigational agents
3.
CYP2D6 inhibitors or CYP3A4 inhibitors and inducers. The medical monitor should be 
consulted for any questions regarding the potential for pharmacokinetic interactions with 
concomitant medications used by subjects during the trial. See Table 4.1-4 below provides a 
select list of CYP2D6 inhibitors and CYP3A4 inhibitors and inducers which are prohibited 
within 14 days prior to the first dose of brexpiprazole in Phase A or Phase B (as appropriate to 
the subject’s point of entry into the trial) and for the duration of the trial.
4.
Barbiturates, except for the treatment of migraine headaches, provided that in the opinion of the 
investigator the dosing is medically appropriate.
5.
Varenicline
aNon-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, and eszopiclone only) are permitted 
for the treatment of insomnia for up to 7 days total in Phase A, up to 7 days total in Phase B, and up 
to 7 days total in Phase C, but not on the same day as administration of a benzodiazepine, regardless 
of indication.  For the non-benzodiazepine sleep aids, sites should only utilize 1 of the listed 
medications that are approved for this indication in their respective countries and the country-specific 
prescribing information is to be used to determine the maximum allowable daily dose for the 
treatment of insomnia.  Non-benzodiazepine sleep aids must not be administered within 12 hours 
prior to scheduled efficacy and safety assessments, including EPS scales.  Investigators are 
encouraged to delay scale administration until 12 hours have elapsed, if at all possible.  However, if 
delaying administration of efficacy and safety scales is not feasible, the scales should still be 
administered and the use of the sleep aid documented, including a notation of the drug name, dose, 
and time of administration on the eSource.
Table 4.1-3 presents the protocol-specified oral benzodiazepines that can be used as 
rescue medication in this trial. Oral lorazepam and oral oxazepam are to be used, if 
available. In countries or at investigative sites where lorazepam and oxazepam are not 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
71
Protocol 331-201-00079
Confidential - Proprietary Information
70
08 Jul 2020
available, use of oral diazepam or oral clonazepam may be acceptable if prior 
authorization is obtained from the medical monitor.
Table 4.1-3
Oral Benzodiazepine Rescue Therapy During the Trial
Oral Benzodiazepinea
Maximum Allowable Weekly Dose (mg/week)
Phase A
Phase B
Phase C
Lorazepamb
12
10
6
Oxazepamb
180
150
90
Diazepamb,c
60
50
30
Clonazepamb,c
6
5
3
aBenzodiazepines must not be administered within 12 hours prior to scheduled efficacy and safety 
assessments, including EPS scales.  Investigators are encouraged to delay scale administration until 
12 hours have elapsed, if at all possible.  However, if delaying administration of efficacy and safety 
scales is not feasible, the scales should still be administered and the use of benzodiazepine 
documented, including a notation of the drug name, dose, and time of administration on the eSource.
bThe 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. 
Short-acting benzodiazepines are to be used whenever possible. 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.
cIn countries or institutions where no short-acting benzodiazepines are commercially available, use of 
oral diazepam or oral clonazepam may be acceptable if prior authorization is obtained from the 
medical monitor.
Table 4.1-4 below provides a select list of CYP2D6 inhibitors and CYP3A4 inhibitors 
and inducers which are prohibited within 14 days prior to the first dose of brexpiprazole 
in Phase A or Phase B and for the duration of the trial.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
72
Protocol 331-201-00079
Confidential - Proprietary Information
71
08 Jul 2020
Table 4.1-4
List of Medications Prohibited During the Trial: CYP2D6 
Inhibitors and CYP3A4 Inhibitors and Inducers
Selected CYP2D6 inhibitorsa
Selected CYP3A4 inhibitors
Selected CYP3A4 inducers
celecoxib
hydroxyzine
chloroquine 
methadone 
chlorpheniramine 
moclobemide 
clemastine 
clomipramine 
pyrilamine 
diphenhydramine 
quinidine 
terbinafine 
halofantrine 
tripelennamine  
amiodarone 
fluvoxamine 
amprenavir 
indinavir
aprepitant 
itraconazole 
chloramphenicol 
ketoconazole 
cimetidine 
nefazodone 
clarithromycin 
nelfinavir 
clotrimazole (if used orally) 
quinupristin/dalfopristin 
delavirdine 
ritonavir 
diltiazem 
saquinavir
erythromycin
troleandomycin
fluconazole 
verapamil
carbamazepine 
oxcarbazepine 
phenytoin 
dexamethasone 
primidone 
efavirenz 
rifampin 
nevirapine
St. John’s Wort 
phenobarbitol 
troglitazone
aFluoxetine, paroxetine, and duloxetine are protocol-defined ADTs that are also CYP2D6 inhibitors. In
order to limit the potential higher exposure of brexpiprazole when coadministered with such 
inhibitors, the upper limit of the therapeutic ADT dose is limited to 40 mg for fluoxetine, 50 mg for 
paroxetine CR, and 60 mg for duloxetine.
4.2
Other Restrictions
The subject’s best medical interests should guide the investigator in the management of 
conditions that are pre-existing or that develop during the trial (intercurrent illness or 
AEs).  The investigator should examine the acceptability of all concomitant medications 
not explicitly prohibited.  In order to ensure that appropriate concomitant therapy is 
administered, it is essential that subjects be instructed not to take any medications (either 
self-administered non-prescription drugs or prescription therapy prescribed by another 
physician) without prior consultation with the investigator.  In particular, the investigator 
should caution the subject about concomitant use of the following during the trial:

Non-steroidal anti-inflammatory drugs, aspirin, or other drugs that interfere with 
coagulation since the combined use of psychotropic drugs that interfere with 
serotonin reuptake and these agents has been associated with an increased risk of 
upper gastrointestinal bleeding.

Triptans (eg, sumatriptan, naratriptan, almotriptan, frovatriptan, rizatriptan, eletriptan, 
and zolmitriptan), linezolid, and methylene blue since there have been rare 
postmarketing reports of serotonin syndrome or serotonin syndrome-like reactions 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
73
Protocol 331-201-00079
Confidential - Proprietary Information
72
08 Jul 2020
(eg, mental status changes, hyperreflexia, autonomic effects, lack of coordination, and 
diarrhea) following the concomitant use of SSRIs or serotonin-norepinephrine 
reuptake inhibitors and these drugs.
All trial personnel should be familiar with the content of the IB for brexpiprazole in order 
to manage the subject’s condition adequately and select appropriate concomitant 
medications, if needed.
5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  Adverse events would not include information recorded 
as medical history at screening for preplanned procedures for which the underlying 
condition was known and no worsening occurred.  An adverse reaction is any untoward 
and unintended response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.  For the purpose of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the IMP and the AE.  
Suspected adverse reaction implies a lesser degree of certainty about causality.
An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions.

Requires in-patient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
74
Protocol 331-201-00079
Confidential - Proprietary Information
73
08 Jul 2020
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious adverse events are all AEs that do not meet the criteria for a "serious" AE.
Immediately Reportable Event (IRE)

Any SAE.

Any AE related to occupational exposure.

Potential serious hepatotoxicity case (see Section 5.4).

Pregnancies are also defined as IREs.  Although normal pregnancy is not an AE, 
it will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor.  Pregnancy will only be documented on the AE eSource if there is an 
abnormality or complication.
Clinical Laboratory Test Value Changes:  It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available.  This review will be 
documented by the investigator’s dated signature on the laboratory report.  For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from Phase A baseline for that individual subject.  This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed.  The investigator may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests.  If this laboratory value is 
considered medically relevant by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE.  
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the eSource.  The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality:  Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related:
There is no temporal or causal relationship between the IMP and 
the AE.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
75
Protocol 331-201-00079
Confidential - Proprietary Information
74
08 Jul 2020
5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  To avoid 
bias in eliciting AEs, subjects should be asked the non-leading question:  “How have you 
felt since your last visit?”  All AEs (serious and nonserious) reported by the subject must 
be recorded on the source documents and on the eSource provided by the sponsor.  
Serious AE collection is to begin after a subject has signed the ICF.
Use medical terminology in AE reporting.  Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms.  Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
A reported AE that undergoes a change in severity, seriousness, or toxicity should be 
reported as a new AE on the source documents and on the eSource provided by the 
sponsor.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3.  Special attention should 
be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events 
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, potential serious hepatotoxicity, or confirmed pregnancy, by 
telephone, fax, or e-mail to the sponsor using the contact information on the cover page 
of this protocol.  An IRE form must be completed and sent by e-mail, fax, or overnight 
courier to the sponsor.  (Please note that the IRE form is NOT the AE eSource).
Subjects experiencing SAEs should be followed clinically until their health has returned 
to Phase A baseline status, or until all parameters have returned to normal or have 
otherwise been explained.  It is expected that the investigator will provide or arrange 
appropriate supportive care for the subject and will provide prompt updates on the 
subject’s status to the sponsor.
5.4
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is 3 times the ULN, a 
total bilirubin level should also be evaluated.  If the total bilirubin is 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the eSource.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
76
Protocol 331-201-00079
Confidential - Proprietary Information
75
08 Jul 2020
5.5
Pregnancy
Women of child-bearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 
12 months).
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures 
(ie, double-barrier method) to prevent pregnancy during the course of the trial and for 
30 days after the last dose of IMP.  Unless the subject is sterile (ie, women who have had 
a bilateral oophorectomy and/or hysterectomy or who have been postmenopausal for at 
least 12 consecutive months; or men who have had a bilateral orchidectomy) or remains 
abstinent, 2 of the following precautions must be used:  vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth control pills, birth control depot injection, birth 
control implant, condom with spermicide, or sponge with spermicide.  Any single method 
of birth control, including vasectomy and tubal ligation, may fail, leading to pregnancy.  
The contraceptive method will be documented at each trial visit.
Before enrolling WOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all WOCBP.  The topics should generally 
include:

General information

ICF

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an eICF stating that the above-mentioned risk factors 
and the consequences were discussed with her.
A urine and/or serum pregnancy test for human chorionic gonadotropin (hCG) will be 
performed at screening on all WOCBP.  If a urine test is performed and is positive, the 
investigator will follow up with a confirmatory serum test.
During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
77
Protocol 331-201-00079
Confidential - Proprietary Information
76
08 Jul 2020
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available.  If the 
pregnancy is confirmed, the subject must not receive the IMP and must not be enrolled in 
the trial.  If pregnancy is suspected while the subject is taking IMP, the IMP must be 
withheld immediately (if reasonable, taking into consideration any potential withdrawal 
risks) until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for subject safety) and the subject will be withdrawn from the trial. Exceptions 
to trial discontinuation may be considered for life-threatening conditions only after 
consultations with the Clinical Safety and Pharmacovigilance department (see the cover 
page of this protocol for contact information).
The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure during the trial and for 30 days after the last dose of IMP, and record the 
event on the IRE form and forward it to the sponsor.  The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy.  
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered, if indicated.  In addition, the 
investigator must report to the sponsor, on appropriate Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome.  Infants will be followed for a minimum of 6 months from the date of 
birth.
5.6
Procedure for Breaking the Blind 
The investigator is encouraged to contact the sponsor/CRO medical advisor to discuss 
their rationale for unblinding.  However, to prevent delays to the investigator or medical 
personnel responding to a potentially emergent situation, unblinding of IMP will not be 
dependent upon the investigator receiving approval from the sponsor/CRO medical 
advisor (ie, the investigator will be able to obtain the code break information independent 
of the sponsor/CRO medical advisor).  The investigator must contact the sponsor/CRO 
medical advisor by telephone or e-mail with an explanation of the need for opening the 
treatment assignment code within 24 hours of opening the code.  If the blind is broken, 
the Clinical Safety and Pharmacovigilance department must be notified immediately (see 
the cover page of this protocol for contact information).  Documentation of breaking the 
blind should be recorded in the subject’s medical record with the date and time the blind 
was broken and the names of the personnel involved.  Once the blind is broken for a 
subject, that subject may not reinitiate treatment with the IMP.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
78
Protocol 331-201-00079
Confidential - Proprietary Information
77
08 Jul 2020
5.7
Follow-up of Adverse Events 
5.7.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eSource with the current status (ongoing or resolved or recovered) noted.  All 
nonserious events (that are not IREs) that are ongoing at the last scheduled contact will 
be recorded as ongoing on the eSource.  For any AE having been identified throughout 
the trial, during analysis, additional relevant medical history information may be 
requested by the sponsor to further ascertain causality (including, but not limited to, 
information such as risk-related behavior, family history and occupation).
5.7.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects be actively monitored for SAEs and IREs up to 21 (± 2) 
days after the last dose of IMP is administered.
Serious AEs and nonserious IREs that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eSource page.  If updated information (eg, 
resolved status) on SAE or 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 eSource page, according to the appropriate reporting procedures.  
The investigator will follow SAEs until the events are resolved, stabilized, or the subject 
is lost to follow-up or has died.  Resolution means that the subject has returned to the 
Phase A 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.
5.7.3
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring after Last Scheduled 
Contact
Any new SAEs or 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 Syneos Health.  This may include SAEs or IREs that 
are captured on follow-up telephone contact or at any other time point after the defined 
trial period.  The investigator should follow SAEs and IREs identified after the defined 
trial period and continue to report any significant follow-up information to the Syneos 
Health until the events are resolved or stabilized, or the subject is lost to follow-up or has 
died.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
79
Protocol 331-201-00079
Confidential - Proprietary Information
78
08 Jul 2020
6
Pharmacokinetic/Pharmacogenomic Analysis
Collected blood samples in the Stabilization Phase (Phase B) during the Week 16 and 
Week 20 visits and in Double Blind Randomized Withdrawal Phase (Phase C) during the 
Week 37 and Week 46/ET visit will be analyzed for plasma concentrations of 
brexpiprazole. The samples will be collected at the same time of collection of clinical 
laboratory samples and the time of the last 3 doses prior to the PK sampling will also be 
collected at the time of PK sample collection. 
A sample to assess the CYP2D6 metabolizing status and other enzymes will be collected 
at the Week 20/Randomization visit. 
 
7
Statistical Analysis
Complete details of the planned statistical analysis will be presented in the statistical 
analysis plan (SAP).
7.1
Sample Size
The primary objective of this trial is to show superiority of brexpiprazole (2 to 3 mg/day) 
+ ADT over placebo + ADT in time to relapse of MDD signs and/or symptoms. 
Time-to-relapse criteria are defined in the blinded addendum to this protocol.  The 2-
sided log-rank test will be used to test for statistical significance of the differences 
between the 2 survival curves.
Based on the results from a completed randomized withdrawal trial of 
olanzapine/fluoxetine combination versus fluoxetine monotherapy to assess prevention of 
relapse in subjects with treatment-resistant depression, it is reasonable to expect that 30% 
of subjects who receive placebo and 16% of subjects treated with brexpiprazole will 
relapse in 6 months, a hazard ratio of 0.49 (brexpiprazole + ADT versus placebo + ADT) 
is derived.  Thus, 104 relapse events are needed in this trial to reach 95% power to test 
the primary hypothesis of the protocol at a 2-sided 0.05 alpha level. The sample size 
estimates used a 1:1 randomization ratio (brexpiprazole + ADT:  placebo + ADT) which 
allowed 2 interim looks at 50% and 75% of events accrual time points.  The O’Brian-
Fleming boundaries were used for sample size calculation of the interim analysis so that 
the first interim analysis will be conducted when 52 relapse events are available and the 
second interim analysis will be conducted when 78 relapse events are available.  The 
2-sided alpha levels for these 2 interim analyses are 0.003 and 0.018 respectively, and the 
alpha left for the final analysis when 104 relapse events are available will be 0.044.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
80
Protocol 331-201-00079
Confidential - Proprietary Information
79
08 Jul 2020
Assuming that each subject will be followed for 6 months after randomization and 
allowing for a 20% loss to follow-up, the projected total number of subjects to be 
randomized into the trial is 450.  Using a 1:1 randomization ratio, the number of subjects 
to be randomized into each treatment group is 225.  Assuming approximately 68% of 
subjects will progress from the Stabilization Phase (Phase B) to Double-blind 
Randomized Withdrawal (Phase C), it is expected that 700 subjects will be enrolled into 
the Stabilization Phase of the trial to allow 450 subjects to be randomized.  Assuming 
approximately 55% subjects will be progress from the Acute Treatment Phase to the 
Stabilization Phase, it is expected that approximately 1450 subjects will be enrolled into 
the Acute Treatment Phase.  However, only the number of relapse events (ie, 104 events) 
is the hard sample size in this protocol.  The other estimates, such as number of 
randomized subjects and number of subjects entering the Acute Treatment Phase and the 
Stabilization Phase, are only based on projection using assumptions that may or may not 
hold in this trial.  Therefore, the actual number of subjects enrolled into the Acute 
Treatment Phase, the Stabilization Phase, or Double-blind Randomized Withdrawal 
Phase may vary from the projected values.
7.2
Datasets for Analysis
The following analysis samples are defined for this trial:

Phase A Safety Sample: Comprises all subjects who took at least 1 dose of 
brexpiprazole in Phase A.

Phase B Safety Sample: Comprises all subjects who took at least 1 dose of 
brexpiprazole in Phase B.

Phase B Efficacy Sample:  All subjects who enter Phase B (ie, receive at least 1 dose 
of brexpiprazole) and have at least one postbaseline efficacy evaluation in Phase B.

Phase C Safety Sample:  All subjects who are randomized to double-blind treatment 
and receive at least 1 dose of double-blind IMP in Phase C.

Phase C Efficacy Sample:  Based on the Intent-to-Treat (ITT) principle, the full 
analysis set of this trial will be composed of all subjects randomized to the 
double-blind treatment who take at least one dose of IMP in Phase C and who have at 
least 1 post-randomization efficacy evaluation in Phase C.
For the primary analysis of time to event, all subjects belonging to the Phase C Efficacy 
Sample will be included in the analysis.  Subjects who withdraw early from the trial or 
who are still in the trial at the end of Week 46 will be considered as providing censored 
observations.
The observed case (OC) dataset will consist of the actual observations recorded at each 
visit and will be used to present summaries per trial week.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
81
Protocol 331-201-00079
Confidential - Proprietary Information
80
08 Jul 2020
The LOCF data set will include data recorded at a given Phase C visit or, if no 
observation is recorded at that visit, data carried forward from the previous Phase C visit.  
Week 20 data (the last visit of Phase B) will not be carried forward to impute missing 
values for the LOCF data set.
The LOCF and OC data sets for Phases A and B will be derived in a manner similar to 
the process described for Phase C.
7.3
Handling of Missing Data
For missing data resulting from early withdrawal from the trial in Phase C, subjects who 
withdraw early will be censored in the primary efficacy analysis at the time when they 
withdraw from the trial.  In order to assess sensitivity of results due to missing data, two 
types of analyses will be performed for analyses by visit in Phases B and C:  LOCF and 
OC.  The LOCF and OC data sets are defined in the SAP.  The OC data set will be used 
for analyses at each trial visit and the LOCF data set will be used for analyses at the last 
visit.
7.4
Primary and Secondary Endpoint Analyses
7.4.1
Primary Endpoint Analysis
The primary efficacy endpoint of this trial is time-to-relapse by any criteria as defined in 
the blinded addendum to this protocol, measured from Week 20 (randomization) into the 
Double-blind, Randomized Withdrawal Treatment Phase).  The objective of the primary 
analysis is to compare the efficacy of brexpiprazole (2 to 3 mg/day) + ADT with that of 
placebo + ADT with regard to time-to-relapse.  The statistical comparison will be 
performed by the log-rank test comparing the 2 treatment groups (brexpiprazole + ADT 
versus placebo + ADT) at an overall nominal significance level of 0.05 (2-sided) using 
the Double-blind Randomized Withdrawal Efficacy Sample.  Interim analyses are 
planned to be performed at approximately 50% and 75% of events accrual time points 
using the O’Brian-Fleming boundaries for rejection of the null hypothesis. Details of the 
interim analyses are provided in Section 7.4.4.
Additionally, for the primary endpoint, a 95% confidence interval for the hazard ratio 
(brexpiprazole + ADT vs placebo + ADT) will be provided using the Cox Proportional 
Hazard model with term of treatment in the model.
The Phase C Efficacy Sample will be used in the above analysis.  Subjects who withdraw 
early from the trial or who are still in the trial at the end of Week 46 will be considered as 
providing censored observations.  Subjects who stay in the trial but have no relapses in an 
interim analysis will be censored at the date of data cut-off for the interim analysis.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
82
Protocol 331-201-00079
Confidential - Proprietary Information
81
08 Jul 2020
7.4.2
Secondary Endpoint Analysis
7.4.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoints are:

Change from randomization in the SDS mean total score at Week 46 (LOCF)

Time to-functional relapse based on SDS criteria.
In order to preserve the overall type I error rate at the 0.05 level, the following testing 
procedure will be used.  If the primary hypothesis of comparing time-to-relapse between 
brexpiprazole + ADT and placebo + ADT is rejected at an overall nominal alpha level of 
0.05, then the hypothesis of comparing first key secondary efficacy endpoint of change 
from randomization in the SDS mean total score at Week 46 between brexpiprazole 
+ ADT and placebo + ADT will be tested at the 0.05 level. If the hypothesis based on the 
first key secondary endpoint is rejected at the 0.05 level, then the hypothesis of 
comparing the other key secondary efficacy endpoint of time-to-functional relapse based 
on SDS criteria between brexpiprazole + ADT and placebo + ADT will be tested at the 
0.05 level.
7.4.2.2
Other Secondary Efficacy Endpoints
Secondary efficacy measures include assessment of rates of relapse and time-to-relapse 
for individual relapse criteria.  Response, stabilization, and remission rates will also be 
assessed for brexpiprazole administration prior to randomization. Response is defined 
based on MADRS and CGI-S criteria, and remission is defined based on MADRS 
criteria.
Other secondary efficacy endpoints evaluated for the Double-blind Randomized 
Withdrawal Phase will include:

Percentage of subjects who relapse

Percentage of subjects maintaining remission 

Mean change from randomization in MADRS score (LOCF)

Mean change from randomization in CGI-S score (LOCF)

Mean change from randomization in each of the SDS individual item scores (LOCF)
Baseline for the Double-blind Randomized Withdrawal Phase (Phase C) is Week 20, 
which is the last visit of the Stabilization Phase prior to the first dose of double-blind IMP 
in the Double-blind Randomized Withdrawal Phase. Analysis of the change from 
randomization for other secondary efficacy endpoints will be based on subjects in the 




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
84
Protocol 331-201-00079
Confidential - Proprietary Information
83
08 Jul 2020
using the Cox Proportional Hazard model with term of treatment in the model. If the null 
hypothesis is rejected at either interim analysis time point, the trial will be terminated for 
having achieved the primary endpoint of a significantly lower incidence with 
brexpiprazole + ADT compared with placebo + ADT. A separate Relapse Event 
Evaluation Committee will review and track each relapse event identified and 
documented. An Interim Analysis Plan will be developed to document the details of data 
flow and other logistical considerations relating to the interim analyses.
Table 7.4.4-1
Boundaries for Rejection of Null Hypothesis for Interim and 
Final Analyses
Analysis
Number of events
2-sided alpha Levela
Interim analysis #1 (~50%)
52
0.003051
Interim analysis #2 (~75%)
78
0.018325
Final analysis (100%)
104
0.044005
aObtained using PASS 14 sample size software.
The interim monitoring of efficacy will be performed by an independent IARC 
(Section 3.7.7). Should the interim analysis be performed at a different time, different 
frequency, the spending function approach as originally introduced by Lan and DeMets29
will be applied to adjust the critical values in order to guarantee an overall 0.05 alpha 
level. The spending functions corresponding to O'Brien-Fleming boundaries will be 
formally applied to the time-to-event analysis (using the log-rank test).
7.5
Analysis of Demographic and Baseline Characteristics
Demographic characteristics at Phase C baseline including age, race, ethnicity, gender, 
weight, height, and body mass index (BMI) for the randomized subjects will be 
summarized by descriptive statistics (frequency, mean, median, standard deviation, 
maximum, minimum, and percentage when applicable).
Disease severity and psychiatric history at Phase C baseline will also be summarized by 
descriptive statistics for the Safety Sample to identify any potential lack of balance 
between the treatment groups for the Phase C efficacy sample.
7.6
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, and physical examinations. In addition, data from the following safety scales will 
be evaluated:  assessments of suicidality (C-SSRS) and EPS (eg, the SAS, AIMS, and 
BARS). Safety analysis will be conducted based on the Safety Sample defined in 
Section 7.2.  In general, baseline of a safety variable is defined as the last observation of 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
85
Protocol 331-201-00079
Confidential - Proprietary Information
84
08 Jul 2020
the variable before taking the first dose of IMP, unless specified otherwise. Prospectively 
defined criteria will be used to identify potentially clinically relevant abnormal values for 
clinical laboratory tests, vital signs, ECGs, and body weight. Details of safety analyses 
will be provided in the SAP.
7.6.1
Adverse Events
7.6.1.1
Phase A
Deaths, serious TEAEs, and AEs leading to discontinuation from trial or trial treatment 
during Phase A will be listed for the Phase A Safety Sample.
7.6.1.2
Phase B
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidence of the following events will be 
summarized:

Treatment-emergent adverse events (TEAEs)

TEAEs by severity

Potentially drug-related TEAEs

TEAEs with an outcome of death

Serious TEAEs

Discontinuations due to TEAEs
7.6.1.3
Phase C
The incidence of the following events will be summarized by treatment group 
(brexpiprazole +ADT versus placebo + ADT):

TEAEs

TEAEs by severity

Potentially drug-related TEAEs

TEAEs with an outcome of death

Serious TEAEs

Discontinuations due to TEAEs
7.6.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements and prolactin concentrations will be provided.  In addition, the incidence 
of potentially clinically relevant values identified using criteria prospectively defined in 
the SAP for laboratory tests will be summarized for Phases B and C.  Analyses will be 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
86
Protocol 331-201-00079
Confidential - Proprietary Information
85
08 Jul 2020
performed using the Safety Sample appropriate to the trial phase.  Results will be 
presented by treatment group (brexpiprazole +ADT versus placebo + ADT) for Phase C.
7.6.3
Physical Examination and Vital Signs Data
Physical examination findings will be listed by subject.  Potentially clinically relevant 
results in vital signs and body weight will also be summarized.
Summary statistics for change from baseline in vital signs, body weight, and waist 
circumference will be provided.
7.6.4
Electrocardiogram Data 
Mean change from baseline and incidence of clinically significant changes will be 
calculated for ECG parameters.  The data will be provided for each trial phase using the 
appropriate Safety Sample.
For the analysis of QT and QTc data from 3 consecutive complexes (representing 
3 consecutive heart beats) will be measured to determine average values.  The following 
QT corrections will be used:
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
Results will be summarized by visit.
7.6.5
Other Safety Data
Descriptive statistics will be provided for change from baseline to end of phase in SAS, 
AIMS, and BARS scores for Phases A, B and C, separately. Results will be summarized 
by visit.  In addition, change from end of Phase B to end of Phase C in scores for the 
SAS, AIMS, and BARS scales will be evaluated using ANCOVA with baseline value as 
covariate and treatment as factor.  The OC data sets will be used in the analyses of these 
EPS scales.
Suicidality monitored during the trial using the C-SSRS will be summarized as number 
and percentage of subjects reporting any suicidal behavior, ideation, behavior by type 
(4 types), ideation by type (5 types), and treatment-emergent suicidal behavior and 
ideation.
8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the IB.13


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
87
Protocol 331-201-00079
Confidential - Proprietary Information
86
08 Jul 2020
8.1
Packaging and Labeling
Trial medication will be provided to the investigators and the persons designated by the 
investigator(s) or institution(s) by the sponsor or designated agent. The IMP will be 
supplied as blister cards. Each blister card used in the dosing period will be labeled to 
clearly disclose the subject ID, compound ID, trial number, sponsor’s name and address, 
instructions for use, route of administration, and appropriate precautionary statements.
Antidepressant therapies will be supplied as bulk drug in commercial packaging 
(eg, bottles) with an ancillary trial-specific label that will be positioned such that it will 
not obscure the original commercial label. The Sponsor reserves the right to use a generic 
equivalent, should any marketed antidepressant become unavailable during the course of 
the trial. Each ADT bottle used in the trial will be labeled to clearly disclose the bottle 
number, subject ID, subject’s initials, protocol number, ADT drug name, the sponsor’s 
name and address, instructions for use, route of administration, and appropriate 
precautionary statements. The amount of open-label ADT dispensed to a subject at each 
visit will be contingent upon the prescribed daily dose of ADT as well as the duration 
between trial visits.
8.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure.  Access will be limited 
to investigators and their designees. Neither investigators nor any designees may provide 
IMP to any subject not participating in this protocol.
The IMP will be stored according to the storage conditions indicated on the clinical 
label(s).  The clinical site staff will maintain a temperature log in the IMP storage area 
recording the temperature at least once each working day.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP (including 
investigational, active control, or placebo) received, dispensed, administered, and 
returned.
8.4
Returns and Destruction
All used IMP containers, unused IMP, and partially-used IMP should be destroyed at the 
trial site(s) or at the site level in accordance with all local and national regulations.
On-site destruction will only occur after drug accountability for the IMP being destroyed 
has been completed by the CRA (clinical research associate). On-site destruction will be 
performed by both site personnel and CRA personnel. On-site Destruction Certificates 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
88
Protocol 331-201-00079
Confidential - Proprietary Information
87
08 Jul 2020
will be linked to specific drug unit ID number(s) or batch number(s) and quantities of 
clinical supplies destroyed at the clinical site. The original Destruction Certificates will 
be retained at clinical sites, and copies will be placed in the trial master file.
8.5
Reporting of Product Quality Complaints
A product quality complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution.  Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor, or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing.  The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail or telephone within 
24 hours of becoming aware of the PQC according to the procedure outlined below.

Online – Send information required for reporting purposes (listed below) to 
OAPI-EQCProductComplaints@Otsuka-us.com

Phone - Rocky Mountain Call Center at 1-800-438-6055.  
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of compliant


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
89
Protocol 331-201-00079
Confidential - Proprietary Information
88
08 Jul 2020

Reporter identification (eg, subject, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return.  If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF.  In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
90
Protocol 331-201-00079
Confidential - Proprietary Information
89
08 Jul 2020
9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings.  The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.
Source documents and source data will be captured electronically in this trial, and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records.  These data will be collected 
into a system that is fully validated.  Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms.  Designated trial site staff will not be given access to 
the system until they have been appropriately trained.  Information to be originally 
captured and reviewed electronically shall include details of the subject visit and the 
protocol-required assessments performed as a part of these visits, medical history, AEs, 
and concomitant medications.  Because this trial is using an electronic source record as 
the original point of data capture, there is no additional data entry step for the trial site for 
data collected directly into the application - rather, the electronic source record directly 
populates the trial database.
Some data may be captured via paper and then entered into the eSource system.  These 
and any other data treated in this manner will be source data verified by the trial clinical


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
91
Protocol 331-201-00079
Confidential - Proprietary Information
90
08 Jul 2020
research associate, and the location of the source data (ie, eSource, paper, or a local 
electronic system) will be documented before the trial start.  Any changes to information 
in paper source documents will be initialed and dated on the day the change is made by a 
trial site staff member authorized to make the change.  Changes will be made by striking 
a single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (eg, wrong data right data).  If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation 
by the clinician.
Another exception will be safety laboratory data, where the official source documentation 
will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source record will take place, however on-
site monitoring inspections will continue to take place in order to review data entry of 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess trial site operational capabilities and to perform 
other monitoring activities that cannot be performed remotely.
At the end of the trial, the investigator must certify that the data entered on the eSource 
application are complete and accurate.  After database lock, the investigator will receive 
an electronic copy of the subject data.
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline E6 and as required by applicable local regulations.  
The investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
Food and Drug Administration (FDA) regulations require all investigators participating in 
clinical drug trials to maintain detailed clinical data for one of the following periods:

A period of at least 2 years after the date on which a New Drug Application is 
approved by the FDA;

A period of 2 years after the sponsor has notified the FDA that investigation with this 
drug is discontinued.
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 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
92
Protocol 331-201-00079
Confidential - Proprietary Information
91
08 Jul 2020
during this trial including any data clarification forms received from the sponsor.  Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities.  
If the investigator withdraws from the trial (eg, due to relocation or retirement), all trial-
related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe.  Notice of such transfer will be given to the sponsor in 
writing.
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP:  Consolidated Guidance, and
applicable regulatory requirements and local laws.  As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications.  In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented.
10.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of data on the eSource application with 
source documents.  The investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA regulations, ICH GCP 
Guideline (E6), international ethical principles derived from the Declaration of Helsinki 
and Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations.  Each trial site will seek approval/favorable opinion 
by an IRB or IEC according to regional requirements, and the investigator will provide 
that documentation to the sponsor.  The IRB/IEC will evaluate the ethical, scientific and 
medical appropriateness of the trial.  Further, in preparing and handling the eSource, the 
investigator, sub-investigator and their staff will take measures to ensure adequate care in 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
93
Protocol 331-201-00079
Confidential - Proprietary Information
92
08 Jul 2020
protecting subject privacy.  To this end, a subject number and subject identification code 
will be used to identify each subject.
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region(s) where the trial 
is conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  All IMPs, subject bodily fluids, and/or other 
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the sponsor.
Subjects will be identified only by unique subject numbers on the eSource.  If further 
subject identification is required, subjects’ full names may be made known to a 
regulatory agency or other authorized officials if necessary, subject to local regulations.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB/IEC.  Any 
permanent change to the protocol, whether an overall change or a change for specific trial 
site(s), must be handled as a protocol amendment.  Any amendment will be written by the 
sponsor.  Each amendment will be submitted to the IRB/IEC, as required by local 
regulations.  Except for “administrative” or “non-substantial” amendments, investigators 
will wait for IRB/IEC approval/favorable opinion of the amended protocol before 
implementing the change(s).  Administrative amendments are defined as having no effect 
on the safety of subjects, conduct or management of the trial, trial design, or the quality 
or safety of IMP(s) used in the trial.  A protocol change intended to eliminate an apparent 
immediate hazard to subjects should be implemented immediately after agreement by the 
sponsor and investigator, followed by IRB/IEC notification within local applicable 
timelines. The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
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 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
94
Protocol 331-201-00079
Confidential - Proprietary Information
93
08 Jul 2020
cases, after approval/favorable opinion of the new ICF by the IRB/IEC, repeat written 
informed consent will be obtained from subjects enrolled in the trial before expecting 
continued participation and before the amendment-specified changes in the trial are 
implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
95
Protocol 331-201-00079
Confidential - Proprietary Information
94
08 Jul 2020
15
References
1
Neirenberg AA, Petersen TJ, Alpert JE. Prevention of relapse and recurrence in 
depression: the role of long-term pharmacotherapy and psychotherapy. J Clin 
Psychiatry. 2003;64 Suppl 15:13-17.
2
American Psychiatric Association.  Practice Guideline for the Treatment of Patients 
with Major Depressive Disorder, Third Edition.  Arlington, VA:  American 
Psychiatric Association; 2010.
3
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. 
Acute and longer-term outcomes in depressed outpatients requiring one or several 
treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-1917.
4
Papakostas GI. Major depressive disorder: Psychosocial impairment and key 
considerations in functional improvement. Am J Manag Care. 2009;15:S316-321.
5
Rush AJ, Kraemer HC, Sackeim HA, Fava M, Trivedi MH, Frank E, et al. Report by 
the ACNP Task Force on response and remission in major depressive disorder. 
Neuropsychopharmacology. 2006;31:1841-1853.
6
Nelson JC. The STAR*D study: a four-course meal that leaves us wanting more. Am 
J Psychiatry. 2006 Nov;163(11):1864-1866.
7
McIntyre RS, O'Donovan C. The human cost of not achieving full remission in 
depression. Can J Psychiatry. 2004;49(Suppl 1):S10-16.
8
Trivedi MH, Thase ME, Osuntokun O, Henley DB, Case M, Watson SB, et al. An 
integrated analysis of olanzapine/fluoxetine combination in clinical trials of 
treatment-resistant depression. J Clin Psychiatry. 2009;70:387-396.
9
Bauer M, El-Khalili N, Datto C, Szamosi J, Eriksson H. A pooled analysis of two 
randomised, placebo-controlled studies of extended release quetiapine fumarate 
adjunctive to antidepressant therapy in patients with major depressive disorder. J 
Affect Disord. 2010;127:19-30.
10 Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, et al. The 
efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: 
a second multicenter, randomized, double-blind, placebo-controlled study. J Clin 
Psychopharmacol. 2008;28:156-165.
11 Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, et 
al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive 
disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin 
Psychiatry. 2007;68:843-853.
12 Gao K, Kemp DE, Fein E, Wang Z, Fang Y, Ganocy SJ, et al. Number needed to treat 
to harm for discontinuation due to adverse events in the treatment of bipolar 
depression, major depressive disorder, and generalized anxiety disorder with atypical 
antipsychotics. J Clin Psychiatry. 2011;72:1063-1071.
13 Otsuka Pharmaceutical Co, Ltd., Otsuka Pharmaceutical Development & 
Commercialization, Inc., H. Lundbeck A/S. REXULTI® (brexpiprazole) 
Investigator's Brochure, Edition 13. Otsuka Report, issued 10 Aug 2017.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
96
Protocol 331-201-00079
Confidential - Proprietary Information
95
08 Jul 2020
14 Brunner E, Tohen M, Osuntokun O, Landry J, Thase ME. Efficacy and safety of 
olanzapine/fluoxetine combination vs fluoxetine monotherapy following successful 
combination therapy of treatment-resistant major depressive disorder. 
Neuropsychopharmacology. 2014;39(11):2549-2559.
15 Rapaport MH, Gharabawi GM, Canuso CM, Mahmoud RA, Keller MB, Bossie CA, 
et al. Effects of risperidone augmentation in patients with treatment-resistant 
depression: Results of open-label treatment followed by double-blind continuation. 
Neuropsychopharmacol. 2006;31:2505-2513.
16 Montgomery SA, Asberg M. A new depression scale designed to be sensitive to 
change. Br J Psychiatry. 1979;134:382-389.
17 Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of 
Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National 
Institute of Mental Health; 1976.
18 Sheehan DV. The Anxiety Disease. New York: Charles Scribner & Sons; 1983.
19 Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin 
Psychopharmacol. 1996;11(Suppl 3):89-95.
20 Sheehan D, Janavs J, Harnett-Sheehan K, Sheehan M, Gray C, Lecrubier Y, et al. 
Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic 
Disorders Studies, Version 6.0.0. Copyright 1992-2010 Sheehan DV & Lecrubier Y.
21 Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc 
Clin Psychol. 1967;6:278-296.
22 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 
1960;23:56-62.
23 Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 
2003;53(8):649-659.
24 Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand Suppl. 1970;212(Suppl 44):S11-19.
25 Guy W. ECDEU Assessment Manual for Psychopharmacology - Revised (DHEW 
Publication No. ADM 76-338). Rockville, MD, US Department of Health, Education, 
and Welfare; 1976.
26 Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-
676.
27 Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): Classification of suicidal events in the 
FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164:1035-1043.
28 O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometric. 
1979;35:549-556.
29 Lan KKG, DeMets DL, Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659-663.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
97
Protocol 331-201-00079
Confidential - Proprietary Information
96
08 Jul 2020
16
Appendices
Appendix 1
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
98
Protocol 331-201-00079
Confidential - Proprietary Information
97
08 Jul 2020
Appendix 2
Criteria for Identifying Vital Signs of Potential Clinical 
Relevance


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
99
Protocol 331-201-00079
Confidential - Proprietary Information
98
08 Jul 2020
Appendix 3
Criteria for Identifying Electrocardiogram Measurements of 
Potential Clinical Relevance


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
100
Protocol 331-201-00079
Confidential - Proprietary Information
99
08 Jul 2020
Appendix 4
Handling and Shipment of Bioanalytical Samples
Pharmacokinetic Sample Collection
A sample of 4 mL of blood for PK testing will be collected into 4-mL Vacutainer tubes 
containing sodium heparin. Each tube should be gently inverted three to four times and 
then centrifuged at 2500 rpm for at least 10 minutes at 4°C.  The separated plasma from 
the tube should then be divided equally between the 2 bar-code labeled polypropylene 
tubes.  All tubes must be labeled using the central lab’s bar-code labels provided with the 
sample collection kits.  The central lab’s requisition form must be completely filled out in 
regards to the PK sample information.  It is important to note the exact date and time of 
the blood collection, the date and time of the last dose of brexpiprazole/placebo prior to 
each blood draw, and the time of the meal closest to the last dose.
The sample must be stored at −70°C, if available, or −20°C or below.  If only a −20°C 
freezer is available, samples must be shipped within 30 days of collection and primary 
and backup samples may be shipped together.  If samples are stored in a −70°C freezer, 
then one tube (primary sample) will be shipped on dry ice to the central lab as soon as 
possible after collection.  Following confirmation that the first tube arrived safely, the 
second tube (backup sample) can also be shipped to the central lab.  If neither a −70°C 
nor −20°C freezer is available, the primary and backup PK samples must be shipped on 
dry ice in the same box to the central laboratory on the day of collection.
Pharmacogenomic Sample Collection
A 4-mL whole blood sample for the pharmacogenomic determination of drug 
metabolizing enzymes and transporters will be collected by venipuncture into a 4-mL 
Vacutainer tube containing potassium ethylenediaminetetraacetic acid (K2EDTA).  Each 
tube should be gently inverted 10 times to ensure proper mixing with the anticoagulant. 
Refrigerate the whole blood samples at 4°C for at least 1 day (but no longer than 4 days), 
then store upright at −20°C or below.  If refrigerating is not possible, samples can be 
frozen directly from ambient.  The tube will be shipped on dry ice to the central 
laboratory.
 
 
 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
101
Protocol 331-201-00079
Confidential - Proprietary Information
100
08 Jul 2020
 
Plasma or whole blood samples must be neatly packed in the kits provided by the central 
lab and restrained in a Styrofoam container. Boxes should be completely filled with dry 
ice to avoid air spaces that allow evaporation of the dry ice.  The Styrofoam container 
should be sealed with tape and placed in a cardboard box.  When possible, samples 
should be shipped together to reduce the number of shipments.
The central laboratory must be alerted of sample shipment.  Packages must not be 
shipped on Thursdays, Fridays, Saturdays, or any day prior to a holiday without the 
expressed consent of OPDC.  Shipments from clinical sites will be via an overnight 
carrier to the central laboratory.










Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
106
This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 331-201-00079 Protocol Amendment 2
Document Number: 
Document Version: 10.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
08-Jul-2020
13:29:20
Biostatistics Approval
08-Jul-2020
00:31:05
Approved for Clinical
Pharmacology
and Nonclinical
09-Jul-2020
16:05:01


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
107
1
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Brexpiprazole (OPC-34712)
ADDENDUM FOR CLINICAL PROTOCOL FOR TRIAL 331-201-00079
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate
the Efficacy, Safety, and Tolerability of Brexpiprazole as Adjunctive Therapy in the
Maintenance Treatment of Adults With Major Depressive Disorder
Protocol No. 331-201-00079
IND No. 103,958
EudraCT No. 2018-000601-22
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc
2440 Research Boulevard
Rockville, Maryland 20850
Immediately Reportable Event 
Syneos Health Pharmacovigilance & Drug 
Safety 
Fax: (877) 464-7787
E-mail: safetyreporting@syneoshealth.com
Issue Date:
16 Jul 2020


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
108
Protocol 331-201-00079
2
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
Trial Conduct for COVID-19
All procedures and assessments in the 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, the appropriate measures to be followed will be provided 
in this document.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
109
Protocol 331-201-00079
3
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
Table of Contents
Trial Conduct for COVID-19.......................................................................2
Table of Contents...........................................................................................3
List of In-text Tables .....................................................................................4
List of In-text Figures....................................................................................5
List of Abbreviations and Definitions of Terms .........................................6
1
Trial 331-201-00079 COVID-19 Protocol Summary.........................7
1.1
Trial Design Schematic ...................................................................................... 7
1.2
Schedule of Assessments.................................................................................... 8
2
General Considerations......................................................................20
2.1
Reconsent ......................................................................................................... 20
2.2
Protocol Deviations.......................................................................................... 20
2.3
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19........................................................................................................ 20
2.4
Statistical Analyses........................................................................................... 21
2.5
Clinical Outcomes............................................................................................ 21
3
Trial Population..................................................................................21
3.1
Inclusion Criteria.............................................................................................. 21
3.2
Exclusion Criteria............................................................................................. 22
4
Trial Procedures .................................................................................22
4.1
Safety Assessments .......................................................................................... 22
4.1.1
Pregnancy ...................................................................................................... 22
4.1.2
Extrapyramidal Symptom Scales................................................................... 23
5
Investigational Medicinal Product....................................................23


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
110
Protocol 331-201-00079
4
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
List of In-text Tables
Table 1.2-1
COVID-19 Impact Schedule of Assessments (Phase A)................ 8
Table 1.2-2
COVID-19 Impact Schedule of Assessments (Phase B) .............. 13
Table 1.2-3
COVID-19 Impact Schedule of Assessments (Phase C) .............. 17


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
111
Protocol 331-201-00079
5
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
List of In-text Figures
Figure 1.1-1
COVID-19 Impact Trial Design Schematic.................................... 7


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
112
6
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
Anti-HCV
Hepatitis C antibodies
aPTT
Activated prothromplastin time
ATRQ
Massachusetts General Hospital 
Antidepressant Treatment Response 
Questionnaire
BARS
Barnes Akathisia Rating Scale
CGI-S
Clinical Global Impression - Severity of 
Illness
C-SSRS
Columbia-Suicide Severity Rating Scale
CRO
Contract Research Organization
ECG
Electrocardiogram
eCRF
Electronic case report form
eICF
Electronic informed consent form
EudraCT
European Clinical Trial Data Base
FOCBP
Females of childbearing potential
HAM-D17
Hamilton Depression Rating Scale
HBsAG
Hepatitis B Surface Antigen
HIV
Human immunodeficiency virus
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
INR
International Normalized Ratio
IRB
Institutional review board
IRE
Immediately reportable event
MADRS
Montgomery Asberg Depression Rating 
Scale
MDD
Major depressive disorder
MINI
Mini International Neuropsychiatric 
Interview
PT
Prothrombin time
SAE
Serious adverse event
SAS
Simpson Angus Scale
SDS
Sheehan Disability Scale
T4
Thyroxine
TSH
Thyroid-stimulating hormone
US
United States




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
114
8
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
1.2
Schedule of Assessments
Table 1.2-1
COVID-19 Impact Schedule of Assessments (Phase A)
Assessment
Screening
Day −42 
to −3
Acute Treatment Phase
Phase 
A 
Base-
line
Week 1
(± 2 
days)
Week 2
(± 2 
days)
Week 3
(± 2 
days)
Week 4
(± 2 
days)
Week 5
(± 2 
days)
Week 6
(± 2 
days)
Week 7
(± 2 
days) (as 
needed)a
Week 8/ 
End-of 
Phase A 
or ETa
(± 2 days)
In-person
In-
person
In-
person
In-
person
In-person
Entrance criteria and subject history
Informed Consent
X
Inclusion/exclusion criteria
X
X
Demography
X
Medical history
X
Psychiatric history
X
MINI
X
HAM-D17
X
X
Antidepressant history 
X
Prior medication washoutb
X
HIV, HBsAg, and anti-HCVc
X
Efficacy
MADRSd
X
Remote
Remote
Remote
Remote
Remote
X
X
X
CGI-Sd
X
Remote
Remote
Remote
Remote
Remote
X
X
X
SDS
X
X
Safety
Physical examinatione
X
X
Vital signsf
X
X
Xg
Xg
Xg
Xg
Xg
X
X
X
12-lead ECGh
X
X
X


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
115
Protocol 331-201-00079
9
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
Table 1.2-1
COVID-19 Impact Schedule of Assessments (Phase A)
Assessment
Screening
Day −42 
to −3
Acute Treatment Phase
Phase 
A 
Base-
line
Week 1
(± 2 
days)
Week 2
(± 2 
days)
Week 3
(± 2 
days)
Week 4
(± 2 
days)
Week 5
(± 2 
days)
Week 6
(± 2 
days)
Week 7
(± 2 
days) (as 
needed)a
Week 8/ 
End-of 
Phase A 
or ETa
(± 2 days)
In-person
In-
person
In-
person
In-
person
In-person
Clinical laboratory tests (hematology, 
serum chemistry, urinalysis)c
X
X
X
Prolactinc
X
X
HbA1cc
X
X
TSH, with reflex to T4 if TSH is 
abnormal
X
Coagulation parameters (PT, aPTT, &
INR)
X
Blood alcoholi
X
Xj
X
Urine drug screeni,k
X
Xj
X
Urine pregnancy test (FOCBP only)l,m
X
X
Remote
Remote
X
SASn
X
X
AIMS
X
X
BARS
X
X
C-SSRSo,p
X
X
Remote
Remote
Remote
Remote
Remote
X
X
X
Adverse eventso
X
X
Remote
Remote
Remote
Remote
Remote
X
X
X
Concomitant medicationso,q
X
X
Remote
Remote
Remote
Remote
Remote
X
X
X
Other
IMP dispensingr
X
Remote
Remote
Remote
Remote
Remote
X
X
X
IMP accountabilityr
Remote
Remote
Remote
Remote
Remote
X
X
X




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
117
Protocol 331-201-00079
11
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
dMADRS and CGI-S can be collected remotely by telephone or video.
eTo include measurement of height and waist circumference at screening and waist circumference at all other time points.
fVital signs include body weight, body temperature, SBP, DBP, and heart rate. Blood pressure and heart rate will be measured in the following order:  supine, 
sitting, and standing after the subject has been in each position for at least 3 minutes. Vital signs scheduled for the same visit as blood samples are to be 
completed before blood is drawn.
gVital signs are not required at remote visits; however, vital signs may be collected by the subject at home if appropriate collection devices are available.
hStandard 12-lead ECGs will be performed after the subject has been supine and at rest for ≥ 5 minutes prior to the ECG.  The ECG results will be evaluated 
at the investigational site to determine the subject’s eligibility and to monitor safety. A QTcF ≥ 450 msec for males and ≥ 470 msec for females at screening 
is exclusionary. Any screening ECG with abnormal result(s) considered to be clinically significant should be repeated to confirm the finding(s) before 
excluding the subject from the trial. A central ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety analysis. 
Subjects will continue in the trial based on Week 8 ECG results from the trial site. ECGs scheduled for the same visit as blood samples are to be completed 
before blood is drawn.
iA 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.
jThe blood alcohol and urine drug screen assessments can be conducted at a local lab if available.
kEligibility for continuation in the trial beyond the Week 8 visit is based in part on the Week 4 urine drug screen and blood alcohol results. Subjects whose 
Week 4 urine drug screen is positive for cocaine or other illicit drugs must be withdrawn from the trial. Subjects with a positive urine drug screen at 
Week 4 due to prescription or OTC medications or products may continue evaluation in the trial only after consultation and approval by the medical 
monitor.
lAll positive urine pregnancy test results must be confirmed by a serum test. Subjects with a positive serum pregnancy test result at screening 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. Pregnancy 
tests can be performed at any point during the trial if pregnancy is suspected.
mFemales of child bearing potential (FOCBP) should be sent pregnancy kits for Weeks 4 and 8 visits if possible with IMP dispensation for the week prior 
(Week 3 visit).
nThe SAS requires assessment of rigidity and requires physical touch, so it will not be possible to conduct via video remotely and this should be documented 
accordingly in eSource.
oC-SSRS, adverse events, and concomitant medication information can be collected using telephone.
pThe “baseline/screening” C-SSRS form will be completed for all subjects at screening to determine eligibility and the “Since Last Visit” C-SSRS form will 
be completed at the baseline visit to assure that the subject continues to qualify for the trial.  Any subject with suicidal ideation within the last 6 months, 
suicidal behaviors within the last 2 years, or who in the clinical judgment of the investigator presents a serious risk of suicide should be excluded from the 
trial (see Table 3.4.3-1 of protocol). The “Since Last Visit” C-SSRS form will also be completed at all visits after the baseline visit.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
118
Protocol 331-201-00079
12
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
qAll medications taken within 30 days of informed consent will be recorded. In addition, all prescription and non-prescription medications taken during the 
trial will be recorded as concomitant medications. Details of prohibited and restricted medications are provided in Section 4.1 of the protocol.
rIMP should be shipped using courier services. If not using local couriers, other IMP dispensation and accountability is reviewed on a case by case basis.
 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
119
Protocol 331-201-00079
13
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
Table 1.2-2
COVID-19 Impact Schedule of Assessments (Phase B)
Assessment
Week
9
(± 2 
days)
Week 
10
(± 2 
days)
Week 
11
(± 2 
days)
Week 
12
(± 2 
days)
Week 
13
(± 2 
days)
Week 
14
(± 2 
days)
Week 
15
(± 2 
days)
Week 
16
(± 2 
days)
Week 
17
(± 2 
days)
Week 
18
(± 2 
days)
Week 
19
(± 2 
days)
Week 
20/ 
Random
-ization/ 
ETa,b
(± 2 
days)
In 
person
Efficacy
MADRSc
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
X
CGI-Sc
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
X
SDSc
Remote
Remote
X
Safety
Physical examinationd
X
Vital signse
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
X
12-lead ECGg
Xh
Clinical laboratory 
tests (hematology, 
serum chemistry, & 
urinalysis)i
X
Prolactini
X
HbA1ci
X
Urine drug screenj
Xh
Urine pregnancy test
(FOCBP only)k,l
Remote
Remote
X
SASm
X
AIMSn
Remote
X




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
121
Protocol 331-201-00079
15
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
aFor subjects who meet stability criteria, the Week 20 visit, Randomization, will be the baseline visit for all subsequent Phase C visits; for subjects who do not 
meet the stability criteria, the Week 20 visit will be the ET visit. Stability criteria are defined in the blinded addendum to this protocol.
bIf a subject discontinues prematurely, procedures noted for Week 20 must be completed at the ET visit.
cMADRS, CGI-S, and SDS can be collected remotely by telephone or video.
dIncludes waist circumference.
eVital signs include body weight, body temperature, SBP, DBP, and heart rate. Blood pressure and heart rate will be measured in the following order: supine, 
sitting, and standing after the subject has been in each position for at least 3 minutes. Vital signs scheduled for the same visit as blood samples are to be 
completed before blood is drawn.
fVital signs are not required at remote visits; however, vital signs may be collected by the subject at home if appropriate collection devices are available.
gStandard 12-lead ECGs will be performed after the subject has been supine and at rest for ≥ 5 minutes prior to the ECG. ECG results will be evaluated at the 
investigational site to monitor safety. A central ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety 
analysis. The ECG is to be completed before any blood sample is collected.
hThe ECG and urine drug screen assessments can be conducted at a local lab if available.
iBlood samples for clinical laboratory tests must be drawn after a minimum 8-hour fast at the Week 20/Randomization visit and should be drawn after a 
minimum 8-hour fast at all other visits. If fasting blood samples are not feasible at visits other than the Week 20/Randomization visit, nonfasting blood 
samples may be collected. Vital sign and ECG assessments should be completed before any blood samples are collected.
jA urine drug screen and a blood alcohol test are required at the designated times, but either or both can be conducted at any time during the trial at the 
discretion of the investigator.
kAll positive urine pregnancy test results must be confirmed by a serum test. Subjects with a positive serum pregnancy test result during the trial must 
discontinue treatment and be withdrawn from the trial. Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.
lFOCBP should be sent pregnancy kits for Weeks 12, 16, and 20 visits if possible with IMP dispensation for the week prior (Week 3 visit).
mThe SAS requires assessment of rigidity and requires physical touch, so it will not be possible to conduct via video remotely and this should be documented 
accordingly in eSource.
nAIMS & BARS can be assessed remotely using only video.
oC-SSRS, adverse events, and concomitant medication information can be collected using telephone.
pIMP should be shipped using courier services. If not using local couriers, other IMP dispensation and accountability is reviewed on a case by case basis.
qPharmacokinetic samples will be collected at the in-clinic visits as per schedule of assessment.
rPharmacogenomic sample is only to be collected during randomization. If a subject early terminates at Week 20, no sample will be collected.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
122
Protocol 331-201-00079
16
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
123
Protocol 331-201-00079
17
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
Table 1.2-3
COVID-19 Impact Schedule of Assessments (Phase C)
Assessments
Week 21
(± 2 days)
Week 23
(± 2 days)
Week 25
(± 2 days)
Week 29
(± 2 days)
Week 33
(± 2 days)
Week 37
(± 2 days)
Week 41
(± 2 days)
Week 45
(± 2 days)
Week 46/ 
ETa/ End 
of Phase 
C or 
MDD 
Relapse
(± 2 days)
Follow-
up 
Safety 
visit (21 
+ 2 
days)
In person
In 
person
Efficacy
MADRSb
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
X
CGI-Sb
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
X
SDSb
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
X
Safety
Physical examinationc
X
Vital signsd
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
X
12-lead ECGf
Xg
X
Clinical laboratory 
tests (hematology, 
serum chemistry, 
urinalysis)h
X
Prolactinh
X
Blood alcoholi
X
Urine drug screeni
Xg
X
Urine pregnancy test 
(FOCBP only)j,k
Remote
X
SASl
X
AIMSm
Remote
Remote
Remote
X




Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
125
Protocol 331-201-00079
19
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
bMADRS, CGI-S, and SDS can be collected remotely by telephone or video.
cIncludes waist circumference.
dVital signs include body weight, body temperature, SBP, DBP, and heart rate.  Blood pressure and heart rate will be measured in the following order: supine, 
sitting, and standing after the subject has been in each position for at least 3 minutes.  Vital signs scheduled for the same visit as blood samples are to be 
completed before blood is drawn.
eVital signs are not required at remote visits; however, vital signs may be collected by the subject at home if appropriate collection devices are available.
fStandard 12-lead ECGs will be performed after the subject has been supine and at rest for ≥ 5 minutes prior to the ECG.  ECG results will be evaluated at the 
investigational site to monitor safety. A central ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety 
analysis.  The ECG is to be completed before any blood sample is collected.
gThe ECG and urine drug screen assessments can be conducted at a local lab if available.
hBlood samples for clinical laboratory tests should be drawn after the subject has been fasting for at least 8 hours, if possible.  If fasting blood samples are not 
feasible, nonfasting blood samples may be collected. Vital sign and ECG assessments should be completed before any blood samples are collected.
iA 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.
jAll positive urine pregnancy test results must be confirmed by a serum test. Subjects with a positive serum pregnancy test result during the trial must 
discontinue treatment and be withdrawn from the trial. Pregnancy tests can be performed at any point during the trial if pregnancy is suspected.
kFOCBP should be sent pregnancy kits for Weeks 33 and 46 visits if possible with IMP dispensation for the week prior (Week 3 visit).
lThe SAS requires assessment of rigidity and requires physical touch, so it will not be possible to conduct via video remotely and this should be documented 
accordingly in eSource.
mAIMS & BARS can be assessed remotely using only video.
nC-SSRS, adverse events, and concomitant medication information can be collected using telephone.
oIMP should be shipped using courier services. If not using local couriers, other IMP dispensation and accountability is reviewed on a case by case basis.
pPharmacokinetic samples will be collected at the in-clinic visits as per schedule of assessment.
 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
126
Protocol 331-201-00079
20
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
2
General Considerations
2.1
Reconsent
If there is an immediate need to reconsent subjects during the period of COVID-19 
restrictions, a paper reconsent process will be followed and sites are encouraged to 
contact the contract research organization (CRO) and sponsor with questions. In regions 
where remote capacity exists to collect remote eConsent, information will be provided by 
the CRO and sponsor will provide the necessary information.
2.2
Protocol Deviations
Prior to approval of this addendum, protocol deviations that occurred as a direct result of 
the COVID-19 pandemic were to be recorded in eSource as a protocol deviation for data 
capture purposes. A “direct result” is defined as being due to actual COVID-19 illness, or 
as a result of quarantine, social distancing, or site closures. All other deviations will 
follow the normal deviation process described in the protocol . Following approval of this 
addendum, the included revised procedures will not longer be classified as protocol 
deviations and therefore will not be documented within eSource as a protocol deviation 
for data capture purposes.
2.3
Guidance to Record Adverse Events and Discontinuations Due to 
COVID-19
If a subject tests positive OR is presumed positive with COVID-19, the subject may 
continue in the trial with virtual visits only as long as they remain asymptomatic for 
COVID-19. An adverse event (AE) of “Coronavirus Infection” OR “Coronavirus Positive
Test Result” must be recorded on the AE page of the electronic case report form (eCRF). 
All subjects who are symptomatic for COVID-19 must be reviewed with the medical 
monitor and approval must be received for the subject to continue in the trial with virtual 
visits. A positive test result or a presumed positive subject is not automatically a serious 
adverse event (SAE), unless an SAE criterion is met (eg, hospitalization). If the event 
meets the criterion for an SAE, then the subject will be discontinued from the trial.
If a subject discontinues due to COVID-19 either because they test positive OR are 
presumed positive with COVID-19, then the primary reason for discontinuation should be 
reported as “Adverse Event” and indicate the AE number in the “Specify the reason for 


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
127
Protocol 331-201-00079
21
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
discontinuation” space that corresponds with the AE of “Coronavirus Infection” OR 
“Coronavirus Positive Test Result.” Be sure to remember to enter an AE in the AE form 
for the “Coronavirus Infection” OR “Coronavirus Positive Test Result.”
If a subject discontinues due to COVID-19 other than the subject testing positive OR 
being presumed positive with COVID-19, then the primary reason for discontinuation
should be reported as “Other.” Be sure to specify the reason as “COVID-19” followed by 
the reason ensuring that the prefix of the description includes “COVID-19.” Do note that 
the reason “Other” should be selected even if the subject decides to withdraw consent or 
if the investigator decides to withdraw the subject due to COVID-19 concerns.
2.4
Statistical Analyses
Any impact of COVID-19 on the planned statistical analyses for the trial will be 
described in the final statistical analysis plan.
2.5
Clinical Outcomes
To decrease variability, sites should attempt to standardize the method of administration 
for a scale for an individual subject and across all subjects in the trial. Assessments 
should be administered by the same qualified/trained rater who rated the subject 
previously; if this is not possible due to staff availability and/or technological limitations, 
discuss relevant information with previous raters to obtain clinical context (note that per 
protocol raters must be trained/qualified to conduct assessments in all cases). Raters 
should conduct all assessments for that visit during the same remote session, where 
possible.
Please refer to “Virtual Visit Instructions for Sites” for modification of administration 
methods for remote visits.
3
Trial Population
3.1
Inclusion Criteria
The subject must provide electronic informed consent form (eICF) at screening and must 
be able to understand that he or she can withdraw from the trial at any time. All eICF
procedures must be in accordance with the trial site’s IRB/IEC and local regulatory 
requirements.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
128
Protocol 331-201-00079
22
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
3.2
Exclusion Criteria
Subjects will be excluded if experiencing COVID-19 infection or infection symptoms.
4
Trial Procedures
4.1
Safety Assessments
4.1.1
Pregnancy
Pregnancy tests will be performed as described in the protocol at the time points defined 
in this COVID-19 Addendum Schedule of Assessments (Table 1.2-1) with the following 
changes: 

For planned visits that require a pregnancy test for females of child bearing potential
(FOCBP), the site will provide the necessary tests and instructions so the test may be 
performed at home;

Applicable subjects will perform a pregnancy test prior to dosing with IMP, ensuring 
a date and time-stamped picture or video of the result is taken, followed by 
notification to the site staff of the results via telephone, or other means, on the 
appropriate visits. Subjects will also provide the site staff with the date- and time-
stamped picture/video.

If negative, site to inform the subject to proceed with dosing.

If positive, the site must instruct the subject to immediately stop taking IMP, and 
the site will refer to the Pregnancy section of the protocol for appropriate 
immediately reportable event reporting.

Further instruction must be agreed upon in consultation with the sponsor but 
an option may include the site informing the subject to continue to withhold 
IMP and to perform a repeat urine pregnancy test in 2 days (> 48 hours from 
first test). Subjects would again be asked to take a date and time-stamped 
picture or video of the result, followed by notification to the site staff of the 
results via telephone, or other means. Subjects would also provide the site 
staff with the date- and time-stamped picture/video.

If the second result is positive, the subject will be discontinued from the 
trial, and be instructed to contact their healthcare professional and the trial 
site (if possible) for further instructions.

If the second result is negative, the site will contact the CRO and sponsor 
for guidance and next steps.


Clinical Study Report 331-201-00079
16.1.1 Protocol and Protocol Amendments
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
129
Protocol 331-201-00079
23
Confidential - Proprietary Information
Issue Date: 16 Jul 2020
4.1.2
Extrapyramidal Symptom Scales
The subjects will be administered extrapyramidal symptom (ESP) assessments (AIMS 
and BARS) remotely by providing the subject verbal instructions and observing their 
movements over video. Any ESP assessments unable to be completed due to COVID-19 
restrictions should be documented accordingly in eSource.
5
Investigational Medicinal Product
Clinical sites are permitted to ship IMP directly to subjects per agreed study processes 
due to COVID-19 restrictions.

SAP_001.pdf: 
 
 
 
Otsuka Pharmaceutical 
Development & Commercialization, Inc. 
 
 
Investigational Medicinal Product 
 
Brexipiprazole 
 
 
 
 
Protocol 331-201-00079 
IND No. 103,958 
 
 
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the 
Efficacy, Safety, and Tolerability of Brexpiprazole as Adjunctive Therapy in the Maintenance 
Treatment of Adults with Major Depressive Disorder 
 
 
Statistical Analysis Plan 
 
 
 
Version 2.0 
(Prior to 1st Interim Analysis) 
 
Date: May 13, 2021 
 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc  
 
 


Protocol 331-201-00079 Statistical Analysis Plan  
Page 2 of 46 
Table of Contents 
Table of Contents .......................................................................................... 2 
 
List of In-text Figures ................................................................................... 5 
 
1 
Introduction .......................................................................................... 7 
2 
Trial Objectives .................................................................................... 7 
3 
Trial Design .......................................................................................... 7 
3.1 
Screening Phase ...................................................................................................7 
3.2 
Conversion/Prohibited Medication Washout (Phase A) .....................................7 
3.3 
Single-blind Stabilization (Phase B) ...................................................................8 
3.4 
Double-blind Maintenance (Phase C) .................................................................8 
3.5 
Follow-up ............................................................................................................9 
3.6 
Trial Population ...................................................................................................9 
3.7 
Interim Analysis Review Committee ................................................................10 
4 
Sample Size and Power Justification ............................................... 12 
5 
Statistical Method .............................................................................. 13 
5.1 
Data/Data Sets Specifications ...........................................................................13 
5.1.1 
Data Sets Analyzed .........................................................................................13 
5.1.2 
Definition of Baseline and Last Visit for Phase B and C ...............................14 
5.1.3 
Handling of Missing Data ...............................................................................14 
5.2 
Disposition of Subjects ......................................................................................15 
5.3 
Demographic and Baseline Characteristics .......................................................16 
5.4 
Protocol Deviations ...........................................................................................16 
5.5 
Efficacy Analysis ..............................................................................................16 
5.5.1 
Primary Efficacy Analysis ..............................................................................16 
5.5.2 
Sensitivity Analysis for the Primary Endpoint ...............................................19 
5.5.3 
Effect of COVID-19 on the Primary Endpoint ...............................................21 
5.5.4 
Secondary Efficacy Analysis ..........................................................................21 


Protocol 331-201-00079 Statistical Analysis Plan  
Page 3 of 46 
5.5.5 
Sub-group Efficacy Analysis ..........................................................................25 
5.5.6 
Exploratory Efficacy Analysis ........................................................................25 
5.6 
Safety Analysis ..................................................................................................25 
5.6.1 
Adverse Events ...............................................................................................26 
5.6.2 
Laboratory Test Results ..................................................................................26 
5.6.3 
Vital Signs Data ..............................................................................................27 
5.6.4 
ECG Data ........................................................................................................27 
5.6.5 
Physical Examination .....................................................................................28 
5.6.6 
Extent of Exposure .........................................................................................28 
5.6.7 
Other Safety Data Analysis ............................................................................29 
5.7 
Other Outcome Analysis ...................................................................................30 
 
 
5.8 
Pooling of small centers ....................................................................................30 
 
 
6 
References ........................................................................................... 32 
  
 




Protocol 331-201-00079 Statistical Analysis Plan  
Page 5 of 46 
List of In-text Figures 
Figure 3-1 
Trial Design Schematic ..................................................................11 


Protocol 331-201-00079 Statistical Analysis Plan  
Page 6 of 46 


Protocol 331-201-00079 Statistical Analysis Plan  
Page 7 of 46 
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 Trial 331-201-00079.  All amendments to the protocol are taken into consideration 
in developing this SAP. 
2 
Trial Objectives 
The primary objective of this trial is to compare the efficacy of brexpiprazole (2 to 3 mg/day) to 
placebo as adjunctive therapy to antidepressant therapy (ADT) for the maintenance treatment in 
adults with major depressive disorder (MDD).  The secondary objective of this trial is to evaluate 
the safety and tolerability of brexpiprazole (2 to 3 mg/day) as adjunctive therapy to ADT in the 
proposed subject population with MDD. 
3 
Trial Design 
This is a randomized, double-blind, placebo-controlled trial consisting of a screening phase and 
three treatment phases.  The trial design Schematic is shown in Figure 3-1.   
3.1 
Screening Phase 
Eligibility will be determined during screening and washout of prohibited medications will 
begin, if applicable.  The screening period will be 3 to 42 days.  After the screening procedures 
are completed, eligible subjects will enter Phase A, as appropriate based on the subject’s current 
antipsychotic treatment(s) and required washout of prohibited medication(s). 
3.2 
Conversion/Prohibited Medication Washout (Phase A) 
At Phase A baseline, all subjects must have either 2 or 3 documented inadequate responses to 
ADT in total for the current episode as defined by the Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire (ATRQ). Subjects will be enrolled into the 6- 
to 8-week, single-blind, Acute Treatment Phase (Phase A) if they meet the entrance criteria. The 
purpose of the Acute Treatment Phase is to identify subjects who respond to adjunctive 
brexpiprazole + protocol-specified ADT.  
Treatment will consist of single-blind brexpiprazole plus continuation of the ADT taken during 
the screening period. 
Subjects will attend weekly visits during the Acute Treatment Phase (Phase A) and will be 
evaluated at Weeks 6 to 8 to determine whether they meet response criteria, defined as: 


Protocol 331-201-00079 Statistical Analysis Plan  
Page 8 of 46 
• An improvement on the Montgomery Asberg Depression Rating Scale (MADRS) total 
score of ≥ 50% from Phase A baseline and 
• A Clinical Global Impression - Severity of Illness (CGI-S) score ≤ 3. 
 
Subjects not meeting the response criteria by the Week 8 visit will be discontinued from the trial. 
Note that all the criteria mentioned for Phase A (in this section), Phase B (Section 3.3), and C 
(Section 3.4) are blinded to the investigators. 
3.3 
Single-blind Stabilization (Phase B) 
The following subjects will enter Phase B and receive single-blind brexpiprazole + open-label 
ADT for 12 weeks: 
• Subjects who successfully complete Phase A 
• Subjects who meet response criteria at the end of Phase A. 
During Phase B, investigators will attempt to stabilize subjects on single-blind brexpiprazole for 
12 weeks.  Visits will occur weekly for; subjects will be assessed for stability at scheduled visits 
using the following criteria: 
• Subjects must show ≥ 50% improvement on the MADRS total score from Phase A 
baseline and a CGI-S score ≤ 3 for 12 consecutive weeks. 
• The dose of brexpiprazole + ADT must be stable for at least the last 4 weeks of Phase B. 
Subjects are allowed a maximum of 3 excursions from meeting the stabilization criteria during 
the 12-week period, as long as the excursions do not occur on 3 consecutive visits or on the last 
visit of Phase B. 
Subjects not meeting stability criteria will be discontinued from the trial. 
 
3.4 
Double-blind Maintenance (Phase C) 
Subjects eligible for the Double-blind Randomized Withdrawal Phase (Phase C) will be 
randomized 1:1 to double-blind treatment with brexpiprazole + ADT or placebo + ADT for up to 
26 weeks. During Phase C, subjects will be evaluated in the clinic at biweekly visits for the first 
2 visits and monthly visits thereafter. 
Time-to-relapse (primary efficacy endpoint) is defined as meeting any of the following criteria 
measured from randomization into Phase C: 
• At the same visit, an increase on the MADRS total score of 50% from randomization 
and CGI-S score ≥ 4, OR 
• Hospitalization for depression, OR 


Protocol 331-201-00079 Statistical Analysis Plan  
Page 9 of 46 
• Discontinuation for lack of efficacy or worsening of depression, OR 
• Active suicidality, defined as a score of  ≥ 4 on the MADRS item 10 OR an answer 
of “yes” on question 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) 
OR an answer of yes to any of the questions on the Suicidal Behavior section of the 
C-SSRS. 
 
Subjects meeting the criteria for relapse will be withdrawn due to lack of efficacy.  In addition, 
functional relapse is defined as a 30% increase in Sheehan Disability Scale (SDS) mean total 
score from Phase C baseline and at least one SDS sub-score at 4 or greater and a SDS total score 
great than or equal to 7 when all 3 sub-scores are available (or SDS total score greater than or 
equal to 5 when work/school item does not apply) at a Phase C visit.  In the event that the SDS 
phase C baseline is 0, the evaluation will be based on the SDS total score and SDS sub-score.  
Time-to-functional relapse will be the earliest time in Phase C a subject met the above criteria.  If 
a visit is needed between scheduled visits in Phase C, it will be considered an unscheduled visit 
unless the subject meets criteria for relapse in which case the visit will be considered the end of 
trial visit and appropriate evaluations for Week 26/End of Phase C/Relapse should occur.   
3.5 
Follow-up 
Subjects who complete the 26-week double-blind treatment phase and those who are 
discontinued or withdrawn from any trial phase will be prescribed appropriate antipsychotic 
treatment as per the investigator or the subject’s psychiatrist or primary care physician and will 
be followed up for safety 21 (+ 2) days after the last dose of investigational medicinal product 
(IMP) via telephone contact or clinic visit at the investigator’s discretion. 
3.6 
Trial Population 
The trial population will include male and female outpatients between 18 and 65 years of age at 
the time of consent, inclusive, with a Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) diagnosis of recurrent MDD and a current major depressive episode 
confirmed by both the Mini International Neuropsychiatric Interview (MINI) and an adequate 
clinical psychiatric evaluation.  The current episode must be at least 8 weeks in duration. 
Subjects must meet all eligibility criteria (inclusion and exclusion criteria) specified in the 
protocol. 
The sponsor reserves the right to utilize external quality oversight methods to ensure the validity 
of diagnosis, severity of illness, and other factors determining appropriateness of subject 
selection. 


Protocol 331-201-00079 Statistical Analysis Plan  
Page 10 of 46 
It is anticipated that approximately 1450 subjects will be enrolled into Phase A in order to enroll 
approximately 700 in Phase B and randomize 450 subjects in Phase C  
3.7 
Interim Analysis Review Committee 
The Interim Analysis Review committee (IARC) is formed to independently review unblinded 
efficacy data for the planned interim analyses (at approximately 50% and 75% of protocol event 
accrual) and make recommendations to the sponsor.  Details are described in the IARC Charter 
for the Protocol.   
 




Protocol 331-201-00079 Statistical Analysis Plan 
Page 12 of 46 
4 
Sample Size and Power Justification 
The primary objective of this trial is to show superiority of brexpiprazole (2 to 3 mg/day) 
+ ADT over placebo + ADT in time to relapse of MDD signs and/or symptoms. The 2-
sided log-rank test will be used to test for statistical significance of the differences 
between the 2 survival curves.   
Based on the results from a completed randomized withdrawal trial of 
olanzapine/fluoxetine combination versus fluoxetine monotherapy to assess prevention of 
relapse in subjects with treatment-resistant depression, it is reasonable to expect that 30% 
of subjects who receive placebo and 16% of subjects treated with brexpiprazole will 
relapse in 6 months, a hazard ratio of 0.49 (brexpiprazole + ADT versus placebo + ADT) 
is derived.  Thus, 104 relapse events are needed in this trial to reach 95% power to test 
the primary hypothesis of the protocol at a 2-sided 0.05 alpha level. The sample size 
estimates used a 1:1 randomization ratio (brexpiprazole + ADT:  placebo + ADT) which 
allowed 2 interim looks at 50% and 75% of events accrual time points.  The O’Brian-
Fleming boundaries were used for sample size calculation of the interim analysis so that 
the first interim analysis will be conducted when 52 relapse events are available, and the 
second interim analysis will be conducted when 78 relapse events are available.  The 
2-sided alpha levels for these 2 interim analyses are 0.003 and 0.018 respectively, and the 
alpha left for the final analysis when 104 relapse events are available will be 0.044.  
Each subject will be followed for 26 weeks after randomization; allowing for a 20% loss 
to follow-up, the projected total number of subjects to be randomized into the trial is 450.  
Using a 1:1 randomization ratio, the number of subjects to be randomized into each 
treatment group is 225.  Assuming approximately 68% of subjects will progress from the 
Stabilization Phase (Phase B) to Double-blind Randomized Withdrawal (Phase C), it is 
expected that 700 subjects will be enrolled into the Stabilization Phase of the trial to 
allow 450 subjects to be randomized.  Assuming approximately 55% subjects will 
progress from the Acute Treatment Phase to the Stabilization Phase, it is expected that 
approximately 1450 subjects will be enrolled into the Acute Treatment Phase.  However, 
only the number of relapse events (i.e., 104 events) is the determinate factor for sample 
size of this protocol.  The other estimates, such as number of randomized subjects and 
number of subjects entering the Acute Treatment Phase and the Stabilization Phase, are 
only based on projection using assumptions that may or may not hold in this trial.  
Therefore, the actual number of subjects enrolled into the Acute Treatment Phase, the 
Stabilization Phase, or Double-blind Randomized Withdrawal Phase may vary from the 
projected values in order to reach the targeted 104 events. 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 13 of 46 
5 
Statistical Method 
5.1 
Data/Data Sets Specifications 
5.1.1 
Data Sets Analyzed 
The following analysis samples are defined for this trial: 
• Enrolled Sample: All subjects who sign the informed consents form for the trial 
and enter Phase A or Phase B. 
• Phase A Safety Sample: All subjects who receive at least one dose of 
brexpiprazole in Phase A. 
• Phase B Safety Sample: All subjects who receive at least one dose of 
brexpiprazole in Phase B. 
• Phase B Efficacy Sample: All subjects who enter Phase B (i.e., receive at least 
one dose of brexpiprazole in Phase B) and have at least one post-baseline efficacy 
evaluation in Phase B. 
• Phase C Safety Sample: All subjects who are randomized to double-blind 
treatment and receive at least one dose of double-blind trial medication in 
Phase C. 
• Phase C Efficacy Sample: Based on the Intent-to-Treat (ITT) principle, the full 
analysis set of this trial will be composed of all subjects randomized to the 
double-blind treatment who take at least one dose of IMP in Phase C. 
 
For the primary analysis of time to event, all subjects belonging to the Phase C Efficacy 
Sample will be included in the analysis.  Subjects who withdraw early from the trial or 
who are still in the trial at the end of Week 46 will be considered as censoring 
observations. 
The observed case (OC) dataset will consist of the actual observations recorded at each 
visit and will be used to present summaries per trial week. 
The last observation carried forward (LOCF) data set for Phase C will include data 
recorded at a given Phase C visit or, if no observation is recorded at that visit, data 
carried forward from the previous Phase C visit.  Week 20 data (baseline of Phase C) will 
not be carried forward to impute missing values for the LOCF data set. 
LOCF and OC data sets for Phases A and B will be derived in a manner similar to the 
process described for Phase C.  Baseline of Phase A will not be carried forward to impute 
missing values for the LOCF in Phase B. 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 14 of 46 
5.1.2 
Definition of Baseline and Last Visit for Phase B and C 
For analysis purpose, Baseline for Phase A is used as the Phase B baseline.  Last visit in 
Phase B is defined as the last visit with available data prior to randomization, or 
on/before early termination in Phase B.  Baseline for the Double-blind Randomized 
Withdrawal Phase (Phase C) is Week 20, which is the last visit of the Stabilization Phase 
prior to the first dose of double-blind IMP in the Double-blind Randomized Withdrawal 
Phased. If an assessment is missing at Week 20 for a specific measurement, the last none 
missing value at the Stabilization Phase will be used as the baseline for that assessment; 
for SDS, the earliest assessment used as phase C baseline cannot be less than Week 14 
due to SDS was not accessed weekly.  Last visit in Phase C is defined as the last visit 
with available data at the completion or on/before early termination for the randomized 
subjects.  These are applicable to all efficacy analysis, safety analysis and other outcome 
analysis. 
5.1.3 
Handling of Missing Data 
For missing data resulting from early withdrawal from the trial in Phase C, subjects who 
withdraw early will be censored in the primary efficacy analysis at the time when they 
withdraw from the trial.  For other efficacy variables, two types of analyses will be 
performed for analyses by visit in Phases B and C:  LOCF and OC.  The LOCF and OC 
data sets are defined in Section 5.1.1.  The OC data set will be used for analyses at each 
trial visit and the LOCF data set will be used for analyses at the last visit. 
The definitions of weeks for Phase A, B and C are described in the following Table 5.1.3-
1 and Table 5.1.3-2.  Trial Days are derived for each phase from the formula: Trial Day = 
Date of assessment - Date of 1st brexpiprazole dosing + 1 in Phase A or B, or Date of 
randomization in Phase C.  Based on the number of trial days, subjects are mapped to the 
corresponding week in each phase in the summary tables.  Only last observation within 
the same week in each phase is used for the summary tables.  The LOCF/OC datasets for 
Phase A consist of data values obtained from visits at Phase A baseline, and week 1 
through week 8 in Phase A.  The LOCF/OC datasets for Phase B consist of data values 
obtained from week 1 through week 12 in Phase B and Phase A baseline as the baseline.  
The LOCF/OC datasets for Phase C consist of data values obtained from visits (after 
randomization) from week 2 through week 26 in Phase C (study Week 21 – Week 46). 
Note: NA = Not Applicable. 
 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 15 of 46 
5.2 
Disposition of Subjects 
Disposition of subjects for the enrolled sample will be summarized for each phase, while 
randomized subjects in Phase C (Phase C efficacy sample) will be summarized by 
treatment group.  Completion rate and reason for discontinuation will be tabulated for the 
enrolled sample in each phase and for randomized subjects by treatment group in 
Phase C.  Subjects who complete Week 46 of Phase C visit are defined as the completers.  
Subjects who meet the stability criteria (as specified in Section 3.3) for the consecutive 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 16 of 46 
12 weeks in Phase B will be summarized for the enrolled sample and randomized sample 
by week in Phase B. 
5.3 
Demographic and Baseline Characteristics 
Baseline and demographic characteristics will be summarized using descriptive statistics 
(frequency, mean, median, standard deviation (SD), maximum, minimum, and percentage 
when applicable).  These characteristics include age, race, ethnicity, gender, weight, 
height, body mass index (BMI), and waist circumference will be tabulated for the 
enrolled sample by phase and for the randomized subjects by treatment group.  Baseline 
disease severity including baseline , MADRS, Clinical Global Impression - Severity of 
Illness scale (CGI-S) score, SDS, will be summarized for the enrolled sample in each 
phase and for the randomized subjects by treatment group. Baseline total 17-item 
Hamilton Depression Rating Scale (HAM-D17) will be summarized for enrolled sample.  
In addition, age at first diagnosis of MDD will be summarized.  If both month and date 
are missing for the first diagnosis date, June 30 is used in calculating age at first 
diagnosis of MDD.  If only date is missing for first diagnosis date, date 15 is used.  If 
only month is missing for first diagnosis date, June is used as the month.  If year of first 
diagnosis date is missing, age at first diagnosis of MDD is missing. 
Disease severity and psychiatric history at Phase C baseline (or at screening) will also be 
summarized by descriptive statistics for the Safety Sample to identify any potential lack 
of balance between the treatment groups for the Phase C efficacy sample. 
5.4 
Protocol Deviations 
Protocol deviations will be summarized by center and type of deviation for randomized 
subjects by treatment group. A listing of protocol deviations will be provided. 
5.5 
Efficacy Analysis 
5.5.1 
Primary Efficacy Analysis 
5.5.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this trial is time-to-relapse by any criteria as defined in 
the blinded addendum to this protocol, measured from Week 20 (randomization) to the 
Double-blind, Randomized Withdrawal Treatment Phase).   
Time-to-relapse (primary efficacy endpoint) is defined as meeting any of the following 
criteria (blinded to investigators) measured from randomization into Phase C: 
I. 
At the same visit, an increase on the MADRS total score of 50% from 
randomization and CGI-S score ≥ 4, OR 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 17 of 46 
II. 
Hospitalization for depression, OR 
III. 
Discontinuation for lack of efficacy or worsening of depression, OR 
IV. 
Active suicidality, defined as a score of  ≥ 4 on the MADRS item 10 OR an 
answer of “yes” on question 4 or 5 on the C-SSRS OR an answer of yes to any of 
the questions on the Suicidal Behavior section of the C-SSRS. 
 
The time origin for measuring this event time is the date of randomization into the 
double-blind, placebo-controlled treatment phase (Phase C).  Phase C Efficacy Sample is 
used in the primary analysis of the primary efficacy endpoint.  The primary objective of 
statistical analysis is to compare the efficacy of brexpiprazole (2 to 3 mg/day) + ADT 
with that of placebo + ADT with regard to time-to-relapse.  This will be achieved by 
testing the equality of the two survival curves by the log-rank test.   
Interim analyses are planned to be performed at approximately 50% and 75% of events 
accrual time points using the O’Brian-Fleming boundaries for rejection of the null 
hypothesis. Details of the interim analyses are provided in the interim analysis plan. 
A group sequential testing procedure will be employed with two planned interim analyses 
at approximately 50% (52 events) and 75% (78 events) events accrual time points, and a 
final analysis using 100% (approx. 104 events) events.  The O’Brian-Fleming boundaries 
will be utilized in this analysis for the rejection of the null hypothesis to maintain an 
overall nominal significance level of 0.05 (two-sided).  
 
 
While the interim analysis follows the boundaries listed in Table 5.5.1.1-1, “final” 
analysis must be performed after a recommendation based on the interim analysis.  This 
“final” analysis will include the relapse events that occur between the data cutoff for the 
interim analysis and the final database lock, and the alpha level for the “final” analysis 
will be derived based on the total number of events using O’Brien-Fleming spending 
function.  Should the interim analysis be performed at a different time, different 
frequency, the spending function approach as originally introduced by Lan and DeMets 
will be applied to adjust the critical values to guarantee an overall 0.05 alpha level. The 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 18 of 46 
spending functions corresponding to O'Brien-Fleming boundaries will be formally 
applied to the time-to-event analysis (using the log-rank test). 
For the primary endpoint, a 95% confidence interval for the hazard ratio (brexpiprazole 
(2 to 3 mg/day) + ADT with that of placebo + ADT) will be provided using the Cox 
Proportional Hazard model with treatment as the fixed effect in the model. 
The Phase C Efficacy Sample will be used in the above analysis.  Subjects who withdraw 
early from the trial without relapse events or who are still in the trial at the end of the 
Week 46 will be considered as censored observations at the discontinuation or 
completion date.  If the time to event of the subject or completion date is greater than 196 
days from randomization, then the subject will be censored at 196 days from 
randomization with no event. Subjects who stay in the trial but have no relapses in an 
interim analysis will be censored at the date of data cut-off for the interim analysis. 
5.5.1.2 
Technical Computational Details for Primary Efficacy Analysis 
Subjects who meet relapse criteria are considered as an event of relapse.  For relapsed 
subjects in Phase C, time to event is calculated as the earliest date of time-to-relapse, 
defined as the time meeting relapse criteria - randomized date + 1.  Below are the criteria 
to determine the relapse time for each relapse criteria: 
1). If subjects meet the relapse criteria per MADRS and CGI-S assessments of 
criteria I, which are conducted on different dates, the later assessment date 
will be used as the relapse event date.   
2). If subjects meet the relapse criteria per criteria IV, C-SSRS or MADRS, the 
earliest date of the evaluation that the criteria are met will be used as the 
relapse event date.   
3). If subjects meet the relapse criteria per hospitalization due to worsening of 
depression and are reported as an adverse event (AE), the AE start date will be 
used as the relapse event date.   
4). If subjects meet the relapse criteria per lack of efficacy or worsening of 
depression but are not reported as an AE, the first two criteria stated prior will 
be checked.  The earliest date that criteria 1) or 2) is met will be the relapse 
event date.  If none of the above is applicable, then the discontinuation date 
will be the relapse data.  
Subjects who complete the double-blind treatment period of 26 weeks or discontinue 
treatment without meeting the relapse criteria (including those who are lost to follow-up 
during treatment period) in Phase C will be considered as censored observations as 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 19 of 46 
mentioned above.  For the withdrawn (rather than lack of efficacy) subjects in Phase C, 
they are considered as censoring at discontinuation, i.e., time to censor = discontinuation 
date - randomization date + 1.  For the completed subjects, they are considered as 
censoring at the completion, i.e., time to censor = completion date - randomized date + 1.  
If the time to event/censor is great than 196 days, the subject, no matter discontinued or 
completed Phase C, will be considered as censoring at Day 196. 
The log-rank test will be used to test the equality of the two survival curves.  
Additionally, a nominal 95% confidence interval for the hazard ratio (brexpiprazole vs. 
placebo) will be provided using the Cox Proportional Hazard model with terms for 
treatment in the model.  Ties in the event times will be handled by using the exact option 
in SAS PROC PHREG. 
5.5.2 
Sensitivity Analysis for the Primary Endpoint 
In order to assess the effect of potential informative censoring prior to the scheduled 26 
weeks of treatment in Phase C, two approaches of sensitivity analysis will be adopted to 
estimates this effect on the primary efficacy analysis results.  These are: (1) multiple 
imputation of discontinued censored observations using the estimated hazard rate from 
the placebo group, (2) treating 20% of randomly selected discontinued patients only from 
the brexpiprazole group as events.  These methods of sensitivity analyses are described 
below.  Subjects who discontinued in Phase C because of trial termination by the sponsor 
will not be imputed in the final analysis.  
5.5.2.1 
Multiple Imputation Method 
Assume that the time to event variable follows an exponential distribution.  The 
following multiple imputation method will be used to impute time to event from their 
time of discontinuation for censored subjects in the sensitivity analysis. 
For a placebo + ADT subject, assume the hazard of the subject to develop an event is 
identical to the estimated hazard of the placebo + ADT group (hazard estimated at 
interim analysis for sensitivity analysis of the interim analysis and hazard estimated in the 
final analysis for sensitivity analysis of the final analysis).  Event time will be simulated 
for the subject using an exponential distribution with the rate parameter (λ) equal to the 
estimated hazard of the placebo group. This same rate is used to simulate Event time of 
all dropout subjects from both brexpiprazole and placebo treatment groups; except that 
the placebo group will use the rate without modification and the brexpiprazole group will 
use the rate multiply by a factor equal to or greater than 1.  The time to event of the 
subject is equal to the sum of the time to discontinuation and the simulated event time of 
the subject.  If the time to event of the subject is greater than 196 days from 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 20 of 46 
randomization, then the subject will be censoring at 196 days from randomization with no 
event.  Otherwise, the subject will have an event at the time to event as calculated above. 
For a brexpiprazole + ADT treated subject, the imputation of time to event or time to 
censor (if the simulated event is greater than 196 days) is similar to the imputation of 
placebo treated subject, except that the exponential distribution will have a rate parameter 
equal to k* λ, where λ is the hazard rate of the placebo group and k ≥1. 
For each imputation, the simulated data will be combined with the data for subjects who 
complete the double-blind treatment period of 6 months without an event and subjects 
with events, to obtain the log-rank test and in the time to event analysis using Cox 
Proportional Hazard model with treatment as the independent variable.  For each k, 30 
imputations will be performed.  The results of these thirty imputations will be combined 
using SAS PROC MIANALYZE to provide a final result for this k.  The k will run from 
1.0 to 1.1, 1.2, …, until the test loses its significance. 
5.5.2.2 
Discontinuations as Events for Brexpiprazole Group 
The second sensitivity analysis will be conducted by considering 20% randomly selected 
discontinued subjects (other than subjects discontinued because of study termination by 
the sponsor) in Phase C on Brexpiprazole treatment without meeting the relapse criteria 
as having the relapse at one day after the discontinuation date.  Then the Cox 
Proportional Hazard model with treatment as the fixed effect will be generated. 
For relapsed subjects in Phase C, time to event will be calculated as the date of meeting 
criteria - randomized date + 1.  For the 20% selected discontinued subjects in the 
brexpiprazole treatment group without meeting the relapse criteria in Phase C, time to 
event will be calculated as the date of discontinuation - randomized date + 2.  For the 
other 80% discontinued subjects on brexpiprazole treatment group without meeting 
relapse criteria in Phase C and all discontinued subjects on placebo treatment group 
without meeting relapse criteria in Phase C, they will be considered as censored 
observations at the discontinuation date.  Time to censoring will be calculated as the date 
of discontinuation - randomized date + 1.  Subjects who complete the double-blind 
treatment period of 6 months in Phase C will be considered as censoring observations.  
Time to censoring will be calculated as completion date - randomization date + 1.  In 
total, 30 imputations will be made for this sensitivity analysis.  Again, SAS PROC 
MIANALYZE will be used to combine the results of these 30 imputations to provide a 
final result. 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 21 of 46 
5.5.3 
Effect of COVID-19 on the Primary Endpoint 
In earlier 2020, an outbreak of respiratory disease caused by a novel coronavirus named 
“Coronavirus Disease 2019” (COVID-19) had widely spread all over the world. On March 
13, 2020, the President of the United States declared a national emergency in response to 
COVID-19. It is after this date, centers enrolled in this study had implemented remote visits 
in response to this pandemic.  In order to assess the effects of this change on the primary 
efficacy endpoint, subgroup analysis is planned to assess the effect of COVID-19 on the 
primary analysis. 
The COVID subgroup is defined for subjects enrolled in Phase C and classified according 
to the following criteria: all subjects randomized into Phase C after March 13th will start 
the remote access or remote changes for their visits and will be classified as 
COVID=Yes; subjects randomized on or before March 13th 2020 will have COVID=No.  
The COVID-19 related changes will include but not limit to remote visit, missed 
visit  (especially for efficacy assessments), missed assessment, discontinuation due to 
COVID-19. 
A Cox Proportional Hazard model with treatment as the fixed effect will be fitted by each 
of the two COVID subgroups. Subjects who are randomized on or before March 13th , 
2020 will be censoring on March 13th 2020 or the last in-person visit whichever is first.  
This way the analysis for the COVID=No subgroup will estimate the hazard ratio of the 
two treatment groups without any impact from the COVID.  The within subgroup p-value 
from the log-rank test from the treatment comparison will be provided for each subgroup, 
together with the hazard ratios and their 95% confidence intervals using the Cox 
Proportional Hazard model with treatment as a fixed effect in the model.  A listing of all 
participants affected by the COVID-19 related study disruption/changes will be presented 
with a description of how the individual’s participation was altered.  
5.5.4 
Secondary Efficacy Analysis 
5.5.4.1 
Secondary Efficacy Analysis 
The secondary efficacy endpoints evaluated for Phase C will include: 
• Time-to-Functional relapse 
• Proportion of subjects meeting relapse criteria 
• Proportion of subjects maintaining remission 
• Change from baseline to endpoint in MADRS total score (LOCF) 
• Change from baseline to endpoint in CGI-S score (LOCF) 
• CGI-I score (LOCF) 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 22 of 46 
• Change from baseline in SDS mean total score and each of the SDS individual 
item scores (LOCF) 
 
5.5.4.2 
Analysis of Functional Relapse 
The secondary efficacy endpoint is time-to-functional relapse based on a 30% increase in 
Sheehan Disability Scale (SDS) mean total score from Phase C baseline and at least one 
SDS sub-score at 4 or greater and a SDS total score great than or equal to 7 when all 3 
sub-scores are available (or SDS total score greater than or equal to 5 when work/school 
item does not apply) at Phase C visits.  In the event that the SDS phase C baseline is 0, 
the evaluation will be based on the total SDS and SDS sub-score criteria at Phase C.  
Time to functional relapse will be the first SDS assessment in Phase C that met the 
functional relapse criteria.   
The Sheehan Disability Scale (SDS) is a self-rated instrument used to measure the effect 
of the patient’s symptoms on work/school, social life, and family/home responsibilities.  
For each of the three items, scores range from 0 through 10. The number most 
representative of how much each area was disrupted by symptoms is marked along the 
line from 0 = not at all, to 10 = extremely. For the work/school item, no response will be 
entered if the patient did not work or go to school for reasons unrelated to the disorder 
and a response therefore not being applicable. The Mean total SDS Score will be 
calculated over the three item scores. All three item scores need to be available with the 
exception of the work/school item score when this item is not applicable.  In the event 
that work/school item does not apply, the other two items will be averaged as the mean 
total score. 
Event/censer time will be defined as the following: if subjects meet the relapse criteria for 
functional relapse, the SDS assessment date during Phase C will be used as an event date; 
If the subject withdraw or discontinue study without meeting the functional relapse 
criteria, the withdraw/discontinuation date will be the censoring date.  For completed 
subjects, they are considered as censoring at the completion, i.e., time to censor = 
completion date - randomized date + 1.  If time to event/censor is great than 196 days, 
this subject no matter if he/she discontinued or completed for Phase C will be considered 
as censoring at Day 196.  At interim analysis, the interim analysis cut-off date will be 
used as the censor date.  Log-rank test will be used for the time-to-functional relapse 
comparisons similar to the primary efficacy analysis.   


Protocol 331-201-00079 Statistical Analysis Plan 
Page 23 of 46 
5.5.4.3 
Analysis of Other Secondary Efficacy Endpoints for Phase C 
Baseline for Phase C is defined as the last visit of Phase B prior to the first dose of 
double-blind trial medication in Phase C.  Analysis of the change from baseline for other 
secondary efficacy endpoints will be based on subjects in the Phase C Efficacy Sample.  
Analysis of the CGI-S score endpoint will be based on subjects in the Phase C Efficacy 
Sample who have post-baseline CGI-S observations.  The analysis will be based on all 
subjects who have been randomized and taken one dose of IMP in Phase C. 
The proportion of subjects meeting relapse criteria as defined in Primary Efficacy 
Endpoint Section 5.5.1.1 will be analyzed by treatment group, visit (OC) and the 
subject’s last visit (LOCF) in Phase C using the Chi-square test.   
Subjects maintaining remission is defined as MADRS total score ≤ 10. Analysis will be 
done at each visit (OC) and the final visit (LOCF) using Chis-square test. 
The MADRS, CGI-S score and individual SDS score at endpoint will be analyzed at the 
last visit (LOCF) using an ANCOVA model.  As an exploratory analysis, change from 
baseline variables including MADRS, CGI-S, and SDS will be analyzed by a Mixed 
Model Repeated Measures (MMRM) approach using observed data, with terms of 
treatment, trial center, visit, treatment-by-visit interaction, baseline and baseline-by-visit 
interaction.  To avoid too many parameters in the statistical model, variance-covariance 
matrix with heterogeneous compound symmetry structure is assumed in the MMRM 
analysis.  In addition, the count and frequency of SDS with work/school item not 
applicable at baseline will be summarized.  
The CGI-I score at endpoint will be analyzed at the last visit of LOCF data using the 
Cochran-Mantel-Haenszel method based on raw mean score statistics. 
Kaplan-Meier curves will be plotted for time to discontinuation due to all causes and the 
log-rank test will be used to test the differences in the survival curves. 
5.5.4.3.1 
Analysis of Other Secondary Efficacy Endpoints for Phase B 
and Phase A 
Descriptive statistics will be provided by visit for change from baseline to End of Phase 
B in MADRS Total Score, CGI-S, SDS scores; analysis will be provided by visit in Phase 
B.  These analyses will be based on OC data at each Phase B visit and the LOCF data at 
the last visit of Phase B, using Phase B Efficacy Sample.  Baseline for Phase B will be 
the same as the baseline for Phase A for all above efficacy endpoint.  Time to 
discontinuation due to all causes will also be examined in Phase B starting from the first 
dose of study medication taken in Phase B to discontinuation or completion. 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 24 of 46 
Efficacy scales assessed during Phase A will be provided in listings for the Phase A 
Safety Sample. 
5.5.4.3.2 
Technical Computational Details for Other Secondary 
Efficacy Analysis 
1) In general, data for MADRS, CGI-S, and SDS assessment after the relapsed dates 
for the relapsed randomized subjects will not be included in the Phase C efficacy 
summary tables.  
2) Time to discontinuations due to all causes rather than the sponsor discontinued 
trial will be measured from the date of randomization to date of early termination 
for withdrawn subjects in Phase C, i.e., time to discontinuation = discontinuation 
date - randomization date +1.  Subjects discontinuing the trial due to the sponsor 
discontinued trial in Phase C will yield censoring observations for time to 
discontinuation and be considered censoring at discontinuation, i.e., time to 
censor= discontinuation date - randomization date +1.  Subjects completing the 
entire treatment duration of Phase C will yield censoring observations for time to 
discontinuation and be considered censoring at completion, i.e., time to censor= 
completion date - randomization date +1.  If time to discontinuation/completion is 
great than 196 days, the subject will be considered as censoring at Day 196, no 
matter if he/she discontinued or completed Phase C. 
Time to discontinuation due to all causes rather than the sponsor discontinued trial 
in Phase B will be calculated for Phase B efficacy sample using the similar 
method.  Time to discontinuations due to all causes rather than the sponsor 
discontinued trial in Phase B will be measured from the 1st dosing date of Phase 
B to date of early termination for withdrawn subjects in Phase B, i.e., time to 
discontinuation in Phase B = discontinuation date - 1st IMP dosing date of 
Phase B +1.  Subjects discontinuing the trial due to the sponsor discontinued trial 
in Phase B will yield censoring observations for time to discontinuation and be 
considered censoring at discontinuation, i.e., time to censor= discontinuation date 
- 1st IMP dosing date of Phase B +1.  Subjects continuing into Phase C will yield 
censoring observations at randomization date, i.e., time to censor in Phase B = 
randomization date - 1st IMP dosing date of Phase B +1.  If time to 
discontinuation/censor is great than 98 days, this subject will be considered as 
censoring at day 98 no matter if she/he is randomized into Phase C. 
3) Computing of Scale Scores 
a) The CGI-S and CGI-I of 0 will be set to missing because value means ‘not 
assessed’.   
 
The MADRS consists of 10 items, all rated on a scale of 0 to 6 with 0 being the 
“best” rating and 6 being the “worst” rating. The MADRS Total Score is the sum of 
ratings for all 10 items. The MADRS Total Score will be un-evaluable if more than 2 
items are missing. If 8 or 9 of the 10 items are recorded, the MADRS Total Score will be 
the mean of the recorded items multiplied by 10 rounded to the first decimal place.  


Protocol 331-201-00079 Statistical Analysis Plan 
Page 25 of 46 
The CGI consists of two scales: CGI Severity (CGI-S), and CGI Improvement (CGI-I). 
CGI-S items are: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill;  3 
= mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most 
extremely ill patients. The score 0 (= not assessed) will be set to missing. The CGI-S is 
therefore a 7-point scale from 1 through 7. 
 
5.5.5 
Sub-group Efficacy Analysis  
Sub-group analysis of the primary endpoint in Phase C will be provided by region (US 
and non-US), gender (male and female), race (Caucasian and non-Caucasian), and age 
(<45 years old and ≥45 years old at Phase C baseline).  Subgroup analyses will be 
performed for the FAS. To explore the beneficial effects of brexpiprazole vs placebo in 
the subgroups, the estimated hazard ratio, two-sided nominal 95% confidence interval, 
and within subgroup p-value from the log-rank test will be provided for each of the 
subgroups based on the Cox’s proportional hazards model in which treatment is included 
as the fixed-effect factor.  It should be aware that positive findings from these subgroup 
analyses have to be interpreted with caution since there is a non-negligible chance of 
false positives.  
5.5.6 
Exploratory Efficacy Analysis 
The number and percentage of subjects meeting the below the specified criteria  are 
summarized by visit: 
• Subjects responding to treatment during Phase A by visit as specified in Section 
3.2.  
• Subjects meeting stabilization criteria of MADRS and CGI-S at any point during 
Phase B Section 3.3. 
• Subjects achieving remission at any time point during Phase B. 
 
Subjects achieving remission in Phase B is defined as a MADRS total score ≤ 10. 
 
5.6 
Safety Analysis 
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
ECGs, body weight, waist circumference, and BMI.  In addition, data from the following 
safety scales will be evaluated:  Simpson-Angus Scale (SAS) Total Score, Abnormal 
Involuntary Movement Scale (AIMS) Total Score, Barnes Akathisia Rating Scale 
(BARS), and C-SSRS. 
In general, safety analysis will be summarized for Phase B safety sample and Phase C 
safety sample respectively.  Listing of safety variables for Phase A safety sample will be 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 26 of 46 
provided.  Baseline for Phase A safety sample will be used as the baseline for safety 
analysis in Phase B as well.  Baseline for Phase C safety sample is defined as the last visit 
with available data in Phase B prior to the first dose in Phase C. 
5.6.1 
Adverse Events 
All adverse events (AE) will be coded by MedDRA System Organ Class (SOC) and 
Preferred Term (PT).  A treatment-emergent AE (TEAE) is defined as an AE which starts 
after start of trial medication), or an AE continues from baseline of the specific phase and 
becomes serious, worsening, trial drug-related or results in death, discontinuation, 
interruption or reduction of trial medication during this phase.  The incidences of the 
following treatment-emergent adverse events (TEAEs) will be summarized by treatment 
groups: 
• TEAEs by severity 
• Potentially drug related TEAEs 
• TEAEs with an outcome of death 
• Serious TEAEs 
• Discontinuations due to TEAEs 
 
Listing and incidences of AEs above will be tabulated by treatment for Phase B safety 
sample and Phase C safety sample, respectively.  Deaths, SAEs, and AEs leading to 
discontinuation from trial will be listed by phase for the enrolled sample. 
5.6.2 
Laboratory Test Results 
Clinical laboratory tests include the routine clinical laboratory measurements, prolactin 
concentrations, coagulation parameters (PT, aPTT, and INR), HbA1c, cortisol, ACTH, 
and TSH as well as laboratory tests identified using prospectively defined criteria.  
Summary statistics for the clinical laboratory measurements at baseline and post-baseline 
visits, and summary statistics of changes from baseline to each visit will be presented by 
treatment group.  Incidence of treatment-emergent potentially clinically significant 
abnormal lab results will also be summarized by treatment groups.  Listings of potentially 
clinically significant abnormalities will also be provided.  Criteria of potentially clinically 
significant lab test abnormalities are provided in Appendix 1. 
According to FDA Guidance, laboratory measurements that signal the potential for 
drug-induced liver injury (DILI) will be reported.  An incidence table and a listing will be 
provided for subjects who meet one or combinations of following criteria:  
1) ALT or AST ≥ 3× upper limit of normal (ULN) or baseline value 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 27 of 46 
2) increase in bilirubin ≥ 2× ULN or baseline value 
 
If laboratory tests assessments are repeated for the same visit, the last repeated values are 
used for summary tables.  This is accomplished by sorting patient data by visit date and 
visit time (if applicable) within the same visit identification.  If the lab data are recorded 
as ranges (i.e., including < or > limit of quantification), these data are not included in the 
calculations for changes from baseline but included in the calculations for incidences. 
Listings and summary tables of clinical laboratory measurements will be presented for 
Phase B safety sample and Phase C safety sample respectively.  Potentially clinically 
significant laboratory abnormalities for Phase A safety sample will be provided by 
listings. 
5.6.3 
Vital Signs Data 
Vital signs include body temperature, heart rate, systolic blood pressure, and diastolic 
blood pressure.  In addition, body weight, waist circumference and body mass index 
(BMI) are measured.  Descriptive statistics will be provided by treatment group, for 
change from baseline in vital signs parameters.  Incidence of treatment-emergent 
potentially clinically significant vital sign results will also be summarized by treatment 
groups.  Listings of potentially clinically significant abnormalities will also be provided.  
Criteria for the potentially clinically significant vital sign abnormalities are provided in 
Appendix 2.   
If vital sign assessments are repeated for the same visit, the last repeat values will be used 
for production of mean change from baseline.  This is accomplished by sorting patient 
data by visit date and visit time (if applicable) within the same visit identification.   
Listings and summary tables of vital sign data will be presented for Phase B safety 
sample and Phase C safety sample.  Potentially clinically significant abnormalities in 
vital sign will be listed by subjects for Phase A safety sample. 
5.6.4 
ECG Data 
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 trial report: 
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett 
formula:  QTcB=QT/(RR)0.5 
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula:  QTcF=QT/(RR)0.33 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 28 of 46 
3) QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula:  QTcN=QT/(RR)0.37 
The potentially clinically significant ECG abnormalities will be listed by subject.  The 
incidences of abnormal ECGs of potential clinical significance will be tabulated.  
Descriptive statistics of change from baseline in heart rate and ECG intervals will be 
provided.  Criteria for potentially clinically significant ECG abnormalities are provided in 
Appendix 3.  The listings and summary tables of ECG abnormalities will be provided for 
Phase B safety sample and Phase C safety sample, and only the listings will be provided 
for Phase A safety sample. 
In summarizing the incidence of abnormalities, a patient must have had an evaluation that 
met abnormality criteria by the end of trial, i.e., last contact date.  Incidence rate is 
calculated as the number of patients having at least one abnormality within a trial period 
divided by the number of patients who are both exposed to the trial medication and have 
an on-treatment evaluation within that trial period. 
5.6.5 
Physical Examination 
Physical examination findings will be listed by subject for each trial phase. 
5.6.6 
Extent of Exposure 
5.6.6.1 
Extent of Exposure to Brexpiprazole and Placebo 
The start date of double-blind study therapy - brexpiprazole or placebo - will be the first 
day of double-blind dosing. The number and percentage of patients who receive 
brexpiprazole/placebo will be presented by phase, week, and  treatment group for the 
Safety Sample of  Phase C. This summary will be performed for Enrolled Sample for 
Phases A and B.  
The mean daily dosage will be summarized by visit and treatment group 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 for each treatment group 
the number of patients receiving double-blind study medication, and the mean and range 
of the mean daily dose for each week. 
5.6.6.2 
Extent of Exposure to ADT 
The number and percent of patients who receive an ADT in Phase C will be presented by 
visit, by ADT treatment group, and by double-blind treatment group for the Safety 
Sample. A similar summary will be prepared for Phase B. For each ADT, the mean daily 
dose will be calculated in the same way as for double-blind study medication. 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 29 of 46 
Summaries will be presented for ADT administered to patients in the ADT Sample 
during Phase A and Phase A+ Sample during Phase A+. 
In addition, the mean daily dosage of ADT will be summarized for the ADT Sample 
during Phase A and the Phase A+ Sample during Phase A+ by week and by ADT group 
using descriptive statistics. 
5.6.7 
Other Safety Data Analysis 
5.6.7.1 
Suicidality Data 
Suicidality monitored during the trial using the C-SSRS will be summarized as the 
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 tables of C-SSRS will be provided for Phase B safety sample and Phase C 
safety sample.  Suicidality is defined as report of at least one occurrence of any type of 
suicidal ideation or at least one occurrence of any type of suicidal behavior during 
assessment period (count each person only once). 
Treatment emergent suicidal behavior and ideation is summarized by four types: 
Emergence of suicidal ideation, Emergence of serious suicidal ideation, Worsening of 
suicidal ideation, Emergence of suicidal behavior.  
Emergence of suicidal behavior/ideation is defined as report of any type of suicidal 
behavior/ideation during treatment when there was no baseline suicidal behavior/ideation. 
Emergence of serious suicidal ideation is defined as observation of suicidal ideation 
severity rating of 4 or 5 during treatment when there was no baseline suicidal ideation.                              
Worsening of suicidal ideation is defined as a suicidal ideation severity rating that is 
more severe than it was at baseline.   
 
5.6.7.2 
EPS Rating scales 
5.6.7.2.1 
Analysis of EPS Rating Scales 
Descriptive statistics will be provided for change from baseline to end of phase in SAS, 
AIMS, and BARS scores for Phases B and C safety samples.  Results will be summarized 
by visit.  In addition, change from end of Phase B to end of Phase C in scores for the 
SAS, AIMS (total of the first 7 item scores), and BARS scales will be evaluated using 
ANCOVA with baseline value as covariate and treatment and center as factors.  OC data 
sets will be used in the analyses of these EPS scales.  In addition, analyses will be 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 30 of 46 
performed using the maximum (i.e. the worst) value observed during Phase C and the last 
visit data to determine the change from baseline score. The ANCOVA model for change 
at the last visit and for change to the maximum value will include the Phase C baseline, 
study center and treatment group. The same analyses will be performed on the AIMS 
individual item scores 8, 9, and 10. In addition, incidence of BARS Global Clinical 
Assessment of Akathisia during Phase B and C by severity category will be provided. 
Analyses of these EPS rating scales will be performed for the Safety Sample.  
5.6.7.2.2 
Technical Computational Details for EPS Rating Scales 
1)  The SAS total score is the sum of the rating scores for 10 items from the SAS 
panel in the CRF.  The SAS Total Score is un-evaluable if less than 8 of the 
10 items are recorded. 
If 8 or 9 of the 10 items are recorded, the Total SAS score is the mean of the 
recorded items multiplied by 10 and then rounded to the first decimal place. 
2) The AIMS movement rating score is the sum of the rating scores for facial and 
oral moments (i.e., item 1 - 4), extremity movements (i.e., item 5 - 6), and trunk 
movements (i.e., item 7).  The AIMS Total score is un-evaluable if less than 6 of 
the 7 items are recorded.  If 6 of the 7 items are recorded, the Total Score is the 
mean of the recorded items multiplied by 7 and then rounded to the first decimal 
place. 
3) The BARS score is based only on the item of Global Clinical Assessment of 
Akathisia. 
 
5.7 
Other Outcome Analysis 
 
 
 
 
 
 
 
 
 
5.8 
Pooling of small centers 
In models such as ANCOVA or MMRM with center included as fixed effect, small 
centers will be pooled. Small centers will be defined as centers that do not have at least 
one evaluable subject (evaluable with regard to the primary efficacy variable) in each 
treatment arm in Phase C. All small centers will be pooled to form “pseudo centers” for 
the purpose of analysis according to the following algorithm. Small centers will be 
ordered from the largest to the smallest based on the number of evaluable subjects (i.e., 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 31 of 46 
subjects who have a baseline value and at least one post-randomization value.  The 
process will start by pooling the largest of the small centers with the smallest of the small 
centers until a non-small center is formed.  This process will be repeated using the centers 
left out of the previous pass.  In case of ties in center size, the center with the smallest 
center code will be selected.  If any centers are left out at the end of this process, they 
will be pooled with the smallest pseudo centers, or if no pseudo centers exist, they will be 
pooled with the smallest non-small center. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 32 of 46 
6 
References 
E. Glimm, W. Maurer and F. Bretz Hierarchical testing of multiple endpoints in group-
sequential trials.   Statist. Med. 2010, 29 219—228. 
 




Protocol 331-201-00079 Statistical Analysis Plan 
Page 34 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 35 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 36 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 37 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 38 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 39 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 40 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 41 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 42 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 43 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 44 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 45 of 46 


Protocol 331-201-00079 Statistical Analysis Plan 
Page 46 of 46