Conditions: Schizophrenia
Keywords: Schizophrenia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 709
Healthy volunteers: no

Brief summary:
The primary objective of this study was to continue to provide aripiprazole intramuscular (IM) depot treatment (400 milligrams \[mg\] or 300 mg) to participants with schizophrenia completing the 52-week, open-label safety and tolerability Study 31-08-248. In addition, the secondary objective was to collect additional long-term safety data on aripiprazole IM depot treatment.

Detailed description:
This was an open-label study that enrolled participants with schizophrenia who had completed the 52-week, open-label safety and tolerability Study 31-08-248 and continued to provide aripiprazole IM depot treatment.

Participants received this treatment until aripiprazole IM Depot was commercially available in any dosage (including generic formulations) in the country where the study was being conducted or the commercial availability of aripiprazole IM Depot was terminated by the sponsor, or until the study completion date of 06 Dec 2018 was reached.

Eligible participants entered this study at the end of treatment visit (Week 52) of Study 31-08-248. Participants continued to receive aripiprazole IM depot every month (study months were every 4 weeks, which were defined as 28 \[-2/+10\] days) as a continuation of their previous monthly dose in Study 31-08-248.

Arms:
arm 1: Active treatment of monthly doses of aripiprazole IM depot (300 mg or 400 mg)

Interventions: intervention 1: Aripiprazole
Intervention descriptions: intervention 1: Aripiprazole IM depot - 300 mg or 400 mg

Protocol document:
Prot_001.pdf: 
Protocol 31-10-270 
Confidential - Proprietary Information 
Protocol number: 31-10-270
Document title:  An Open-Label, Multicenter, Rollover, Long-term 
Study of Aripiprazole Intramuscular Depot in Patients With 
Schizophrenia   
Version number: 4.0
Date of the document: 08 July 2015
NCT number:    NCT01129882 


Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Aripiprazole OPC-14597 
REVISED CLINICAL PROTOCOL
An Open-Label, Multicenter, Rollover, Long-term Study of Aripiprazole Intramuscular 
Depot in Patients with Schizophrenia
Protocol No. 31-10-270
IND No. 67,380
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Development &
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850
United States
Clinical Director/Medical Director
Phone: 
Fax: 
E-mail: 
Senior Manager, Clinical Management
 
Phone: 
Fax: 
E-mail: 
Manager, Clinical Management
Phone: 
Fax: 
E-mail: 
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PPD


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Immediately Reportable Event 
Covance Drug Safety Services
Phone:  
Fax:  
Issue Date:
30 Mar 2010
Date of Amendment 1: 
23 Nov 2010
Date of Amendment 2:
08 Apr 2013
Date of Amendment 3:
11 Apr 2013
Date of Amendment 4:  
08 Jul 2015
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Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical Development & 
Commercialization, Inc.
Name of Investigational Medicinal Product:  Aripiprazole (OPC-14597)
Protocol# 31-10-270
IND# 67,380
Protocol Title:
An Open-Label, Multicenter, Rollover, Long-term Study of Aripiprazole 
Intramuscular Depot in Patients with Schizophrenia
Clinical Phase/Trial 
Type:
3/Therapeutic use
Treatment Indication: 
Schizophrenia 
Objective(s):
The primary objective of this open-label study is to continue to provide 
aripiprazole intramuscular (IM) Depot treatment (400 mg or 300 mg) to 
subjects with schizophrenia completing the 52-week, open-label safety and 
tolerability Study 31-08-248 (hereafter referred to as Study 248).  Subjects
can receive this treatment until aripiprazole IM Depot is commercially 
available in any dosage (including generic formulation[s]) in the country that 
the study is being conducted or until the study end date of 31 Dec 2018 is 
reached.
The secondary objective is to collect long-term safety data on aripiprazole 
IM Depot in addition to what was collected in Study 248 (52-weeks).
Trial Design:
This is an open-label, multicenter rollover non-comparative trial designed to 
continue to provide aripiprazole IM Depot (400 mg or 300 mg) to adult 
subjects with schizophrenia who completed aripiprazole IM Depot treatment 
in Study 248.  The decision to enroll into the long-term open-label study will 
be a joint decision by the investigator and subject.  No subjects who 
discontinued or did not complete Study 248 are allowed to enroll in Study 
31-10-270 (hereafter referred to as Study 270).
Eligible subjects will enter this study directly after completing the End of
Treatment visit (Week 52) of Study 248.  The End of Treatment evaluations 
conducted at the last study visit for Study 248 will serve as the baseline 
evaluations for Study 270.  
Subjects in this study will continue to receive aripiprazole IM Depot every 
month (study months are every 4 weeks which is defined as 
28 [−2/+10] days) as a continuation of their previous monthly dose in 
Study 248.  The minimum interval of 26 days and maximum interval of 
38 days between injections is to ensure that therapeutic plasma concentrations 
of aripiprazole are maintained.  The monthly dose can be modified, either 
reduced from 400 mg to 300 mg to address tolerability or increased from 
300 mg to 400 mg to address efficacy, at the discretion of the investigator.
Following the baseline visit, subjects will receive monthly injections and at 
the same visit, adverse events (AEs) and concomitant medications will be 
recorded and the Columbia Suicide Severity Rating Scale (C-SSRS) will be 
completed.  
Every 3 months, all of the monthly assessments will be completed along with 
a urine pregnancy test for women of childbearing potential (WOCBP).  Every 
6 months, all of the 3-month assessments will be completed along with the 
Clinical Global Impression - Severity (CGI-S) scale, vital signs, and 
extrapyramidal symptoms (EPS) assessments (including the Abnormal 
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Involuntary Movement Scale [AIMS], Simpson-Angus Scale [SAS], and 
Barnes Akathisia Rating Scale [BARS]).  At the 12-month visit, all of the 
6-month assessments will be completed along with clinical laboratory tests 
and assessments of body weight, height, and waist circumference.  
Urine drug screening and blood alcohol testing will be obtained at baseline 
and can be re-obtained at the investigator’s discretion at any time during the 
study.  A Visual Analog Scale (VAS) for subject-reported rating of pain at 
the most recent injection site and the investigator’s assessment for pain, 
redness, induration, and swelling of the most recent injection site will be 
performed at baseline and may be reassessed at the discretion of the 
investigator.  Clinical laboratory tests, physical examination, and 
electrocardiogram (ECG) obtained at baseline may also be performed at the 
discretion of the investigator based on clinical necessity.  
A Study Completion visit or Early Termination visit (−2/+10 days) will 
include the following assessments: C-SSRS, AEs, concomitant medications, a 
urine pregnancy test for WOCBP, CGI-S, vital signs, EPS assessments 
(AIMS, BARS, SAS), clinical laboratory tests, and body height and weight.
A 30-Day Post Treatment Follow-up phone call will be made 30 days 
(3 days) after it has been determined that the subject will no longer 
participate in this study and will include questions about any AEs that have 
occurred and any concomitant medications taken since the last visit.
No oral antipsychotic rescue medication (including aripiprazole) is allowed in 
this study.  If a subject experiences an exacerbation of psychotic symptoms, 
the investigator should assess the suitability of the subject’s continuation in 
the study and ensure that the subject is treated appropriately.  If the 
investigator deems that other antipsychotic therapy is warranted, the subject
should be discontinued from this study.
Aripiprazole IM Depot treatment in this open-label rollover study will 
continue until there are clinical and/or administrative reasons for 
discontinuation of the subject’s study treatment or until the study end date of 
31 Dec 2018 is reached, whichever occurs first.  
Clinical reasons for discontinuing study treatment include, but are not limited 
to: the subject voluntarily withdrawing consent; the subject becoming lost to 
follow-up; if a subject misses 2 consecutive injections at any time in the 
study or if a subject misses 3 injections in a 52-week time period; or the 
investigator determines that the subject is no longer receiving benefit from 
aripiprazole IM Depot.  Administrative reasons for discontinuing study 
treatment include, but are not limited to: aripiprazole IM Depot becomes
commercially available in any dosage (including a generic formulation) in the 
country where the study is being conducted, the commercial availability of 
aripiprazole IM Depot is terminated by the sponsor, or until the study end 
date of 31 Dec 2018 is reached, whichever occurs first.  
Once aripiprazole IM Depot becomes commercially available in any dosage 
(including generic formulation[s]) in the country where the subject is 
participating in the study or the commercial availability of aripiprazole 
IM Depot is terminated by the sponsor, study treatment will be discontinued 
within approximately 6 weeks of the subject’s previous injection for clinical 
transition purposes.
If the sponsor terminates the study prior to 31 Dec 2018 for any reason other 
than commercial availability, investigators in some countries where the 
sponsor has limited or delayed commercialization plans, or where no 
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commercialization activity is anticipated, may be eligible to participate in a 
managed access program until aripiprazole IM Depot is commercially 
available in their country or until 31 Dec 2018.
Subject Population:
The subject population will be comprised of subjects who have completed 
Study 248 and in the investigator’s judgment may benefit from continued 
participation in an aripiprazole IM Depot study, in countries where 
aripiprazole IM Depot is not commercially available.
It is anticipated that approximately 500 to 800 subjects from Study 248 will 
enroll in this study.
Inclusion/Exclusion 
Criteria:
Subjects enrolling into Study 270 from Study 248 will have fulfilled the 
inclusion and exclusion criteria for Study 248.
A complete list and description of inclusion and exclusion criteria is provided 
in Section 3.4.
Key inclusion criteria for Study 270 include subjects with a current diagnosis 
of schizophrenia, (as defined by Diagnostic and Statistical Manual of Mental 
Disorders, Fourth Edition, Text Revision [DSM-IV-TR] criteria), who 
completed the open-label extension Study 248; subjects who, in the 
investigator’s judgment, may benefit from continued participation in 
aripiprazole IM Depot study; and subjects who have an outpatient status.  The 
baseline visit for Study 270 (which is the Week 52 visit of Study 248) and the 
first injection for Study 270 must occur within 4 weeks (which is defined as 
28 [−2/+10] days) of the last injection in Study 248.
Key exclusion criteria include subjects with a current DSM-IV-TR diagnosis 
other than schizophrenia, including schizoaffective disorder, major 
depressive disorder, bipolar disorder, delirium, dementia, amnestic or other 
cognitive disorders; subjects who are known to be allergic, intolerant, or 
unresponsive to prior treatment with aripiprazole or other  quinolinones; 
dependence on substances of abuse; a history of violent behavior, seizures, 
neuroleptic malignant syndrome, clinically significant tardive dyskinesia, or 
other medical condition that would expose the subject to undue risk or 
interfere with study assessments; involuntary incarceration; electroconvulsive 
therapy within 180 days prior to entry; clinically significant abnormalities in 
laboratory test results, vital signs, or ECG results; require hospitalization; 
may require any other antipsychotic medication, varenicline, cytochrome 
P450 (CYP) 2D6 or CYP3A4 inhibitors, or CYP3A4 inducers during the 
study; and if aripiprazole IM Depot (including generic formulation) is 
commercially available in the country where the study is being conducted.
Trial Site(s):
Approximately 250 sites globally (the number of sites globally in Study 248).  
New sites will not be used.
Investigational Medicinal 
Product(s), Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of Administration:
The investigational products will be aripiprazole IM Depot 400 mg supplied 
as lyophilized vials.  Both doses of aripiprazole IM Depot used in this trial 
(400 mg and 300 mg) will be obtained from the 400-mg lyophilized vials.  
IM Depot will be administered every month (study months are every 4 weeks 
which is defined as 28 [−2/+10] days).  All doses of IM Depot must be 
injected into the gluteal muscle, and care must be taken to avoid inadvertent 
injection into a blood vessel.
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Trial Assessments:
Safety:  Safety will be assessed by adverse event and concomitant 
medication reporting at baseline (post-IM administration) and at each 
subsequent monthly injection visit (study months are every 4 weeks which is 
defined as 28 [−2/+10] days).  The C-SSRS will be used to assess suicidality 
at baseline and at each subsequent monthly injection visit.  Extrapyramidal 
symptoms will be assessed using the AIMS, SAS, and BARS assessment 
questionnaires at baseline, every 6 months, at the discretion of the 
investigator at any subsequent visit, and at Study Completion or the 
Early Termination visit.  Clinical laboratory tests will be performed at 
baseline, every 12 months, and at Study Completion or the Early Termination
visit.  Vital signs will be assessed every 6 months and at Study Completion or 
the Early Termination visit.  Body height and weight, body mass index 
(BMI), and waist circumference will be assessed at baseline; body height, 
weight, and waist circumference will be reassessed every 12 months; and 
body height and weight will be assessed at Study Completion or the 
Early Termination visit.  For WOCBP, a urine pregnancy test will be 
administered at baseline, every 3 months, and at Study Completion or the 
Early Termination visit. 
Efficacy:  Efficacy will be evaluated using the CGI-S administered every 
6 months.
Criteria for Evaluation:
Safety Endpoints:  

Frequency and severity of adverse events, serious adverse events 
(clinical and laboratory) and discontinuations from the study due to 
adverse events.

Suicide risk as assessed and classified by the C-SSRS.

Extrapyramidal symptoms will be evaluated by calculating the mean 
change from baseline in AIMS, SAS, and BARS.

The incidence of clinically significant changes will be calculated for 
vital signs.  Mean change from baseline and incidence of clinically 
significant changes will be calculated for body weight and waist 
circumference.  
Efficacy Endpoint: 

CGI-S score will be evaluated by calculating mean change from baseline.
Statistical Methods:
Due to the open-label single-arm nature of the study, all data on safety and 
efficacy/outcome will be summarized by descriptive statistics (eg, mean, 
standard deviation, maximum, minimum, and proportions).
Trial Duration:
Subjects will continue to receive aripiprazole IM Depot in this open-label 
rollover study until there are clinical and/or administrative reasons for 
discontinuation of the subject’s study treatment or until the study end date of 
31 Dec 2018 is reached, whichever occurs first (see “Trial Design” section 
above).  
Once aripiprazole becomes available commercially at any dosage (including 
generic formulation[s]) in the country where the study is being conducted, the 
commercial availability of aripiprazole IM Depot is terminated by the 
sponsor, or until the study end date of 31 Dec 2018 is reached, treatment will 
be discontinued.  If aripiprazole IM Depot is commercially available or if the 
availability of aripiprazole IM Depot is terminated by the sponsor, then the 
subject will discontinue treatment within approximately 6 weeks of last 
injection for clinical transition purposes.
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Table of Contents
Protocol Synopsis...........................................................................................3
Table of Contents...........................................................................................7
List of In-text Tables ...................................................................................11
List of In-text Figures..................................................................................12
List of Appendices........................................................................................13
List of Abbreviations and Definitions of Terms .......................................14
1
Introduction ........................................................................................16
1.1
Nonclinical Data................................................................................................18
1.2
Clinical Data......................................................................................................20
1.3
Known and Potential Risks and Benefits ..........................................................22
2
Trial Rationale and Objectives..........................................................24
2.1
Trial Rationale...................................................................................................24
2.2
Trial Objectives.................................................................................................25
3
Trial Design.........................................................................................25
3.1
Type/Design of Trial .........................................................................................25
3.2
Treatments.........................................................................................................28
3.3
Trial Population.................................................................................................29
3.4
Eligibility Criteria..............................................................................................29
3.4.1
Informed Consent ...........................................................................................29
3.4.2
Inclusion Criteria ............................................................................................30
3.4.3
Exclusion Criteria...........................................................................................30
3.5
Primary and Secondary Endpoints ....................................................................32
3.5.1
Safety Endpoints.............................................................................................32
3.5.2
Efficacy Endpoint ...........................................................................................32
3.6
Trial Procedures ................................................................................................32
3.6.1
Schedule of Assessments................................................................................36
3.6.1.1
Baseline.......................................................................................................36
3.6.1.2
Injection and Assessments Performed Every Month ..................................36
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3.6.1.3
Assessments Performed Every 3 Months....................................................36
3.6.1.4
Assessments Performed Every 6 Months....................................................37
3.6.1.5
Assessments Performed Every 12 Months..................................................37
3.6.1.6
Study Completion or Early Termination Visit............................................37
3.6.1.7
30-Day Post Treatment Follow-up Phone Call...........................................37
3.6.2
Efficacy Assessment (CGI-S).........................................................................37
3.6.3
Safety Assessments.........................................................................................38
3.6.3.1
Adverse Events............................................................................................38
3.6.3.2
Clinical Laboratory Assessments................................................................38
3.6.3.3
Physical Examination and Vital Signs........................................................40
3.6.3.3.1
Physical Examination..............................................................................40
3.6.3.3.2
Vital Signs ...............................................................................................40
3.6.3.3.3
Body Height and Weight and Body Mass Index.....................................41
3.6.3.3.4
Waist Circumference...............................................................................42
3.6.3.4
ECG Assessments .......................................................................................42
3.6.3.5
Extrapyramidal Symptoms..........................................................................43
3.6.3.5.1
Abnormal Involuntary Movement Scale .................................................43
3.6.3.5.2
Simpson-Angus Scale..............................................................................43
3.6.3.5.3
Barnes Akathisia Rating Scale ................................................................43
3.6.3.6
Suicidality ...................................................................................................44
3.6.3.7
Injection Site Evaluation.............................................................................44
3.6.4
End of Trial.....................................................................................................45
3.7
Stopping Rules, Withdrawal Criteria, and Procedures......................................45
3.7.1
Entire Trial or Treatment Arm(s) ...................................................................45
3.7.2
Individual Center ............................................................................................45
3.7.3
Individual Subject...........................................................................................46
3.8
Screen Failures ..................................................................................................46
3.9
Definition of Completed Subjects.....................................................................47
3.10
Definition of Subjects Lost to Follow-up..........................................................47
3.11
Subject Compliance...........................................................................................47
3.12
Protocol Deviations...........................................................................................48
4
Restrictions..........................................................................................48
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4.1
Prohibited Medications......................................................................................48
4.2
Other Restrictions..............................................................................................49
4.2.1
Restricted Therapies and Precautions.............................................................49
4.2.2
Non-therapy Precautions and Restrictions......................................................50
5
Reporting of Adverse Events.............................................................51
5.1
Definitions.........................................................................................................51
5.2
Eliciting and Reporting Adverse Events ...........................................................53
5.3
Immediately Reportable Events ........................................................................53
5.4
Pregnancy..........................................................................................................54
5.5
Follow-up of Adverse Events............................................................................55
5.5.1
Follow-up of Non-serious Adverse Events.....................................................55
5.5.2
Follow-up of Serious Adverse Events ............................................................55
6
Pharmacokinetic or Pharmacodynamic Analysis ...........................56
7
Statistical Analysis..............................................................................56
7.1
Dataset for Analysis ..........................................................................................56
7.2
Baseline Values.................................................................................................57
7.3
Primary Outcome Measures ..............................................................................57
7.4
Secondary Outcome Measures ..........................................................................57
7.5
Sample Size.......................................................................................................57
8
Management of Investigational Medicinal Product........................58
8.1
Packaging and Labeling ....................................................................................58
8.2
Storage...............................................................................................................58
8.3
Accountability ...................................................................................................58
8.4
Returns and Destruction....................................................................................58
9
Records Management.........................................................................59
9.1
Source Documents.............................................................................................59
9.2
Data Collection..................................................................................................59
9.3
File Management at the Trial Site.....................................................................60
9.4
Records Retention at the Trial Site....................................................................60
10
Quality Control and Quality Assurance...........................................61
10.1
Monitoring.........................................................................................................61
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10.2
Auditing.............................................................................................................61
11
Ethics and Responsibility...................................................................61
12
Confidentiality ....................................................................................61
13
Amendment Policy..............................................................................62
14
References............................................................................................63
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List of In-text Tables
Table 3.4.2-1
Inclusion Criteria ...........................................................................30
Table 3.4.3-1
Exclusion Criteria ..........................................................................30
Table 3.6-1
Schedule of Assessments (Study 31-10-270) ................................33
Table 3.6.3.2-1
Baseline Clinical Laboratory Assessments....................................39
Table 4.1-1
List of Medications Prohibited or Restricted in Study 270............49
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List of In-text Figures
Figure 3.1-1
Study 31-10-270 Trial Design Schema..........................................28
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List of Appendices
Appendix 1
Names of Sponsor Personnel .........................................................66
Appendix 2
Institutions Concerned With the Trial............................................67
Appendix 3
Criteria for Identifying Vital Signs of 
Potential Clinical Relevance..........................................................68
Appendix 4
Criteria for Identifying Laboratory Values of 
Potential Clinical Relevance..........................................................69
Appendix 5
Criteria for Identifying ECG Measurements of 
Potential Clinical Relevance..........................................................70
Appendix 6
Clinical Global Impression Severity (CGI-S) Scale......................71
Appendix 7
Abnormal Involuntary Movement Scale (AIMS)..........................72
Appendix 8
The Simpson-Angus Neurologic Rating Scale (SAS) ...................73
Appendix 9
Barnes Akathisia Rating Scale (BARS).........................................76
Appendix 10
Suicide Severity Rating Scale (C-SSRS).......................................78
Appendix 11
Visual Analog Scale (VAS) for Subject-reported Rating of 
Pain at Most Recent Injection Site.................................................88
Appendix 12
Investigator’s Assessment of Most Recent Injection Site..............89
Appendix 13
Product Labels ...............................................................................90
Appendix 14
Protocol Amendment(s)/Administrative Change(s) ......................91
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List of Abbreviations and Definitions of Terms
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC
Area under the concentration curve
BARS
Barnes Akathisia Rating Scale
BMI
Body mass index
Cmax
Maximum plasma concentration
CGI-I
Clinical Global Impression – Improvement
CGI-S
Clinical Global Impression – Severity
CNS
Central nervous system
CRF
Case report form
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
Cytochrome P450
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 
Text Revision
ECG
Electrocardiogram
EDC
Electronic data capture
EPS 
Extrapyramidal symptoms
EU
European Union
FDA
Food and Drug Administration
GERD
Gastroesophageal reflux disease
GCP
Good Clinical Practice
IAQ
Investigator’s Assessment Questionnaire
ICF
Informed consent form
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ICH
International Conference on Harmonisation
IEC
Independent ethics committee
IM 
Intramuscular
IRB
Institutional review board
IRE
Immediately reportable event
IUD
Intrauterine device
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
No-observable-adverse-effect-level
OPDC
Otsuka Pharmaceutical Development and Commercialization, Inc.
PANSS
Positive and Negative Syndrome Scale
PE
Physical examination
QTc
Corrected QT interval
QTcB
QTc (Bazett correction)
QTcF
QTc (Fredericia correction)
SAE
Serious adverse event
SAS
Simpson-Angus Scale
SmPC
Summary of Product Characteristics
US
United States
USPI
Unites States Prescribing Information
VAS
Visual Analog Scale
WOCBP
Women of childbearing potential
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1
Introduction
Schizophrenia is a chronic condition that requires continual treatment to maintain 
adequate cognitive and social functioning.  Noncompliance with antipsychotic 
medications remains a frequent cause of relapse among patients with schizophrenia.  
An estimated 50% of patients do not adhere to prescribed medication regimens for a 
variety of reasons.1  This lack of compliance leads to increased morbidity, decreased 
quality of life, and consequently, an associated increase in healthcare costs.2  One of the 
patient-driven reasons for noncompliance is their inability to adhere to daily dosing on 
a long-term basis, particularly in those who abuse or are dependent on alcohol or illegal 
drugs.3  In this respect, an intramuscular (IM) depot formulation administered every 
month (study months are every 4 weeks which is defined as 28 [−2/+10] days) may have 
a positive impact on compliance, and potentially on patient outcomes.4,5  Limited data 
comparing oral and depot formulations of typical antipsychotic agents suggest that depot 
formulations may have an advantage over oral formulations for relapse prevention.6  And 
yet, existing depot formulations, particularly for typical antipsychotics, are not ideal in 
that they exhibit many of the same undesirable effects that have been observed with oral 
administration (eg, hyperprolactinemia and extrapyramidal symptoms [EPS]).4,7,8
ABILIFY(aripiprazole, OPC-14597, BMS-337039), a second generation antipsychotic, 
which exhibits partial agonism (agonism/antagonism) at dopamine D2 and serotonin 
5-HT1A receptors and antagonism at serotonin 5-HT2 receptors, is approved and marketed 
in the United States (US) for use in the following indications.9
In adults, aripiprazole is indicated:

for treatment of schizophrenia and manic or mixed episodes associated with bipolar I 
disorder as monotherapy or adjunctive to lithium or valproate.

for adjunctive treatment of major depressive disorder (MDD) in adults.

as an injection for treatment of adults with agitation associated with schizophrenia or 
bipolar I disorder, manic or mixed episodes.

as an IM depot formulation for treatment of schizophrenia.
In pediatrics, aripiprazole is indicated:

for treatment of schizophrenia (ages 13 to 17 years). 

for treatment of manic or mixed episodes associated with bipolar I disorder as 
monotherapy or adjunctive to lithium or valproate (ages 10 to 17 years). 
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
for treatment of irritability associated with autistic disorder in children and 
adolescents (ages 6 to 17 years). 
In the European Union (EU), aripiprazole is also approved for the treatment of moderate 
to severe manic episodes in bipolar I disorder and for the prevention of new manic 
episodes in those patients who experienced predominantly manic episodes and whose 
manic episodes responded to aripiprazole treatment, as well as for the treatment of 
schizophrenia in adults and adolescents (Appendix 13).  The aripiprazole 
immediate-release IM injection formulation is approved for the treatment of agitation 
associated with schizophrenia or bipolar mania in the US and EU.  In addition, an oral 
solution formulation and orally disintegrating (dispersible) tablets have been approved 
and marketed in the US and EU.  
The favorable side effect profile of oral aripiprazole, including its low incidence of EPS, 
low risk of prolactin elevation, decreased adrenergic and anticholinergic side effects, and 
minimal weight gain, makes it an excellent candidate for a long-acting depot formulation.  
Aripiprazole IM depot formulation is currently being developed for maintenance 
treatment of schizophrenia and bipolar I disorder, and was approved for the treatment of 
schizophrenia in the US in February 2013.  Its efficacy was demonstrated in a pivotal 
phase 3 registrational trial (Study 31-07-246) designed to evaluate the efficacy, safety, 
and tolerability of the long-acting IM depot formulation of aripiprazole administered to 
adult subjects with a diagnosis of schizophrenia as defined by the Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).  
A marketing application was submitted in September 2011 to the Food and Drug 
Administration (FDA) for use of the aripiprazole IM depot formulation as maintenance 
treatment in patients with schizophrenia, which was approved in February 2013
(Appendix 13).  A marketing application was submitted in December 2012 to the 
European Medicines Agency.  
Study 31-08-248 is included in the development plan for aripiprazole IM Depot to 
supplement the safety data that will be generated as part of the phase 3 program and to 
provide additional efficacy data for the maintenance treatment of patients with 
schizophrenia.  The current study (31-10-270, hereafter referred to as Study 270), will 
allow subjects who completed Study 31-08-248 (hereafter referred to as Study 248) to 
continue treatment with aripiprazole IM Depot until it is commercially available in any 
dosage (including generic formulation[s]) in the country where the study is being 
conducted, the commercial availability of aripiprazole IM Depot is terminated by the 
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sponsor, or until the study end date of 31 Dec 2018 is reached.  This study will provide 
additional long-term safety information.
If the sponsor terminates the study prior to 31 Dec 2018 for any reason other than 
commercial availability, investigators in some countries where the sponsor has limited or 
delayed commercialization plans, or where no commercialization activity is anticipated, 
may be eligible to participate in a managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.  Availability and 
requirements of such a program varies by jurisdiction, and would only be an option for 
subjects who were receiving aripiprazole IM Depot in the current study, and who in the 
physician’s opinion, may benefit from continued treatment with aripiprazole.  To gain 
access to aripiprazole IM Depot for eligible subjects via a managed access program, each 
physician will be responsible for gaining appropriate local regulatory approvals, which 
will be granted by authorities on a case-by-case basis.  The sponsor makes no guarantee 
that such a program is available or approvable in all of the jurisdictions where the study is 
conducted.
Please refer to the Investigator’s Brochure9, ABILIFY US Prescribing Information 
(USPI) (Appendix 13), and EU Summary of Product Characteristics (SmPC) 
(Appendix 13) for detailed information on preclinical and clinical data.  A brief summary 
is included below.
1.1
Nonclinical Data
The mechanism of action of aripiprazole differs from that of currently marketed typical 
and atypical antipsychotics.  It has been proposed that aripiprazole’s effectiveness in 
schizophrenia is mediated through a combination of partial agonism 
(agonism/antagonism) at dopamine D2 and serotonin 5-HT1A receptors and antagonism at 
serotonin 5-HT2 receptors.  Aripiprazole has the properties of an agonist in an animal 
model of dopaminergic hypoactivity and the properties of an antagonist in animal models 
of dopaminergic hyperactivity.  Aripiprazole exhibits high affinity for dopamine D2 and 
D3, serotonin 5-HT1A and 5-HT2A receptors and moderate affinity for dopamine D4
serotonin 5-HT2C and 5-HT7, alpha1-adrenergic, histamine H1 receptors and the serotonin 
reuptake site.  Aripiprazole also displays 5-HT1A partial agonist and 5-HT2A antagonist 
activity in nonclinical studies.  The emerging literature for other antipsychotics indicates 
that 5-HT1A and 5-HT2A activity may be correlated with the clinical observation of 
effectiveness against negative symptoms in patients with schizophrenia.  It seems likely 
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that the favorable safety and tolerability profile of aripiprazole is also mediated by its 
unique profile of interaction with central neuroreceptors.
Toxicokinetic evaluations of a prototype formulation of aripiprazole IM Depot were 
conducted in single-dose IM irritation and toxicity studies in rats and dogs.  Systemic 
exposures to aripiprazole were dose-related and generally higher in females than in 
males.  Plasma concentrations of aripiprazole were measurable at all doses up to Day 43 
in rats (maximum plasma concentration [Cmax] approximately 190 ng/mL at 1 mg/kg)10
and Day 42 in dogs (Cmax approximately 30 ng/mL, area under the concentration curve 
[AUC]0-28 days approximately 300 ng-days/mL at 100 mg/dog),11 indicating sustained 
absorption over these periods.  Clinically relevant exposures were not readily achieved in 
rats or dogs due to the markedly greater metabolic clearance of aripiprazole in animals 
versus humans, and because release of drug from the injection site, as desired, was slow.  
Plasma concentrations of the pharmacologically active metabolite, BMS-337040, were 
generally below the lower limit of quantitation in both species, whereas plasma 
concentrations of BMS-337044 (dehydro-aripiprazole, another active metabolite) were 
measurable at most time points in dogs, but not in rats. 
The IM depot formulation was well tolerated by all species; the principal gross finding at 
injection sites was generally dose-related, linear foci of white or tan discoloration in 
skeletal muscle that slowly decreased in size over time. Microscopically, the foci of 
white/tan discoloration were characterized as a localized and generally dose-dependent 
foreign-body type of granulomatous inflammation (minimal to mild in rats; minimal to 
moderate in rabbits and dogs) associated with deposits of drug (birefringent polymorphic 
crystalline material) that remained localized at the injection site.  As is characteristic of a 
foreign-body reaction, resolution of the granulomatous inflammation at injection sites 
was slow, and recovery was incomplete by Day 43 and 45 postdose in dogs and rats, 
respectively, and by Day 57 postdose in rabbits.
Pivotal nonclinical studies to support the IM depot formulation for clinical use included 
single-dose IM irritation and toxicity studies in rats (0, 75, or 100 mg/kg), rabbits (0, 150, 
or 200 mg), and dogs (0, 150, 200, 300, or 400 mg), and repeated-dose toxicity studies in 
rats (0, 25, 50, and 100 mg/kg weekly for 26 weeks) and beagle dogs (0, 10, 20, and 
40 mg/kg weekly for 26 weeks).  All doses of this IM depot formulation were well 
tolerated by all species.  As with the earlier IM irritation and toxicity studies, the 
principal injection site findings in all species were deposits of drug that remained 
localized at the injection site and associated foreign-body type of granulomatous 
inflammation, both of which resolved slowly over time.  Importantly, there was no 
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significant muscle injury or fibroplasia/fibrosis associated with the drug deposits or the 
associated inflammation.  Considering that the local tissue reaction (foreign-body type of 
granulomatous inflammation) was consistent in all species tested, it is anticipated that the 
depot formulation will produce a similar local reaction in humans that will resolve over 
time.
Repeated IM doses of the depot formulation for clinical use were also well tolerated by 
rats and dogs.  The local tissue reactions of both repeated dose studies were comparable 
to those of the single dose studies.  For the systemic toxicity in rats, 6 months of 
intermittent repeated IM injections at the maximal dose of 100 mg/kg were well tolerated, 
and no morphological changes were observed, except for the findings considered to be 
pharmacologically mediated and a consequence of the D2 partial agonistic activity of 
aripiprazole.  The no-observable-adverse-effect-level (NOAEL) in the rat study was 
considered to be 50 mg/kg/week in the males and 100 mg/kg/week in the females.  For 
the systemic toxicity in dogs, 6 months intermittent repeated IM injections at the maximal 
dose of 40 mg/kg were well tolerated, and the NOAEL was considered to be 
40 mg/kg/week under the conditions of the study.  Thus, preclinical safety data of the 
IM depot formulation revealed no special hazard for clinical use based on the studies of 
single and repeat-dose toxicity.
Further details of results of nonclinical studies with the IM depot formulation and 
information on nonclinical studies following aripiprazole administration via other dose 
routes can be found in the Investigator’s Brochure.9
1.2
Clinical Data
A comprehensive clinical program to evaluate the effectiveness of aripiprazole was 
conducted.  The studies of subjects with an acute exacerbation of schizophrenia 
established the effectiveness of aripiprazole in the treatment of schizophrenia, including 
positive and negative symptoms.  These studies also demonstrated its early onset of 
action.  The long-term studies showed that aripiprazole treatment maintained stability in 
subjects with schizophrenia.  The Investigator’s Brochure provides additional safety data 
on studies not described below.9
Two phase 2, double-blind, placebo-controlled studies conducted in acutely relapsing 
hospitalized schizophrenic subjects gave support for the effectiveness, safety, and 
tolerability of aripiprazole in this population.  Three phase 3 trials established the efficacy 
of oral doses of aripiprazole 10, 15, 20, and 30 mg/day for the treatment of acute relapse 
of schizophrenia or schizoaffective disorder.  The two 4-week studies (31-97-201 and 
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31-97-202) 12,13 each included 2 fixed doses of aripiprazole (15 mg and 30 mg for 
31-97-201 and 20 mg and 30 mg for 31-97-202), an active comparator (for comparison of 
safety profiles), and placebo.  Review of the data from these trials indicated that all of the 
doses of aripiprazole were effective in the treatment of acute psychosis.  All aripiprazole 
doses were statistically significant compared to placebo with regard to the primary 
endpoints of change from baseline in the Positive and Negative Syndrome Scale 
(PANSS) Total Score, PANSS positive score, and Clinical Global Impression - Severity 
(CGI-S) score.  As expected, the active comparators (haloperidol and risperidone), 
demonstrated effectiveness in the treatment of psychosis as measured by these endpoints.  
The third double-blind, placebo-controlled, phase 3 study (CN138001)14 was 6 weeks in 
duration and included aripiprazole oral doses of 10, 15, and 20 mg/day.  All doses of 
aripiprazole demonstrated significant improvement compared with placebo for change 
from baseline in the PANSS Total Score and the positive and negative subscales.  
Three phase 3, double-blind, controlled studies were conducted to show the long-term 
efficacy of aripiprazole.  Study CN13804715,16 was a 26-week study designed to 
document the long-term efficacy of oral aripiprazole 15 mg/day compared with placebo 
in stable schizophrenic subjects.  The primary efficacy variable was time to relapse from 
randomization, as measured by Clinical Global Impression - Improvement (CGI-I) score 
≥ 5, PANSS scores for hostility or uncooperativeness ≥5, or ≥ 20% increase in PANSS 
Total Score.  The results indicated that subjects treated with aripiprazole 15 mg daily 
experienced a significantly longer time to relapse over the 26-week assessment period 
compared with those receiving placebo.  Two 52-week studies (Studies 31-98-217 and 
31-98-304-01)17,18 of aripiprazole 30 mg versus haloperidol 10 mg were conducted in 
acutely relapsing schizophrenic subjects with the intention of pooling the data for 
analysis.  On the primary efficacy measure (time to failure to maintain response in 
responders) no difference was seen between aripiprazole and haloperidol.  However, 
analysis of secondary efficacy measures showed that aripiprazole 30 mg was superior to 
haloperidol on negative symptoms, depressive symptoms, and discontinuation for any 
reason.
The subject-rated and investigator-rated acceptability of aripiprazole treatment has been 
examined in open-label studies.  Subjects treated with open-label oral aripiprazole 10 to 
30 mg for 8 weeks indicated a general preference for aripiprazole over the antipsychotic 
medication(s) taken prior to entering the study (CN138087 and CN138100).  A separate 
open-label study (CN138152)19,20 compared aripiprazole (oral doses of 10 to 30 mg 
daily) to standard of care treatment (clinician-prescribed olanzapine, risperidone, or 
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quetiapine) in community-treated schizophrenic subjects for whom an alteration in 
antipsychotic medication was clinically warranted.  Aripiprazole demonstrated superior 
effectiveness as measured by the Investigator’s Assessment Questionnaire (IAQ), which 
provides an overall assessment of efficacy and tolerability.21
Aripiprazole showed an excellent safety and tolerability profile both in acute or chronic 
schizophrenia, with no evidence of increased rates of somnolence, EPS-related side 
effects, clinically significant weight gain, hyperprolactinemia, or prolongation of 
corrected QT interval (QTc).  The recommended starting and target oral dose for 
aripiprazole in the treatment of schizophrenia is 10 mg or 15 mg/day administered on a 
once-a-day schedule without regard to meals.  Aripiprazole has been systematically 
evaluated and shown to be effective in an oral dose range of 10 mg to 30 mg/day; 
however, there is no evidence that doses higher than 15 mg per day are associated with 
increased efficacy.
1.3
Known and Potential Risks and Benefits
As of 01 Jun 2014, all voluntary reports of adverse events (AEs) in patients taking 
aripiprazole received since market introduction that were considered by the sponsor as 
medically relevant have been listed in the USPI and EU SmPC (Appendix 13).  The USPI 
and EU SmPC also contain the currently available phase 2/3/4 clinical safety information
(Appendix 13). Across the short-term, double-blind, placebo-controlled studies 
conducted in schizophrenic subjects, the AE profile of oral aripiprazole was generally 
comparable to that of placebo.  There was little difference in the incidence of 
discontinuation due to AEs between aripiprazole-treated (7%) and placebo-treated (9%) 
subjects.  Akathisia was the only commonly observed AE that occurred in ≥5% of 
aripiprazole-treated subjects and at an incidence more than twice that of placebo (8% vs. 
4%, respectively).  Aripiprazole was well-tolerated in the long-term studies.  Changes in 
body weight, fasting glucose, lipid profile, and serum prolactin levels were similar 
between aripiprazole- and placebo-treated subjects.  No clinically relevant changes in 
QTc were observed in either group.16 In the pooled analysis of the two 52-week studies 
comparing aripiprazole with haloperidol, the incidence of EPS-related AEs was 
significantly higher for haloperidol (58%) compared with aripiprazole (27%).  In the one 
52-week study in which prolactin levels were measured, significantly fewer 
aripiprazole-treated subjects (3.4%) experienced prolactin elevations above the upper 
limit of normal compared with the haloperidol group (61%).18
The comparative safety profile of oral aripiprazole relative to placebo in subjects with 
acute bipolar mania raised no new safety concerns and was similar to that observed in 
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subjects with schizophrenia.  Additionally, aripiprazole exhibited a more favorable safety 
profile than haloperidol in the 26-week active-controlled study in acute bipolar mania.  
The safety profile was consistent with that observed in haloperidol-controlled 
schizophrenia studies, as evidenced by a lower incidence of AE discontinuation;
EPS-related AEs, and prolactin elevation.22
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar 
coma or death, has been reported in patients treated with atypical antipsychotics.  There 
have been few reports of hyperglycemia in subjects treated with aripiprazole.  Although 
fewer subjects have been treated with aripiprazole, it is not known if this more limited
experience is the sole reason for the paucity of such reports.  Assessment of the 
relationship between atypical antipsychotic use and glucose abnormalities is complicated 
by the possibility of an increased background risk of diabetes mellitus in subjects with 
schizophrenia and the increasing incidence of diabetes mellitus in the general population.  
Given these confounders, the relationship between atypical antipsychotic use and 
hyperglycemia-related AEs is not completely understood.  However, epidemiological 
studies which did not include aripiprazole suggest an increased risk of 
treatment-emergent hyperglycemia-related AEs in subjects treated with the atypical 
antipsychotics included in these studies.  Because aripiprazole was not marketed at the 
time these studies were performed, it is not known if aripiprazole is associated with this 
increased risk.  Precise risk estimates for hyperglycemia-related AEs in subjects treated 
with atypical antipsychotics are not available.
Elderly patients with dementia-related psychosis treated with atypical antipsychotic 
drugs, including aripiprazole, are at an increased risk of death compared with placebo.  
Over the course of three 10-week, placebo-controlled studies of aripiprazole in elderly 
subjects with psychosis associated with Alzheimer’s disease, the rate of death in 
aripiprazole-treated subjects was 3.5%, compared with a rate of 1.7% in the placebo 
group during or within 30 days after termination from the double-blind phase of the 
studies.  Although the causes of death were varied, most of the deaths were either 
cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature.  
Overall, 1.3% of aripiprazole-treated subjects reported cerebrovascular AEs (eg, stroke, 
transient ischemic attack) compared with 0.6% of placebo-treated subjects in these trials.  
This difference was not statistically significant.  However, in one of these trials, a 
fixed-dose trial, there was a significant dose-response relationship for cerebrovascular 
AEs in subjects treated with aripiprazole.  Aripiprazole is not approved for the treatment 
of dementia-related psychosis.  In clinical studies and postmarketing experience, 
accidental or intentional acute overdose of aripiprazole alone was reported in adult 
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patients with estimated doses up to 1260 mg with no fatalities.  The potentially medically 
important signs and symptoms observed included lethargy, increased blood pressure, 
somnolence, tachycardia, and vomiting.  In addition, reports of accidental overdose with 
aripiprazole alone (up to 195 mg) in children were received with no fatalities.  The 
potentially medically serious signs and symptoms reported included somnolence and 
transient loss of consciousness.  In the patients who were evaluated in hospital settings, 
there were no reported observations indicating clinically important adverse change in 
vital signs, laboratory assessments, or electrocardiograms (ECGs).  Additional 
information can be obtained from the ABILIFY USPI and EU SmPC (Appendix 13).
2
Trial Rationale and Objectives
2.1
Trial Rationale
The efficacy, safety, and tolerability of aripiprazole IM Depot administered every month 
are being investigated in two phase 3 clinical trials (Studies 31-07-246 and 31-07-247).  
The main efficacy objective of these studies is relapse prevention with aripiprazole 
IM Depot relative to placebo (Study 31-07-246) and to oral aripiprazole (Study 31-07-
247).  Study 248 was included in the development plan for aripiprazole IM Depot to 
supplement the safety data that will be generated as part of the phase 3 program by 
allowing an additional 52 weeks of treatment with open-label aripiprazole IM Depot to 
qualifying subjects.  Current literature suggests that remission of symptoms should be 
explored as a goal of ongoing longer-term schizophrenia treatment.23,24,25,26
The current study (31-10-270) will allow the long-term subjects who completed 
Study 248 to continue to receive aripiprazole IM Depot treatment until aripiprazole 
IM Depot is either commercially available in any dosage (including generic 
formulation[s]) in the country where the study is being conducted, the commercial 
availability of aripiprazole IM Depot is terminated by the sponsor, or until the study end 
date of 31 Dec 2018 is reached.  
If the sponsor terminates the study prior to 31 Dec 2018 for any reason other than 
commercial availability, investigators in some countries where the sponsor has limited or 
delayed commercialization plans, or where no commercialization activity is anticipated, 
may be eligible to participate in a managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.  Availability and 
requirements of such a program varies by jurisdiction, and would only be an option for 
subjects who were receiving aripiprazole IM Depot in the current study, and who in the 
physician’s opinion, may benefit from continued treatment with aripiprazole.  To gain 
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access to aripiprazole IM Depot for eligible subjects via a managed access program, each 
physician will be responsible for gaining appropriate local regulatory approvals, which 
will be granted by authorities on a case-by-case basis.  The sponsor makes no guarantee 
that such a program is available or approvable in all of the jurisdictions where the study is 
conducted.
Aripiprazole IM Depot 400 mg is the highest dose being studied in the pivotal trials and 
in the current study.  However, investigators will have the option to decrease the dose of 
aripiprazole IM Depot to 300 mg, if needed for tolerability.  Dose-adjustment between 
aripiprazole IM Depot 400 mg and 300 mg will be permitted as often as necessary to 
maintain stability with acceptable tolerability. 
2.2
Trial Objectives
The primary objective of this open-label study is to continue to provide aripiprazole 
IM Depot treatment (400 mg or 300 mg) to subjects with schizophrenia who completed 
the 52-week, open-label safety and tolerability Study 248.  Subjects can receive this 
therapy until aripiprazole IM Depot is commercially available in any dosage (including 
generic formulation[s]) in the country where the study is being conducted, the 
commercial availability of aripiprazole IM Depot is terminated by the sponsor, or until 
the study end date of 31 Dec 2018 is reached.
The secondary objective is to collect long-term safety data on aripiprazole IM Depot in 
addition to what was collected in Study 248 (52-weeks). 
3
Trial Design
3.1
Type/Design of Trial
This is an open-label, multicenter rollover non-comparative study designed to continue to 
provide aripiprazole IM Depot (400 mg or 300 mg) to adult subjects with schizophrenia 
who completed aripiprazole IM Depot treatment in Study 248.  The decision to enroll 
into the long-term open-label study will be a joint decision by the investigator and 
subject.  No subjects who discontinued or did not complete Study 248 are allowed to 
enroll in Study 270.
Eligible subjects will enter this study directly after completing the End of Treatment visit 
(Week 52) of Study 248.  The End of Treatment (Week 52) evaluations conducted at the 
last study visit for Study 248 will serve as the baseline evaluations for Study 270.  The 
baseline visit for Study 270 (which is the Week 52 visit for Study 248) and the first 
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injection for Study 270 must occur within 4 weeks (which is defined as 28 [−2/+10] days) 
of the last injection in Study 248.
Subjects will continue to receive aripiprazole IM Depot (400 mg or 300 mg) every month 
(study months are every 4 weeks which is defined as 28 [−2/+10] days) as a continuation 
of their previous monthly dose in Study 248.  The minimum interval of 26 days and 
maximum interval of 38 days between injections is to ensure that therapeutic plasma 
concentrations of aripiprazole are maintained.  The monthly dose can be modified, either 
reduced from 400 mg to 300 mg to address tolerability or increased from 300 mg to 
400 mg to address efficacy, at the discretion of the investigator.
Following the baseline visit (described in detail in Section 3.6.1.1), subjects will receive 
monthly injections and at the same visit, AEs and concomitant medications will be 
recorded and the Columbia Suicide Severity Rating Scale (C-SSRS) will be completed
(Section 3.6.1.2).  Every 3 months (Section 3.6.1.3), all of the monthly assessments will 
be completed along with a urine pregnancy test for women of childbearing potential 
(WOCBP) (see Section 5.4 for the definition of WOCBP).  Every 6 months
(Section 3.6.1.4), all of the 3-month assessments will be completed along with the CGI-S 
scale, vital signs, and EPS assessments (Abnormal Involuntary Movement Scale [AIMS], 
Simpson-Angus Scale [SAS], and Barnes Akathisia Rating Scale [BARS]).  Every 
12 months (Section 3.6.1.5), all of the 6-month assessments will be completed along with 
clinical laboratory tests and assessments of body weight, height, and waist circumference.  
At the discretion of the investigator, the baseline assessments for clinical chemistry and 
hematology, urine drug screening, and blood alcohol testing may be repeated at any 
subsequent study visit. For each visit, all the assessments, except for those specified as 
post-injection assessments, should be performed prior to the aripiprazole IM Depot 
injection.
A Study Completion visit or Early Termination visit (−2/+10 days) will include the 
following assessments (Section 3.6.1.6): C-SSRS, AEs, concomitant medications, a urine 
pregnancy test for WOCBP, CGI-S, vital signs, EPS assessments (AIMS, BARS, SAS), 
clinical laboratory tests, and body height and weight.  
A 30-Day Post Treatment Follow-up phone call will be performed 30 days (3 days) 
after it has been determined that the subject will no longer participate in this study and 
include the recording of AEs that have occurred and any concomitant medications taken 
since the last study visit.
No oral antipsychotic rescue medication (including aripiprazole) is allowed in this study.  
If a subject experiences an exacerbation of psychotic symptoms, the investigator should 
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assess the suitability of the subject’s continuation in the study and ensure that the subject
is treated appropriately.  If the investigator deems that other antipsychotic therapy is 
warranted, the subject should be discontinued from this study. 
Aripiprazole IM Depot treatment in this open-label rollover study will continue until 
there are clinical and/or administrative reasons for discontinuation of the subject’s study 
treatment or until the study end date of 31 Dec 2018 is reached, whichever occurs first.  
Clinical reasons for discontinuing study treatment include, but are not limited to: the 
subject voluntarily withdraws consent; the subject becomes lost to follow-up; if a subject
misses 2 consecutive injections at any time in the study or 3 injections in any 52-week 
time period; or the investigator determines that the subject is no longer receiving benefit 
from aripiprazole IM Depot.  Administrative reasons for discontinuing study treatment 
include, but are not limited to: aripiprazole IM Depot is commercially available in any 
dosage (including a generic formulation) in the country where the study is being 
conducted, the commercial availability of aripiprazole IM Depot is terminated by the 
sponsor, or until the study end date of 31 Dec 2018 is reached, whichever occurs first.
If the sponsor terminates the study prior to 31 Dec 2018 for any reason other than 
commercial availability, investigators in some countries where the sponsor has limited or 
delayed commercialization plans, or where no commercialization activity is anticipated, 
may be eligible to participate in a managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.  Availability and 
requirements of such a program varies by jurisdiction, and would only be an option for 
subjects who were receiving aripiprazole IM Depot in the current study, and who in the 
physician’s opinion, may benefit from continued treatment with aripiprazole.  To gain 
access to aripiprazole IM Depot for eligible subjects via a managed access program, each 
physician will be responsible for gaining appropriate local regulatory approvals, which 
will be granted by authorities on a case-by-case basis.  The sponsor makes no guarantee 
that such a program is available or approvable in all of the jurisdictions where the study is 
conducted.
Once aripiprazole IM Depot becomes commercially available in the country where the 
subject is participating in the study (including generic formulation[s]) or the commercial 
availability of aripiprazole IM Depot is terminated by the sponsor, study treatment will be 
discontinued within approximately 6 weeks of the subject’s previous injection for clinical 
transition purposes.
The study design is presented in Figure 3.1-1.
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Study Entry
Open-label IM Depot Treatment
Follow-up
Study 248 
Completers only
Every month:
Injection, C-SSRS, AEs, and 
concomitant medications
One 30-day post 
End of Study 
phone call - AEs
and concomitant 
medications 
Every 3 monthsa:
Urine pregnancy test for WOCBP
Every 6 monthsa:
CGI-S, vital signs, and EPS 
assessments (AIMS, BARS, SAS)
Every 12 monthsa:
Clinical laboratory tests, body weight 
and height, and waist circumference
Week 52 Visit of 
Study 248 = 
Baseline for 
Study 270
Injection visit window = 28 (−2/+10) days
Assessment visit window = −2/+10 days
± 3 days
Figure 3.1-1
Study 31-10-270 Trial Design Schema
BMI = body mass index.
aThe 3-month, 6-month, and 12-month visits include assessments from the previous visit.  For example, 
the 3-month visit includes all of the monthly visit assessments in addition to the 3-month visit 
assessments.  A Study Completion or Early Termination visit will also be performed.  Refer to 
Table 3.6-1 for a comprehensive Schedule of Assessments at each visit. 
3.2
Treatments
Subjects meeting the eligibility criteria will receive aripiprazole IM Depot (400 mg or 
300 mg) every month (study months are every 4 weeks which is defined as 
28 [−2/+10] days) as a continuation of their previous monthly dose in Study 248.  
The monthly dose can be modified, either reduced from 400 mg to 300 mg to address 
tolerability or increased from 300 mg to 400 mg to address efficacy, at the discretion of 
the investigator.
Needle length for injection of aripiprazole IM Depot will be selected based on body mass 
index (BMI) obtained at baseline as follows: 21 gauge, 1.5 inch for BMI ≤ 28 kg/m2; 
21 gauge, 2 inch for BMI > 28 kg/m2.  The BMI should be calculated in kg/m2 from the 
baseline height and the weight using one of the following formulas, as appropriate:
Weight (kg) ÷ [Height (m)]2 or Weight (lb) ÷ [Height (in)]2 x 703.
The BMI should be provided to the individual administering each dose of IM depot.  If a 
noticeable fluctuation in body height and weight has occurred during the study, at the 
investigator’s discretion, body weight can be remeasured and BMI recalculated and used 
for the next aripiprazole IM Depot injection.  All doses of aripiprazole IM Depot must be 
injected into the gluteal muscle (rotate sites of injection), and care must be taken to avoid 
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inadvertent injection into a blood vessel, as per the administration guidance in the 
Operations Manual.  
No oral antipsychotic rescue therapy (including aripiprazole) is allowed in this study.  
If a subject experiences an exacerbation of psychotic symptoms, the investigator should 
assess the suitability of the subject’s continuation in the study and ensure that the subject
is treated appropriately.  If the investigator deems that other antipsychotic therapy is 
warranted, the subject should be discontinued from this study. 
3.3
Trial Population
The subject population will be comprised of subjects who have completed Study 248 and 
in the investigator’s judgment, may benefit from continued participation in an 
aripiprazole IM Depot study, in countries where aripiprazole IM Depot is not 
commercially available.
It is anticipated that approximately 500 to 800 subjects from Study 248 will be enrolled 
from the 250 sites involved in Study 248 worldwide.  New sites will not be utilized.
3.4
Eligibility Criteria
3.4.1
Informed Consent
Each investigator has both ethical and legal responsibility to ensure that subjects being 
considered for inclusion in this trial are given a full explanation of the protocol.  This 
shall be documented on a written informed consent form (ICF) that shall be approved by 
the same institutional review board/independent ethics committee (IRB/IEC) responsible 
for approval of this protocol.  Each ICF shall include the elements required by the 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) 
Guideline27 and local regulatory requirements and must adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.  The investigator agrees to obtain 
approval from the sponsor of any written ICF used in the trial, prior to submission to the 
IRB/IEC. 
Written informed consent will be obtained from all subjects (or their legal representative, 
as applicable for local laws).  Any patient stipend as indicated in the ICF should be 
documented in the source documentation.  Investigators may discuss the availability of 
the trial and the possibility for entry with a potential subject without first obtaining 
consent.  However, informed consent must be obtained and documented prior to initiation 
of any procedures that are performed solely for the purpose of determining eligibility for 
this trial, including withdrawal from current medication(s).  When this is done in 
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anticipation of, or in preparation for, the research, it is considered to be part of the 
research. 
Once the appropriate essential information has been provided to the subject and fully 
explained in layman’s language by the investigator (or a qualified designee) and it is felt 
that the subject understands the implications of participating, the IRB/IEC-approved 
written ICF shall be personally signed and dated by both the subject and the person 
obtaining consent (investigator or designee), and by any other parties required by the 
IRB/IEC.  The subject shall be given a copy of the signed ICF; the original shall be kept 
on file by the investigator.  All of the above mentioned activities must be completed prior 
to the subject’s participating in the trial.  
3.4.2
Inclusion Criteria
The following inclusion criteria must be met by subjects entering the open-label rollover 
study at the End of Treatment visit of Study 248 (Week 52):  
Table 3.4.2-1
Inclusion Criteria
1.
Subjects with a current diagnosis of schizophrenia, as defined by DSM-IV-TR criteria, who 
completed the open-label extension Study 248 (completed Study 248 Study Completion visit, 
Week 52).
2.
Subjects who, in the investigator’s judgment, may benefit from continued participation in an 
aripiprazole IM Depot study.
3.
The baseline visit for Study 270 (which is the Week 52 visit of Study 248) and the first injection for 
Study 270 must occur within 4 weeks (which is defined as 28 [−2/+10] days) of the last injection in 
Study 248.
4.
Subjects who are able to provide written informed consent and/or consent obtained from a legally 
acceptable representative (as required by IRB/IEC), prior to the initiation of any protocol-required 
procedures.
5.
Subjects able to understand the nature of the study and follow protocol requirements and who can 
read and understand the written word in order to complete patient-reported outcomes measures.
6.
Outpatient status.
3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria:
Table 3.4.3-1
Exclusion Criteria
Sex and Reproductive Status
1.
Sexually active males who are not practicing double-barrier birth control or who will not remain 
abstinent during the study and for 180 days following the last dose of study medication, or sexually 
active females of childbearing potential who are not practicing double-barrier birth control or who 
will not remain abstinent during the study and for 150 days following the last dose of study 
medication.  If employing birth control, two of the following precautions must be used: vasectomy, 
tubal ligation, vaginal diaphragm, intrauterine device (IUD), birth control pill, birth control implant, 
condom with spermicide, or sponge with spermicide.
2.
Females who have a positive serum pregnancy test result at study entry.
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Table 3.4.3-1
Exclusion Criteria
Target Disease
3.
Subjects with a current DSM-IV-TR diagnosis other than schizophrenia, including schizoaffective
disorder, MDD, bipolar disorder, delirium, dementia, amnestic or other cognitive disorders.  Also, 
subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality 
disorder.
Medical History and Concurrent Disease
4.
Subjects with a significant risk of violent behavior or a significant risk of committing suicide based 
on the investigator’s judgment.
5.
Subjects who currently meet DSM-IV-TR criteria for substance dependence; including alcohol and 
benzodiazepines, but excluding caffeine and nicotine.
6.
Subjects who have a history or evidence of a medical condition that would expose them to an undue 
risk of a significant AE or interfere with assessments of safety or efficacy during the course of the 
trial, including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, 
hematologic, or immunologic disease as determined by the clinical judgment of the investigator.
7.
Subjects with epilepsy or a history of seizures, except for a single childhood febrile seizure, post 
traumatic, alcohol withdrawal, etc.
Physical and Laboratory Test Findings
8.
Any subject with a positive drug screen for cocaine or other drugs of abuse (excluding marijuana, 
stimulants, and other prescribed medications).
9.
The following laboratory test, vital sign, and ECG results are exclusionary:
a) Platelets ≤ 75,000/mm3
b) Hemoglobin 9 g/dL
c) Neutrophils, absolute ≤ 1000/mm3
d) Aspartate transaminase (AST) > 3x upper limit of normal
e) Alanine transaminase (ALT) > 3x upper limit of normal
f) Creatinine ≥ 2 mg/dL 
g) Diastolic blood pressure > 105 mm Hg
h) At baseline, QTc > 475 msec on either the QTcB (Bazett) or QTcF (Fridericia) corrections 
on 2 of 3 time points of triplicate ECGs performed (refer to NOTE below).
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 
that would impact the safety of the subject or the interpretation of the study results.  Criteria are 
provided in Appendix 3, Appendix 4, and Appendix 5 to assist investigators in their assessments of 
results that may be potentially medically significant, depending on the subject’s medical history and 
clinical presentation.  Abnormal results for laboratory parameters, or vital signs should be repeated 
to ensure reproducibility of the abnormality before excluding a subject based on the criteria noted 
above.  The ECG criteria for baseline ECG for Study 270 (which is the Week 52 visit of Study 248) 
will be done per Study 248 requirements.  The central ECG service will provide the corrections for 
the three ECGs done approximately five minutes apart (each ECG result reported is derived from the 
average of the triplicate ECG done at each time point.)  Based on the QTcB or QTcF corrections 
reported by the central service, a subject will be excluded if either of the corrections exceed 
475 msec for 2 of the 3 time points of triplicate ECGs done.  If only one triplicate ECG time point 
has a corrected QTc greater than 475 msec on either correction factor, and this is not reproduced at 
the other 2 time points, this subject can be included in the study.  Subjects may enroll into the study 
prior to obtaining baseline results, but will be subsequently withdrawn if clinically significant results 
are identified.
Allergies and Adverse Drug Reactions
10.
Subjects who are known to be allergic, intolerant, or unresponsive to prior treatment with 
aripiprazole or other quinolinones.
11.
Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive 
dyskinesia at screening.
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Table 3.4.3-1
Exclusion Criteria
Prohibited Therapies and/or Medications
12.
Subjects likely to require prohibited concomitant therapy during the trial (see Table 4.1-1).
13.
Subjects who may require cytochrome P450 (CYP) 2D6 or CYP3A4 inhibitors or CYP3A4 inducers 
during the trial (see Table 4.1-1 and Section 4.2.1).
14.
Any subject who requires or may need any other antipsychotic medications during the course of the 
study.
Other Exclusion Criteria
15.
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for any reason must 
not be enrolled into this trial.
16.
Electroconvulsive therapy within 180 days prior to entry.
17.
Aripiprazole IM Depot (including generic formulation) is commercially available in the subject’s 
country.
3.5
Primary and Secondary Endpoints
3.5.1
Safety Endpoints
Adverse events will be examined by frequency, severity, seriousness, and discontinuation 
due to AEs.  The C-SSRS will be completed at baseline and every subsequent monthly 
visit to assess the risk of suicide events and to classify reported suicide events.  
Extrapyramidal symptoms will be evaluated by calculating mean change from baseline in 
AIMS, SAS, and BARS every 6 months (more frequently if warranted, see Table 3.6-1)
and at Study Completion or the Early Termination visit. Clinical laboratory tests will be 
performed at baseline, every 12 months, and at Study Completion or the Early 
Termination visit.  Vital signs will be assessed every 6 months and at Study Completion 
or the Early Termination visit. Body weight, height, and waist circumference will be 
assessed every 12 months; body weight and height will also be assessed at 
Study Completion or the Early Termination visit.
3.5.2
Efficacy Endpoint
CGI-S will be evaluated by calculating mean change from baseline every 6 months over 
the course of the study.
3.6
Trial Procedures
A schedule of assessments is provided in Table 3.6-1.
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Table 3.6-1
Schedule of Assessments (Study 31-10-270)
Assessment
Baseline
(Week 52 Visit of 
previous Otsuka 
31-08-248 study)a
Study Visits
Study 
Completion 
or Early 
Termination
30-Day Post 
Treatment 
Follow-up 
Phone Callc
Every 
Monthb
Every 3 
Monthsb
Every 6 
Monthsb
Every 12 
Monthsb
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(3 days)
STANDARD
Informed consent
X
Inclusion/exclusion criteria
X
Medical history
X
STUDY ASSESSMENTS
CGI-S
X
X
X
X
C-SSRS
X
X
X
X
X
X
AIMSd
X
X
X
X
SASd
X
X
X
X
BARSd
X
X
X
X
VAS pain at injection sitee
X
At the discretion of the investigator
Investigator rating of injection sitee
X
At the discretion of the investigator
Body height and weightf
X
X
X
BMIf
X
At the discretion of the investigator
Waist circumferencef
X
X
Adverse eventsg
X
X
X
X
X
X
X
Clinical laboratory tests (hematology, 
serum chemistry, and urinalysis)
X
At the discretion of the investigator
X
X
Vital signs
X
X
X
X
Physical exam
X
At the discretion of the investigator
ECG
X
At the discretion of the investigator
Urine pregnancy testh
X
X
X
X
X
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Table 3.6-1
Schedule of Assessments (Study 31-10-270)
Assessment
Baseline
(Week 52 Visit of 
previous Otsuka 
31-08-248 study)a
Study Visits
Study 
Completion 
or Early 
Termination
30-Day Post 
Treatment 
Follow-up 
Phone Callc
Every 
Monthb
Every 3 
Monthsb
Every 6 
Monthsb
Every 12 
Monthsb
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(3 days)
Urine drug screen and blood alcohol testi
X
At the discretion of the investigator
Concomitant medications
X
X
X
X
X
X
X
STUDY MANAGEMENT
Administer open-label IM Depotj
X
X
X
X
X
VAS = visual analog scale.
aBaseline visit for Study 270 will be the End of Treatment visit for Study 248 (Week 52).
bStudy months (study months are every 4 weeks which is defined as 28 [−2/+10] days) for assessments:
Every month:
Months 1 through 104.
Every 3 months:
Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 
and 102.
Every 6 months:
Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, and 102.
Every 12 months: Months 12, 24, 36, 48, 60, 72, 84, and 96.
cThe 30-Day Post Treatment Follow-up Phone Call will be conducted 30 days (3 days) after it has been determined that the subject will no longer 
participate in this open-label, rollover study, regardless of the reason. 
dExtrapyramidal symptoms (EPS) will be assessed using AIMS, SAS, and BARS at baseline, every 6 months, at Study Completion or the Early Termination
visit, and at other any study visit at the discretion of the investigator if warranted by the presence of symptoms.
eAt baseline (Week 52 visit of the previous Otsuka 31-08-248 study), each subject will complete the pain evaluation and the investigator (or qualified 
designee) will assess the most recent injection site for localized pain, redness, swelling, and induration.  These assessments will occur as the last 
evaluations prior to the IM Depot injection.  Approximately 30 minutes prior to the injection, the investigator and subject will complete the injection site 
evaluation and VAS pain assessment, respectively, with the most recent injection site as the basis for the evaluation (ie, the site from the last injection).  
These assessments will be repeated at 1 hour (± 15 min) after the injection is administered with focus again on the most recent injection site.  The pre- and 
post-injection evaluations must be completed on the same day (ie, the day the injection is administered).  The 1-hour post injection follow-up is to assess 
the injection site and any reaction to medication.  This assessment may be repeated at the discretion of the investigator.
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fNeedle length for injection of aripiprazole IM Depot will be selected based on BMI (21 gauge, 1.5 inch for BMI 28 kg/m2; 21 gauge, 2 inch for BMI 
> 28 kg/m2).  The BMI will be calculated in kg/m2 from the baseline height and weight at the baseline visit using one of the following formulae, as 
appropriate: Weight (kg) ÷ [Height (m)]2 or Weight (lb) ÷ [Height (in)]2 x 703.  If a noticeable fluctuation in body height and weight has occurred during 
the study, at the investigator’s discretion, body weight can be remeasured and BMI recalculated and used for the next aripiprazole IM Depot injection.  
Body weight, height, and waist circumference will be reassessed annually, and body weight and height will also be assessed at Study Completion or the 
Early Termination visit.
gAll ongoing AEs and clinically significant AEs from Study 248 will be recorded as Medical History of Study 270.
hA urine pregnancy test is required for all WOCBP at baseline, every 3 months, and at Study Completion or the Early Termination visit, but can be 
performed at any point during the trial if pregnancy is suspected.  All positive urine pregnancy test results must be confirmed by a serum test.  WOCBP is 
defined as ALL women unless they have had an oophorectomy and/or hysterectomy or have been menopausal for at least 12 consecutive months.  This 
should be documented in their medical history.  Subjects with positive serum test results will be excluded from the study.  Treated subjects with a positive 
serum pregnancy test must discontinue treatment, be withdrawn from the study, and an immediately reportable event (IRE) form should be completed.
iUrine drug screen and blood alcohol test are required at baseline and anytime at the investigator’s discretion.
jAripiprazole IM Depot (400 mg or 300 mg) will be injected every month (study months are every 4 weeks which is defined as 28 [−2/+10] days).
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3.6.1
Schedule of Assessments
For each visit, all assessments, except for post-injection assessments, should be 
performed prior to the aripiprazole IM Depot injection.
3.6.1.1
Baseline
The baseline visit for Study 270 (which is the Week 52 visit of Study 248) and the first 
injection for Study 270 must occur within 4 weeks (which is defined as 28 [−2/+10] days) 
of the last injection in Study 248.  At this visit, subjects will sign an Informed Consent 
for Study 270 and their eligibility will be confirmed.
The Study 248 Week 52 assessments will also serve as the baseline assessments for 
Study 270: CGI-S; C-SSRS; EPS assessments (AIMS, SAS, BARS); injection site pain 
assessed by the subject using VAS; investigator’s injection site assessment for pain, 
redness, swelling, and induration; body weight and height; BMI; waist circumference; 
AEs; clinical laboratory tests; vital signs; physical exam; ECG; urine pregnancy test for 
WOCBP (see Section 5.4 for the definition of WOCBP); urine drug screen; blood alcohol 
test; and concomitant medications (see Table 3.6-1).  All ongoing AEs and clinically 
significant AEs from Study 248 will be recorded as Medical History of Study 270; please 
refer to the Operations Manual or case report form (CRF) Completion Guidelines for 
additional detail.
In addition to the assessments, the baseline visit will also include the first aripiprazole 
IM Depot injection for Study 270.
3.6.1.2
Injection and Assessments Performed Every Month
Monthly assessments (study months are every 4 weeks which is defined as 
28 [−2/+10] days) include a C-SSRS assessment and recording of AEs experienced since 
the last visit and concomitant medications, followed by the aripiprazole IM Depot 
injection.  The monthly injections and assessments should be performed on 
Study Months 1 through 104.
3.6.1.3
Assessments Performed Every 3 Months
Every 3 months (study months are every 4 weeks which is defined as 28 [−2/+10] days), 
the following assessments will be performed: injection, C-SSRS, AEs, concomitant 
medications, and a urine pregnancy test for WOCBP.  These assessments should be 
performed on Study Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 
54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, and 102.
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3.6.1.4
Assessments Performed Every 6 Months
Every 6 months (study months are every 4 weeks which is defined as 28 [−2/+10] days)
the following assessments will be performed:  injection, C-SSRS, AEs, concomitant 
medications, a urine pregnancy test for WOCBP, CGI-S, vital signs, and EPS 
assessments (AIMS, BARS, SAS). These assessments should be performed on 
Study Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, and 102.
3.6.1.5
Assessments Performed Every 12 Months
Every 12 months (study months are every 4 weeks which is defined as 28 [−2/+10] days)
the following assessments will be performed:  injection, C-SSRS, AEs, concomitant 
medications, a urine pregnancy test for WOCBP, CGI-S, vital signs, and EPS 
assessments (AIMS, BARS, SAS), clinical laboratory tests, body height and weight, and 
waist circumference. These assessments should be performed on Study Months 12, 24, 
36, 48, 60, 72, 84, and 96.
3.6.1.6
Study Completion or Early Termination Visit 
A Study Completion visit or Early Termination visit (−2/+10 days) will be performed and 
will include the following assessments: C-SSRS, AEs, concomitant medications, a urine 
pregnancy test for WOCBP, CGI-S, vital signs, and EPS assessments (AIMS, BARS, 
SAS), clinical laboratory tests, and body height and weight.  
3.6.1.7
30-Day Post Treatment Follow-up Phone Call
A 30-Day Post Treatment Follow-up phone call will be performed 30 days (3 days) 
after it has been determined that the subject will no longer participate in this study and 
will include the recording of AEs that have occurred since the last visit and any 
concomitant medications taken since the last visit.
3.6.2
Efficacy Assessment (CGI-S)
The severity of illness for each subject will be rated using the CGI-S scale.28 To assess 
CGI-S, the rater or investigator will answer the following question: “Considering your 
total clinical experience with this particular population, how mentally ill is the patient at 
this time?” Response choices include: 0 = not assessed; 1 = normal, not ill at all; 
2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 
6 = severely ill; and 7 = among the most extremely ill patients.  A sample of the CGI-S 
Scale is provided in Appendix 6.
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3.6.3
Safety Assessments
3.6.3.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
3.6.3.2
Clinical Laboratory Assessments
A central laboratory designated by the sponsor will be used for all laboratory testing 
required. 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.   
Samples for serum chemistry, hematology, and urinalysis will be obtained at baseline, 
every 12 months (study months are every 4 weeks which is defined as 28 [−2/+10] days), 
and at Study Completion or the Early Termination visit as specified in Table 3.6-1.  Urine 
and blood samples may be collected for further evaluation of safety as warranted by the
investigator’s judgment.
Subjects should be fasting for a minimum of 10 hours prior to any blood draws for 
assessment of safety, including baseline.  If a nonfasting blood sample is initially 
obtained and the test results possibly impacted, a fasting blood sample should be drawn 
shortly afterwards and the affected lab test(s) repeated.  The laboratory tests to be 
evaluated in this trial are listed in Table 3.6.3.2-1.
For Study 270, a urine pregnancy test will be performed at baseline, every 3 months, at 
Study Completion or the Early Termination visit, and at any time at the discretion of the 
investigator when pregnancy is suspected for all WOCBP (see Section 5.4 for the 
definition of WOCBP) to confirm that the subject is not pregnant.  Any positive urine 
pregnancy test result will be confirmed by a serum test.
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Table 3.6.3.2-1
Baseline Clinical Laboratory Assessments
Hematology:
White Blood Cell Count (WBC) with differential 
Red Blood Cell Count (RBC)
Hematocrit
Hemoglobin
Platelet count
Urinalysis
Specific gravity
pH
Glucose
Protein
Ketones
Blood
Microscopic exam (performed only if any part of the 
urinalysis is not negative)
Other
Urine pregnancy (WOCBP)a
Serum beta-human chorionic gonadotropin (-hCG)
(WOCBP)a
Urine drug screen
Blood alcohol
Serum Chemistry:
Blood Urea Nitrogen (BUN)
Creatinine
Creatine Phosphokinase (CPK)
Aspartate Transaminase (AST or SGOT)
Alanine Transaminase (ALT or SGPT)
Lactate Dehydrogenase (LDH)
Alkaline Phosphatase (ALP)
Total Bilirubin
Triglycerides 
Cholesterol (total, low-density lipoprotein [LDL], 
and high-density lipoprotein [HDL])
Calcium
Glucose
Hemoglobin A1cb
Insulin
Sodium
Potassium
Total Protein
Uric acid
Gamma Glutamyl Transferase (GGT)
Prolactin
NOTE:  Subjects should be fasting for a minimum of 10 hours prior to any blood draws for assessment 
of safety.  If a nonfasting blood sample is initially obtained and the test results possibly impacted, a 
fasting blood sample should be drawn shortly afterwards and the affected lab test(s) repeated.
aA urine pregnancy test will be performed at baseline for all WOCBP (see Section 5.4 for the definition 
of WOCBP) to assess eligibility for the study and will be repeated every 3 months throughout the 
trial, at Study Completion or the Early Termination visit, and at any time at the discretion of the 
investigator when pregnancy is suspected.  All positive urine pregnancy test results must be 
confirmed by a serum test.
bAt the discretion of the investigator, hemoglobin A1c will be measured if the subject’s fasting glucose 
is ≥ 125 mg/dL and/or the urinalysis is positive for glucose.  If the subject’s glucose is ≥125 mg/dL, 
but the sample was not obtained with the subject in a fasted state, a fasting glucose should be 
performed to confirm that the value is ≥ 125 mg/dL before testing hemoglobin A1c.
Any baseline 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.  Subjects may enroll 
into the study prior to obtaining baseline results, but will be subsequently withdrawn if 
clinically significant results are identified.  In addition, follow-up unscheduled labs 
should be performed on clinically significant abnormalities.  Unscheduled laboratory 
tests may be repeated at any time at the discretion of the investigator for appropriate 
medical care.
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The following laboratory test results are exclusionary:
1) Platelets ≤ 75,000/mm3
2) Hemoglobin 9 g/dL
3) Neutrophils, absolute 1000/mm3
4) AST > 3x upper limit of normal
5) ALT > 3x upper limit of normal
6) Creatinine 2 mg/dL
In addition, subjects should be excluded if they have any other abnormal laboratory test 
result at baseline that, in the investigator’s judgment, is medically significant in that it 
would impact the safety of the subject or interpretation of the study results.  Appendix 4
is included to assist investigators in their assessments of the results that may be 
potentially medically significant, depending on the subject’s medical history and clinical 
presentation.
3.6.3.3
Physical Examination and Vital Signs
3.6.3.3.1
Physical Examination
A complete physical examination, including height, will be performed at baseline.  The 
physical examination may be repeated at the discretion of the investigator at any 
subsequent visit.  Height will be measured with a stadiometer, measuring stick, or tape.  
The principal investigator or his/her appointed designee is primarily responsible to 
perform the physical exam.  If the appointed designee is to perform the physical exam, 
he/she must be permitted by local regulations and his/her name must be included on the 
US FDA Form 1572.  Whenever possible, the same individual should perform all 
physical exams.  Any condition present at subsequent physical exams that was not 
present at the baseline exam should be documented as an AE and followed to a 
satisfactory conclusion.
3.6.3.3.2
Vital Signs
Vital sign measurements will be performed at baseline, every 6 months (study months are 
every 4 weeks which is defined as 28 [−2/+10] days), and at Study Completion or the 
Early Termination visit, and will include body temperature, systolic and diastolic blood 
pressure, and heart rate.  Orthostatic assessments of blood pressure and heart rate will be 
made after the subject has been supine for at least 5 minutes and again after the subject
has been sitting for 2 minutes.
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A diastolic blood pressure > 105 mm Hg is exclusionary.  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 study results.  Appendix 3 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.
3.6.3.3.3
Body Height and Weight and Body Mass Index
Body height and weight will be measured at baseline prior to the first dose of aripiprazole 
IM Depot, every 12 months (study months are every 4 weeks which is defined as 
28 [−2/+10] days), and at Study Completion or the Early Termination visit. The 
following guidelines will aid in the standardization of these measurements:

The same scale should be used to weigh a given subject each time.

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.
BMI (kg/m2) will be calculated from the baseline height and the weight using one of the 
following formulae, as appropriate: 
Weight (kg) ÷ [Height (m)]2 or Weight (lb) ÷ [Height (in)]2 x 703.
For the IM depot injection, the BMI will be supplied to the individual administering the 
injection so that the appropriate needle length can be selected based on BMI (21 gauge, 
1.5 inch for BMI ≤ 28 kg/m2; 21 gauge, 2 inch for BMI > 28 kg/m2).  If a noticeable 
fluctuation in body weight has occurred during the study, at the investigator’s discretion, 
body height and weight can be remeasured and BMI recalculated and used for the next 
aripiprazole IM Depot injection. BMI may be calculated at subsequent visits at the 
discretion of the investigator.  Body height and weight (not BMI) will be reassessed 
annually and at any study visit at the discretion of the investigator.  
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3.6.3.3.4
Waist Circumference
Waist circumference will be measured at baseline and every 12 months (study months are 
every 4 weeks which is defined as 28 [−2/+10] days), or at other visits at the discretion of 
the investigator.  The following procedures will aid in the standardization of these 
measurements:

The subject should be minimally clothed (ie, lightweight clothing; no heavy over
garments).

Waist circumference should be recorded before a subject’s meal and at approximately 
the same time at each visit.

Measurement will be accomplished by locating the upper hip bone and the top of the 
right iliac crest and placing the 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.28
3.6.3.4
ECG Assessments
Twelve-lead ECGs will be recorded at baseline and at the discretion of the investigator.  
The ECG criteria for baseline ECG for Study 270 (which is the Week 52 visit of Study 
248) will be done per Study 248 requirements.  
At baseline, three ECG recordings will be obtained approximately 5 minutes apart.  All 
ECGs will be evaluated at the investigational site to determine the subject’s eligibility.  
The principal investigator or qualified designee will review, sign, and date each ECG 
reading obtained, noting whether or not any abnormal results are of clinical significance.  
The ECG will be repeated if any results are considered to be clinically significant.  As of 
Amendment 4, ECG results will not be obtained centrally after the baseline assessment.  
Any subsequent ECG assessments will be obtained locally at the discretion of the 
investigator.
At baseline, QTc > 475 msec on either the QTcB (Bazett) or QTcF (Fridericia) 
corrections on 2 of 3 time points of triplicate ECGs performed is exclusionary (see 
Exclusion #9 in Table 3.4.3-1).  In addition, subjects should be excluded if they have any 
other abnormal ECG finding at baseline that, in the investigator’s judgment, is medically 
significant in that it would impact the safety of the subject or the interpretation of the 
study results.  However, 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 study.  Appendix 5 is provided as a guide for determining potentially 
clinically relevant ECG abnormalities.
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3.6.3.5
Extrapyramidal Symptoms
Extrapyramidal symptoms are assessed at baseline, every 6 months (study months are
every 4 weeks which is defined as 28 [−2/+10] days), and at Study Completion or the 
Early Termination visit.  The EPS symptoms may also be reassessed at the discretion of 
the investigator using the instruments described in Section 3.6.3.5.1, Section 3.6.3.5.2, 
and Section 3.6.3.5.3.  
3.6.3.5.1
Abnormal Involuntary Movement Scale
The AIMS29 assessment (Appendix 7) 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 0 representing absence of symptoms (for item 10, no 
awareness), and a score of 4 indicating a severe condition (for item 10, awareness/severe 
distress).  For this scale, the subject is to be sitting on a hard, firm chair.  In addition, the 
AIMS includes two yes/no questions that address the subject’s dental status.
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 through 6, extremity movements; and 
item 7, trunk movements).
3.6.3.5.2
Simpson-Angus Scale
The SAS30 (Appendix 8) 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 1 representing absence of symptoms, and a score of 5 representing a severe condition.  
The SAS Total Score is the sum of the scores for all 10 items.
3.6.3.5.3
Barnes Akathisia Rating Scale
The BARS31 (Appendix 9) consists of 4 items related to akathisia:  objective observation 
of akathisia by the investigator, subjective feelings of restlessness by the subject, subject
distress due to akathisia, and global evaluation of akathisia.  The first 3 items will be 
rated on a 4-point scale, with a score of 0 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 0 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 
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other situations (eg, while engaged in neutral conversation or engaged in activity on the 
ward) may also be rated.  Subjective phenomena are to be elicited by direct questioning.
The BARS Global Score is from the global clinical assessment of akathisia from the 
panel BARS in the CRF.
3.6.3.6
Suicidality
Suicidality will be monitored using the C-SSRS at baseline, every subsequent monthly
visit, and at Study Completion or the Early Termination visit.  The C-SSRS was 
developed by a team of researchers at Columbia University to address the need for 
standardized classification of suicide reports to assess suicide risk.  This scale consists of 
a baseline evaluation that assesses the lifetime experience of the subject with suicide 
events and suicidal ideation and a post-baseline evaluation that focuses on suicidality 
since the last study visit.  A baseline C-SSRS will be completed and a C-SSRS Since Last 
Visit form will be completed at all designated visits.  Copies of the C-SSRS forms are 
provided in Appendix 10.
3.6.3.7
Injection Site Evaluation
Injection site reaction will be assessed at baseline and at the discretion of the investigator 
(or qualified designee) and the subject at any subsequent study visit in a manner similar 
to that used for the evaluation of other IM depot compounds.5,32  Investigators (or 
qualified designees) at baseline will rate localized pain, redness, swelling, and induration 
at the most recent injection site using a 4-point categorical scale ranging from absent to 
severe (Appendix 12).  The subject will indicate the degree of pain at the most recent 
injection site using a VAS (Appendix 11).  Ratings will range from 0 (no pain) to 
100 (unbearably painful).  If required, these assessments will be completed both pre- and 
post-injection, after all other study assessments, and within 30 minutes prior to the 
IM depot injection.  The subject will then receive the injection and will be followed for 
1 hour post-injection to assess the injection site and any reaction to medication.  The 
subject will complete the VAS and the investigator (or qualified designee) will re-assess 
localized pain, redness, swelling, and induration at the injection site at 1 hour (± 15 min) 
post-injection with focus on the current injection site which is now the new injection site 
from the latest injection.  Pre- and post-injection evaluations must be completed on the 
same day (ie, the day the injection is administered).  As of Amendment 4, VAS and 
injection site assessments are no longer required at any post-baseline study visits.
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3.6.4
End of Trial
The End of Trial Date is defined as the last Date of Contact or the Date of Final Contact 
Attempt from the Post-treatment Follow-up case report form (CRF) page for the last 
subject completing or withdrawing from the trial.
3.7
Stopping Rules, Withdrawal Criteria, and Procedures
3.7.1
Entire Trial or Treatment Arm(s)
The sponsor should be notified promptly if the trial is terminated at your site.  If the 
sponsor decides to terminate or suspend the trial for safety or unanticipated other reasons
or if aripiprazole IM Depot becomes commercially available in the country of the study 
site, the sponsor will promptly notify investigators, IRBs/IECs, and regulatory authorities 
as required by the applicable regulatory requirements.
The sponsor will terminate the study in countries where aripiprazole IM Depot becomes 
commercially available (including generic formulation[s]), the commercial availability of 
aripiprazole IM Depot is terminated by the sponsor, or if the study end date of 
31 Dec 2018 is reached.
If the sponsor terminates the study prior to 31 Dec 2018 for any reason other than 
commercial availability, investigators in some countries where the sponsor has limited or 
delayed commercialization plans, or where no commercialization activity is anticipated, 
may be eligible to participate in a managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.  Availability and 
requirements of such a program varies by jurisdiction, and would only be an option for 
subjects who were receiving aripiprazole IM Depot in the current study, and who in the 
physician’s opinion, may benefit from continued treatment with aripiprazole.  To gain 
access to aripiprazole IM Depot for eligible subjects via a managed access program, each 
physician will be responsible for gaining appropriate local regulatory approvals, which 
will be granted by authorities on a case-by-case basis.  The sponsor makes no guarantee 
that such a program is available or approvable in all of the jurisdictions where the study is 
conducted.
3.7.2
Individual Center
A particular center may be terminated from the trial at the discretion of the investigator, 
sponsor, or IRB, eg, for non-enrolment of subjects or non-compliance with the protocol.
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3.7.3
Individual Subject
All subjects have the right to withdraw at any time during treatment without prejudice.  
The investigator can discontinue a subject’s participation in the trial at any time if 
medically necessary.  In addition, subjects meeting the following criteria must be 
withdrawn from the trial:
1) Occurrence of any AE, intercurrent illness or abnormality in laboratory 
assessment results which, in the opinion of the investigator, warrants the subject’s 
permanent withdrawal from the trial;
2) Treatment with a prohibited concomitant medication other than the use of 
appropriate medications for the treatment of AEs under direction of the 
investigator;
3) Subject noncompliance, defined as refusal or inability to adhere to the trial 
schedule or procedures (see Section 3.11);
4) At the request of the subject, investigator, sponsor, or regulatory authority; 
5) Subject becomes pregnant;
6) Subject is hospitalized due to exacerbation of psychotic symptoms;
7) Subject is lost to follow-up;
8) Subject misses 2 consecutive or 3 non-consecutive aripiprazole IM Depot 
injections in a 52-week period; 
9) Aripiprazole IM Depot is commercially available (including a generic 
formulation) in the country where the study is being conducted or the commercial 
availability of aripiprazole IM Depot is terminated by the sponsor.
The sponsor should be notified promptly when a subject is withdrawn according to 
procedures outlined in the Operations Manual and/or in the Adverse Events Reporting 
Plan.
3.8
Screen Failures
There is no screening period in Study 270 as only subjects completing Study 248 and 
directly rolling over to Study 270 are eligible for inclusion.  However a subject who does 
not meet baseline inclusion/exclusion criteria for Study 270 may still be considered a 
screening failure, which is defined as a subject from whom informed consent is obtained 
and is documented in writing (ie, subject signs an ICF), but who is not started on 
Study 270 open-label treatment.  Subjects who meet this criterion and are listed as screen 
failure subjects in Study 270 are not permitted to be re-screened at a later date.
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3.9
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether or not the subject
actually received all doses of the study medication.  Subjects who are evaluated at the last 
scheduled visit during the treatment period will be defined as trial completers.  Subjects
who have their last visit by 31 Dec 2018, because they have reached the end of the study, 
will be defined as completers. For purposes of this trial, subjects who discontinue due to 
the commercial availability of study drug in the country where the study is being 
conducted will be defined as completers.  In addition, subjects in countries where a 
managed access program is available for continued treatment with aripiprazole at the time 
of trial closure in their respective country, regardless of whether they transition to a 
managed access program, will also be defined as completers.  Protocol-specified 
post-treatment follow-up contacts will not qualify as “last scheduled” visit.
3.10
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted at any time up through the last scheduled follow-up 
visit and who do not have a known reason for discontinuation (eg, withdrew consent or 
AE, etc) will be classified as “lost to follow-up” as the reason for discontinuation.  Three 
attempts will be made by investigative sites to reach subjects, two by phone and one via 
certified mail.
3.11
Subject Compliance
Visit compliance is critical to achieving and maintaining stability of psychotic symptoms 
and to maintaining subjects on a schedule that will lead to completion of the IM Depot 
treatment within an acceptable time window.  The key features of compliance can be 
summarized as follows:
1) IM depot injections are to be administered within an interval of 28 days between 
injections.  The minimum allowable interval between IM depot injections is 
26 days and the maximum interval is 38 days.  Every effort should be made to 
adhere to the 28-day cycle.
2) If a subject misses 2 consecutive injections at any time in the study, or if a subject
misses 3 injections in a 52-week time period, then this subject is considered 
noncompliant and must be withdrawn from the study.
Evaluations conducted outside of the windows defined in Table 3.6-1 will be considered 
deviations, but will not impact the subject’s ability to continue the study.
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Visit windows are provided not only to allow flexibility with scheduling, but also to 
assure an adequate supply of study medication between injections.  If a subject misses an 
injection, the injection should be given at the earliest opportunity.  A missed dose of 
IM depot is defined as a lapse of > 38 days between injections.  The minimum interval of 
26 days and maximum interval of 38 days between injections is to ensure that therapeutic 
plasma concentrations of aripiprazole are maintained.
The time and date of each dose of aripiprazole IM Depot will be recorded on the CRF.  
If a dose was not administered as scheduled, an explanation will be provided in the CRF 
and supported by source documentation.  The accountability of IM depot vials will be 
maintained at the vial level.  Subjects who, in the investigator’s judgment, are 
noncompliant with the IM depot injection schedule should be counseled on the 
importance of adhering to the treatment schedule.  Reasons for noncompliance should be 
determined, if possible.  Investigators should use their judgment to assess the feasibility 
of continuing subjects in the study who are significantly noncompliant.
3.12
Protocol Deviations
This trial is intended to be conducted as described in this protocol.  In the event of a 
significant deviation from the protocol due to an emergency, accident, or mistake (eg, 
study drug dispensing or subject dosing error, treatment assignment error, subject
enrolled in violation of significant eligibility criteria or concomitant medication criteria), 
the investigator or designee must contact the sponsor’s designee (Medical Monitor) at the 
earliest possible time according to the Approval for Study Continuation process which is 
outlined in the Operations Manual.  This will allow an early joint decision regarding the
subject’s continuation in the trial.  This decision will be documented by the investigator 
and the designated Medical Monitor, and reviewed by the study monitor.
4
Restrictions
4.1
Prohibited Medications
Medications that are prohibited or restricted prior to screening and/or during the trial are 
listed by phase in Table 4.1-1.  No prohibited or restricted medications should be used 
within the visit windows when transitioning from Study 248 to Study 270.  The 
prohibited and restricted medications also apply to any clinical transition period within 
allowed visit windows from Study 248 into Study 270.
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Table 4.1-1
List of Medications Prohibited or Restricted in Study 270
Psychotropic Medications
Antipsychotics
Not allowed
Antidepressants (including MAOIs)
Allowed, except for CYP2D6 or CYP3A4 inhibitors or 
CYP3A4 inducers
Benzodiazepinea
Allowed
Mood stabilizers
Allowed
Non-benzodiazepine sleep aidsa
Allowed
Other Medications
Anticholinergics
Allowed
Propranolol (for akathisia, tremor, or if taking 
for cardiac reasons)b
Allowed
Varenicline
Not allowed
Nutritional supplements and non-prescription 
herbal preparations with CNS effects (eg, St. 
John’s Wort, omega-3 fatty acids, kava extracts, 
GABA supplements, etc.)
Allowed, but use caution
CYP3A4 or CYP2D6 inhibitors or CYP3A4 
inducers (see Section 4.2.1)
Not allowed
CNS = central nervous system; GABA = gamma-aminobutyric acid.
Note:  No prohibited or restricted medications should be used within the visit windows when 
transitioning from Study 248 to Study 270.  The prohibited and restricted medications also apply to 
any clinical transition period within allowed visit windows from Study 248 into Study 270.
aBenzodiazepine use is allowed during the study to manage treatment emergent AEs such as agitation, 
anxiety, and insomnia; however, non-benzodiazepine sleep aids are recommended for insomnia.  
Combined use of both drug classes (ie, benzodiazepines and non-benzodiazepine sleep aids) as 
treatment for insomnia is not allowed.  Benzodiazepine use 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.
bSubjects receiving propranolol for heart disease may remain on stable, pre-trial doses, as needed, 
throughout the study so long as the total dose does not exceed 60 mg/day.
4.2
Other Restrictions
4.2.1
Restricted Therapies and Precautions
No prohibited or restricted medications should be used within the visit windows when 
transitioning from Study 248 to Study 270.  The prohibited and restricted medications 
also apply to any clinical transition period within allowed visit windows from Study 248 
into Study 270.
The subject’s best medical interests should guide the investigator in the management of 
conditions that are pre-existing or that develop during the study (intercurrent illness or 
AEs).  All study personnel should be familiar with the content of the Investigator’s
Brochure for aripiprazole9 in order to manage the subject’s condition adequately and 
select appropriate concomitant medications, if needed.  The investigator should carefully 
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assess the potential for interaction with aripiprazole before prescribing any concomitant 
medications.
The use of CYP3A4 or CYP2D6 inhibitors and CYP3A4 inducers is not permitted during 
the study, as they may affect the pharmacokinetics of aripiprazole.  Examples of 
inhibitors include, but are not limited to, amiodarone, celecoxib, chlorpheniramine, 
cimetidine, clarithromycin, clemastine, diltiazem, erythromycin, itraconazole, 
ketoconazole, methadone, nafazodone, pyrilamine, quinidine, rifampin, terbinafine, 
tripelennamine, verapamil, and human immunodeficiency virus protease inhibitors 
(eg, amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir).  Examples of inducers 
include, but are not limited to, carbamazepine, dexamethasone, phenobarbital, phenytoin, 
and non-nucleoside reverse transcriptase inhibitors (eg, efavirenz and nevirapine).  The 
Medical Monitor should be consulted for any questions regarding the potential for 
pharmacokinetic interactions with concomitant medications used by subjects during the 
trial.
Other guidelines for use of concomitant medications during the trial include:

Treatment of allergy symptoms: Non-sedating antihistamines are permitted.

Treatment of cold/flu symptoms: Medications containing ingredients that have central 
nervous system (CNS) effects should be limited to short-term use and discontinued as 
soon as the symptom(s) resolve.

Treatment of gastroesophageal reflux disease (GERD): The use of cimetidine is 
prohibited.  All other medications for the treatment of GERD are permitted.

Treatment of hypertension: Medications that are CYP3A4 or CYP2D6 inducers or 
inhibitors (eg, verapamil) are prohibited.

Treatment of diabetes: No additional guidelines.

Treatment of infection: No additional guidelines.
4.2.2
Non-therapy Precautions and Restrictions
Subjects will be instructed to refrain from drinking alcoholic beverages or using illicit 
drugs during participation in the trial.  The investigator should consult with the Medical 
Monitor in the event that a false-positive drug screen result is suspected (eg, drug screen 
testing in subjects taking medications that have phenylpropanolamine or pseudoephedrine 
may produce a false-positive result for amphetamine).  The investigator may request a 
blood or urine drug screen at any time during the study if there is a suspicion of illicit 
drug use.
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5
Reporting of Adverse Events
The following describes the methods and timing for assessing, recording, and analyzing 
safety parameters, as well as the procedures for eliciting reports of and recording and 
reporting AEs and intercurrent illnesses and the type and duration of the follow-up of 
subjects after AEs.
5.1
Definitions
An adverse event (AE) is defined as any new medical problem, or exacerbation of an 
existing problem, experienced by a subject while enrolled in the study, whether or not it 
is considered drug-related by the investigator.
A serious AE (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 disability/incapacity.

Requires in-patient hospitalization or prolongs hospitalization.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above, eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse.
Non-serious adverse events are all AEs that do not meet the criteria for a "serious" 
adverse event.
Immediately Reportable Event (IRE):  

Any serious adverse event.

Any AE that necessitates discontinuation of study drug.

Potential Hy’s Law cases (Any increase of AST or ALT ≥ three times the upper 
normal limit with ≥ two times increase in total bilirubin).

Pregnancies are also defined as IREs.  Although normal pregnancy is not an adverse 
event, it will mandate drug discontinuation and must be reported on an IRE form to 
Otsuka Pharmaceutical Development and Commercialization, Inc. (OPDC).  
Pregnancy will only be documented on the AE-CRF if there is an abnormality or 
complication.
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Clinical Laboratory Changes:  It is the investigator’s responsibility to review the results 
of all laboratory tests as they become available.  This review will be documented by the 
investigator’s dated signature on the laboratory report.  For each abnormal laboratory test 
result, the investigator needs to ascertain if this is an abnormal (ie, clinically significant) 
change from baseline for that individual subject.  (This determination, however, does not 
necessarily need to be made the first time an abnormal value is observed.  The 
investigator may repeat the laboratory test or request additional tests to verify the results 
of the original laboratory tests).  If this laboratory value is determined by the investigator 
to be an abnormal change from baseline for that subject, this is considered an AE.
Severity: AEs will be graded on a 3-point scale and reported as indicated on the CRF.
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.  
The causal relationship of the study drug to an AE is assessed as related or unrelated, as 
follows:
Related:
Definite:  There is a reasonable causal relationship between the study drug and 
the AE or the event responds to withdrawal of the study drug (dechallenge) and 
the Investigator’s assessment of the event is deemed “Definitely Related” based 
on the sum of available clinical information gathered.
Probable:  There is a reasonable causal relationship between the study drug and 
the AE.  The event may respond to dechallenge or the Investigator’s assessment 
of the event is deemed “Probably Related” based on the sum of available clinical 
information gathered.
Possible:  There is a reasonable causal relationship between the study drug and 
the AE.  Dechallenge is lacking or unclear and the Investigator’s assessment of 
the event is deemed “Possibly Related” based on the sum of clinical information 
gathered.
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Unrelated:
Not Likely:  There is a temporal relationship to study drug administration, but 
based on the available clinical information the Investigator deems that there is no 
reasonable causal relationship between the study drug and the event.
Not Related:  Based on the available clinical information the Investigator deems 
that there is no temporal or causal relationship to study drug administration.
5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs.  In order to 
avoid bias in eliciting AEs, subjects should be asked the following nonleading question: 
"How have you felt since your last visit?"  All AEs (serious and nonserious) reported by 
the subject must be recorded on the source documents and CRFs provided by the sponsor 
or designee. 
Note: Normal pregnancy is not an AE and should not be recorded on the AE form of the 
CRF; guidelines outlined in Section 5.4 should be followed for pregnancy reporting.
In addition, OPDC or their designee (see Appendix 2) must be notified immediately by 
telephone or fax of any immediately reportable events according to the procedure 
outlined below (Section 5.3).  Special attention should be paid to recording 
hospitalization and concomitant medications.
5.3
Immediately Reportable Events
The investigator must report any SAE, potential Hy’s law case or confirmed pregnancy, 
by telephone [(888) 724-4908] or by fax [(888) 887-8097] to OPDC or their designee 
immediately after the investigator becomes aware of the event. An Immediately 
Reportable Event (IRE) form should be completed and sent by fax or overnight courier to 
the sponsor or their designee up to and including 24 hours of knowledge of the event by 
the site. (Please note that the IRE form is NOT the adverse event case report form.)
Non-serious events that require discontinuation of study drug (including laboratory 
abnormalities) should be reported to OPDC or their designee up to and including 
3 working days. The IRE form should be completed and sent by fax or overnight courier 
to OPDC or their designee.
Subjects experiencing serious adverse events should be followed clinically until their 
health has returned to baseline status or until all parameters have returned to normal, or 
have otherwise been explained. It is expected that the investigator will provide or 
arrange appropriate supportive care for the subject.
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5.4
Pregnancy
WOCBP is defined as ALL women unless they have had an oophorectomy and/or 
hysterectomy or have been menopausal for at least 12 consecutive months.  This should 
be documented in their medical history.  Subjects with positive serum test results will be 
excluded from the study.
WOCBP who are sexually active must use an effective method of birth control during the 
course of the trial so risk of failure is minimized.  Unless the subject and his/her 
partner(s) are sterile (ie, women who have had an oophorectomy and/or hysterectomy or 
have been postmenopausal for at least 12 consecutive months; or men who have had 
orchidectomy) or remain abstinent, two of the following precautions must be used: 
vasectomy, tubal ligation, vaginal diaphragm, IUD, birth control pills, 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.
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about 
trial participation for WOCBP.  The topics should include:

General information

Informed Consent Form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Prior to trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  Males should also be instructed not to impregnate their partners while on 
study drug.  The subject must sign an ICF stating that the above-mentioned risk factors 
and the consequences were discussed.
During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle). 
If a subject or investigator suspects that the subject may be pregnant prior to 
administration of the study drug, administration must be withheld until the results of 
blood serum pregnancy tests are available.  If the pregnancy is confirmed, the subject
must not receive the study drug or be enrolled in the trial.  If pregnancy is suspected 
while the subject is receiving treatment, the study drug must be withheld immediately 
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(if reasonable, taking into consideration any potential withdrawal risks) until the result of 
the pregnancy test is known.  If pregnancy is confirmed, the study drug 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 Drug Safety Services (see Appendix 2).]
The investigator must immediately notify Drug Safety Services of any pregnancy 
associated with exposure to aripiprazole IM Depot.  For subjects who received at least 
one dose of IM depot, the reporting period includes 150 days after last injection for 
female subjects and 180 days after the last injection for female partners of male subjects.  
For all pregnancy reports, the investigator will record the event on the IRE form and 
forward it to the Drug Safety Services department of the sponsor’s designee.  Drug Safety 
Services will forward Pregnancy Surveillance Form(s) for monitoring the outcome of the 
pregnancy.  Pregnancy will only be documented on the AE CRF if there is an 
abnormality or complication to be reported.
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 (or sponsor’s designee) 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.
5.5
Follow-up of Adverse Events
5.5.1
Follow-up of Non-serious Adverse Events
Non-serious AEs that are identified on the last scheduled contact must be recorded on the 
AE CRF with the current status noted.  All non-serious events that are ongoing at this 
time will be recorded as ongoing on the CRF.  Site personnel will make a follow-up call 
to the subject 30 days (3 days) after the last study visit to inquire about any AEs that 
were ongoing at the time of the last visit and any new AEs and to assess if any new SAEs 
have occurred.  
5.5.2
Follow-up of Serious Adverse Events
SAEs that are identified on the last scheduled contact must be recorded on the AE CRF 
page and reported to the sponsor’s designee according to the reporting procedures 
outlined in Section 5.3.  This may include unresolved previously reported SAEs, or 
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new SAEs.  The investigator should follow these SAEs until the events are resolved, or 
the subject is lost to follow-up.  Resolution means the subject has returned to the baseline 
state of health, or the investigator does not expect any further improvement or worsening 
of the subject’s condition.  The investigator should continue to report any significant 
follow-up information to the sponsor’s designee up to the point the event has been 
resolved.
This trial requires that withdrawn subjects be actively monitored for SAEs up to 30 days 
(± 3 days) after discharge from the trial.  Any new SAEs reported by the subject to the 
investigator that occur after the last scheduled contact, and are determined by the 
investigator to be reasonably associated with the use of the study drug, should be reported 
to the sponsor’s designee.  This may include SAEs that are captured on follow-up 
personal or telephone contact or at any other time point after the defined trial period (ie, 
up to last scheduled contact).  The investigator should follow serious related AEs 
identified after the last scheduled contact until the events are resolved, or the subject is 
lost to follow-up.  The investigator should continue to report any significant follow-up 
information to the sponsor’s designee up to the point the event has been resolved. 
6
Pharmacokinetic or Pharmacodynamic Analysis
No pharmacokinetic or pharmacodynamic assessments will be conducted.
7
Statistical Analysis
The safety and tolerability evaluated will be based on safety parameters, eg, AEs, vital 
signs, ECGs, laboratory assessments, and injection pain assessments by the subject and 
investigator.  Additionally, the risk of suicide will be evaluated using the C-SSRS.  
Efficacy will be evaluated using the CGI-S.
Due to the open-label single-arm nature of the study, all data on safety and 
efficacy/outcome will be summarized using descriptive statistics (eg, mean, standard 
deviation, maximum, minimum, and proportions).
Withdrawn subjects will not be replaced. 
7.1
Dataset for Analysis
Since subjects in this study will be rolling over from another open-label study of 
aripiprazole IM Depot and will already be exposed to aripiprazole, all enrolled subjects
will constitute the core data set for analysis.  All safety analyses will be based on this 
core dataset.  The dataset for efficacy outcome analyses will be derived from the core 
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dataset.  In particular, for a change from baseline analysis, only subjects having a 
baseline and a post-baseline value on the efficacy outcome measure will be included.
7.2
Baseline Values
Since subjects will be rolling over in the study from Study 248, evaluations at the 
Week 52 visit of Study 248 will be used as baseline for this study.
7.3
Primary Outcome Measures
In this safety and tolerability study, the primary measures are (1) frequency and severity 
of adverse events, (2) frequency and severity of serious adverse events (including adverse 
events related to laboratory abnormalities), and (3) rates of discontinuation from study 
due to adverse events.  
Safety and tolerability data will be summarized as follows:  Incidence of adverse events 
and serious adverse events (with severity grades) will be tabulated by Medical Dictionary 
for Regulatory Activities (MedDRA) terms; similarly, incidence of discontinuations due 
to AE will be tabulated by MedDRA terms. 
7.4
Secondary Outcome Measures
Mean change from baseline of vital signs parameters, laboratory tests, and ECG 
parameters will be provided by visit.  Incidence of clinically significant abnormalities in 
vital signs parameters, laboratory tests, and ECG parameters will be tabulated.  
Percentage of subjects showing significant weight gain or loss from enrollment to 
endpoint (significant weight change is defined as a ≥7% increase or decrease in weight) 
will be provided.  Injection site reactions will be summarized by visit using the mean of 
VAS subject-reported rating scores and investigator’s rating of local pain, swelling, 
redness and induration at the injection site.  Data collected on the C-SSRS will be 
summarized by visit also.
Mean and mean change from baseline in the efficacy endpoint CGI-S score will be 
summarized by visit.  Descriptive statistics of EPS will be provided by calculating mean 
change from baseline in AIMS, SAS, and BARS.  Results will be summarized by visit.  
7.5
Sample Size
In this open-label, single arm rollover study, no formal sample computations were 
employed.  The anticipated number of subjects from Study 248 that is predicted to enroll 
in this study is approximately 500 to 800 subjects.
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8
Management of Investigational Medicinal Product
8.1
Packaging and Labeling
The study drug will be provided to the investigator(s) by the sponsor or designated agent.  
The aripiprazole IM Depot formulation will be supplied as aripiprazole 400 mg 
lyophilized vials packaged in supply cartons labeled similarly to the oral study 
medication.  Prior to injection, vials of aripiprazole IM Depot 400 mg will be 
reconstituted with a designated quantity of Sterile Water for Injection.  A volume 
corresponding to the dose to be administered (ie, aripiprazole 400 mg or aripiprazole 
300 mg) will be withdrawn from the proper vial using an appropriate size syringe.
The reconstituted drug product must be prepared using aseptic technique and 
administered intramuscularly.  The dose must be administered to the subject within the 
required timeframe of preparation.  Needle length for injection of aripiprazole IM Depot 
will be selected based on BMI (21 gauge, 1.5 inch for BMI ≤ 28 kg/m2; 21 gauge, 2 inch 
for BMI > 28 kg/m2).  All doses of aripiprazole IM Depot must be injected into the 
gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel.  
Specific directions for the reconstitution and administration of IM depot injections will be 
provided in the Operations Manual.
8.2
Storage
Study drug will be stored in a securely locked cabinet or enclosure.  Access should be 
strictly limited to the investigators and their designees.  Neither the investigators nor any 
designees may provide study drug to any subject not participating in this protocol.
Lyophilized vials of aripiprazole IM Depot should be stored in a refrigerator at 2 to 8°C 
(36 to 46°F) and protected from light.  The clinical site staff will maintain a temperature 
log in the drug storage area recording the temperature at least once each working day.
8.3
Accountability
The investigator, or designee, must maintain an inventory record of the study drug 
received, dispensed, administered, and returned to assure regulatory authorities and the 
sponsor that the study drug will not be dispensed to any person who is not a subject under 
the terms and conditions set forth in this protocol. 
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused and/or partially used study drug 
must be returned to the sponsor or a designated agent.
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All study drug returned to the sponsor must be accompanied by the appropriate 
documentation and be clearly identified by protocol number and trial site number on the 
outermost shipping container.  Returned supplies should be in the original containers 
(eg, subject kits).  The assigned trial monitor should facilitate the return of unused and/or 
partially used study drug.
If the study drug is authorized to be destroyed at the site by the sponsor, it is the 
investigator’s responsibility to ensure that arrangements have been made for the disposal.  
Written authorization should be issued by the sponsor, procedures for proper disposal 
should be established according to applicable regulations, guidelines and procedures, and 
appropriate records of the disposal should be documented and forwarded to 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 as defined in the ICF.
9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

The date of the visit and the corresponding Visit 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 study drug 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.  Any changes to information in the trial progress notes and other source 
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documents will be initialed and dated on the day the change is made by a 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.
Information from the trial progress notes and other source documents will be data entered 
by investigative site personnel directly onto electronic CRFs in the electronic data capture 
(EDC) system provided by the sponsor (or sponsor’s designee).
9.3
File Management at the Trial Site
It is the responsibility of the investigator to ensure that the trial site file is maintained in 
accordance with Section 8 of the ICH GCP Guideline and as required by applicable local 
regulations.  The investigator/institution should take measures to prevent accidental or 
premature destruction of these documents.
9.4
Records Retention at the Trial Site
Regulatory requirements for the archiving of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
three periods:

A period of at least 3 years following the date on which approval to manufacture the 
drug is obtained (or, if development of the study drug is discontinued, the date on 
which development is discontinued); OR

A period of at least 3 years after the date on which the trial is completed or 
terminated.

In addition, longer, region-specific storage requirements may apply as described in 
the Operations Manual for this trial.
The investigator must not dispose of any records relevant to this trial without either (1) 
written permission from the sponsor or (2) providing an opportunity for the sponsor to 
collect such records.  The investigator shall take responsibility for maintaining adequate 
and accurate electronic or hard copy source documents of all observations and data 
generated during this trial, including the CRF data on the CD-ROM received from the 
sponsor (or designee).  Such documentation is subject to inspection by the sponsor, 
sponsor’s designee, and relevant regulatory authorities.  If the investigator withdraws 
from the trial (eg, relocation, retirement), all trial-related records should be transferred to 
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a mutually agreed-upon designee within a sponsor-specified timeframe.  Notice of such 
transfer will be given to the sponsor in writing, prior to the action taking place.  
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial carefully in a 
detailed and orderly manner in accordance with established research principles, the ICH 
GCP Guideline, and applicable regulatory requirements and local laws.  As part of a 
concerted effort to fulfill these obligations (maintain current personal knowledge of the 
progress of the trial), the sponsor's monitors (or designees) will visit the site during the 
trial in addition to maintaining frequent telephone and written communication.  
10.2
Auditing
The sponsor's Quality Management Unit (or representative) may conduct audits at the 
trial site(s).  Audits will include, but are not limited to, drug supply, presence of required 
documents, the informed consent process, and comparison of CRFs with source 
documents.  The investigator agrees to participate with audits conducted at a reasonable 
time in a reasonable manner.
Regulatory authorities worldwide may inspect the investigator site during or after the 
trial.  The investigator should contact the sponsor immediately if this occurs, and must 
fully cooperate with the inspections conducted at a reasonable time in a reasonable 
manner.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, the ICH GCP Guideline, 
and applicable local laws and regulatory requirements.
12
Confidentiality
All information generated in this trial must be considered highly confidential and must 
not be disclosed to any persons not directly concerned with the trial without written prior 
permission from the sponsor.  Subject confidentiality requirements of the region(s) where 
the trial is conducted must be met.  However, authorized regulatory officials and sponsor 
personnel (or their representatives) will be allowed full access to inspect and copy the 
records.  All study drugs, subject bodily fluids, and/or other materials collected shall be 
used solely in accordance with this protocol, unless otherwise agreed to in writing by the 
sponsor.
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Subjects will be identified only by initials and unique subject numbers in CRFs.  Their 
full names may, however, be made known to a regulatory agency or other authorized 
officials if necessary. 
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval by the IRB/IEC.  Any permanent change to the 
protocol, whether it is an overall change or a change for specific trial site(s), must be 
handled as a protocol amendment.  Any amendment will be written by the sponsor.  Each 
amendment will be submitted to the IRB/IEC.  Except for “non-substantial (ie, 
administrative)” amendments, investigators will wait for IRB/IEC approval of the 
amended protocol before implementing the change(s).  Non-substantial amendments are 
defined to have no effect on the safety or physical or mental integrity of subjects, the 
conduct or management of the trial, the scientific value of the trial, or the quality or 
safety of the study drug(s) used in the trial.  However, a protocol change intended to 
eliminate an apparent immediate hazard to subjects should be implemented immediately, 
followed by IRB/IEC notification within 5 working days.  The sponsor will submit 
protocol amendments to the FDA or other regulatory agencies.
When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written ICF will require similar modification.  In such 
cases, after the approval of the new ICF by the IRB/IEC, repeat informed consent will be 
obtained from subjects in a timely manner before expecting continued participation.
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14
References
1
Lacro JP, Dunn LB, Dolder CR, Leckband SG, Jeste DV. Prevalence of and risk 
factors for medication nonadherence in patients with schizophrenia: A comprehensive 
review of recent literature. J Clin Psychiatry. 2002;63:892-909.
2
Sun SX, Liu GG, Christensen DB, Fu AZ. Review and analysis of hospitalization 
costs associated with antipsychotic nonadherence in the treatment of schizophrenia in 
the United States. Curr Med Res Opin. 2007;23:2305-12.
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Ascher-Svanum H, Zhu B, Faries D, Lacro JP, Dolder CR. A prospective study of 
risk factors for nonadherence with antipsychotic medication in the treatment of 
schizophrenia. J Clin Psychiatry. 2006;67:1114-23.
4
Fleischhacker WW, Eerdekens M, Karcher K, Remington G, Llorca P-M, 
Chrzanowske W, et al. Treatment of schizophrenia with long-acting injectable 
risperidone: a 12-month open-label trial of the first long-acting second-generation 
antipsychotic. J Clin Psychiatry. 2003;64:1250-7.
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Kane JM, Eerdekens M, Lindenmayer J-P, Keith SJ, Lesem M, Karcher K. 
Longacting injectable risperidone: Efficacy and safety of the first long-acting atypical 
antipsychotic. Am J Psychiatry. 2003;160:1125-32.
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Schooler NR. Relapse and rehospitalization: comparing oral and depot antipsychotics. 
J Clin Psychiatry. 2006;64 (Suppl 16):14-17.
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Simpson GM, Mahmoud RA, Lasser RA, Kujawa M, Bossie C, Turkoz I, et al. A 
1-year double-blind study of 2 doses of long-acting risperidone in stable patients with 
schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2006;67:1194-203.
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Adams CE, Fenton MKP, Quraishi S, David AS. Systematic meta-review of depot 
antipsychotic drugs for people with schizophrenia. Br J Psychiatry. 2001;179:290-9.
9
Aripiprazole Investigator’s Brochure, edition 18.1. Otsuka IB, issued 18 Nov 2014.
10 Mably TA, Peden WM. BMS-337039: Two-week intramuscular tolerance study in 
rats. Bristol-Myers Squibb Company Study DM00005/Report BMS Document 
Control No. 920007291, 2000.
11 BMS-337039: Single-dose intramuscular exploratory study of prototype depot 
formulations in dogs. Bristol-Myers Squibb Company Study DM01019/Report BMS 
Document Control No. 930001970, 2002.
12 Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, et al. 
Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with 
schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2002;63:763-71.
13 Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, et al. Aripiprazole, an 
antipsychotic with a novel mechanism of action, and risperidone vs placebo in 
patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry.  
2003;60:681-90.
14 Carson WH. A multicenter, randomized, double-blind, placebo-controlled study of 
three fixed doses of aripiprazole in the treatment of patients with acute schizophrenia. 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Bristol-Myers Squibb Company Study No. CN138001/Report BMS Document 
Control No. 930000317, 2001.
15 Carson, WH. A multicenter, randomized, double-blind, placebo-controlled, 26 week 
study of a fixed dose of aripiprazole in the treatment of stabilized patients with 
chronic schizophrenia. Bristol-Myers Squibb Company Study No. CN138047/Report 
BMS Document Control No. 930000855, 2001.
16 Pigott TA, Carson WH, Saha AR, Torbeyns AF, Stock EG, Ingenito GG, et al. 
Aripiprazole for the prevention of relapse in stabilized patients with chronic 
schizophrenia: a placebo-controlled 26-week study. J Clin Psychiatry. 
2003;64:1046-56.
17 A multicenter, randomized, double-blind, active-controlled study to compare the 
long-term maintenance effects and safety of aripiprazole and haloperidol following 
acute relapse in schizophrenic patients. Otsuka Study Nos. 31-98-217 and 
31-98-304-01, BMS Document Control No. 930000732, Report issued 08 Oct 2001.
18 Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, et al. Efficacy 
and safety of aripiprazole vs. haloperidol for long-term maintenance treatment 
following acute relapse of schizophrenia. Int J Neuropsychopharmacol. 
2003;6:325-37.
19 A multicenter, randomized, naturalistic, open-label study between aripiprazole and 
standard of care in the management of community-treated schizophrenic patients.  
Bristol-Myers Squibb Company Study No. CN138152/Report BMS Document 
Control No. 930015051, 2006.
20 Kerwin R, Millet B, Herman E, Banki CM, Lublin H, Pans M, et al. A multicentre, 
randomized, naturalistic, open-label study between aripiprazole and standard of care 
in the management of community-treated schizophrenic patients - Schizophrenia Trial 
of Aripiprazole: (STAR) study. Eur Psychiatry. 2007;22:433-43.
21 Tandon R, DeVellis RF, Han J, Li H, Frangou S, Dursun S for the IAQ Validation 
Study Group. Validation of the Investigator's Assessment Questionnaire, a new 
clinical tool for relative assessment of response to antipsychotics in patients with 
schizophrenia and schizoaffective disorder. Psychiatry Research. 2005;136:211-21.
22 Vieta E, Bourin M, Sanchez R, Marcus R, Stock E, McQuade R. Effectiveness of 
aripiprazole v. haloperidol in acute bipolar mania: Double-blind, randomised, 
comparative 12-week trial. Br J Psychiatry. 2005;187:235-42.
23 Llorca PM, Sacchetti E, Lloyd K, Kissling W, Medori R. Long-term remission in 
schizophrenia and related psychoses with long-acting risperidone: Results obtained in
an open-label study with an observation period of 18 months. In J Clin Pharmacol 
Ther. 2008;46:14-22.
24 Opler MGA, Yang LH, Caleo S, Alberti P. Statistical validation of the criteria for 
symptom remission in schizophrenia: Preliminary findings. BMC Psychiatry.
2007;7:35.
25 van Os J, Drukker M, Campo J, Meijer J, Bak M, Delespaul P. Validation of 
remission criteria for schizophrenia. Am J Psychiatry. 2006;163:2000-2.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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26 Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR.
Remission in schizophrenia: Proposed criteria and rationale for consensus. Am J 
Psychiatry. 2005;162:441-9.
27 International Conference on Harmonisation (ICH). E6:  Good Clinical Practice:  
Consolidated Guideline [finalized 01 May 1996, corrected 10 Jun 1996; cited
06 Dec 2005]. Available from:  
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html.
28 The Practical Guide: Identification, evaluation, and treatment of overweight and 
obesity in adults. Developed by National Institutes of Health National Heart, Lung 
and Blood Institute. North American Association for the Study of Obesity. NIH 
Publication Number 00-4084, October 2000.
29 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.
30 Simpson GN, Angus JWS. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand. 1970;212:S11-S19.
31 Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 
1989;154:672-6.
32 Lindenmayer JP, Jarboe K, Bossie CA, Zhu Y, Mehnert A, Lasser R. Minimal 
injection site pain and high patient satisfaction during treatment with long-acting 
risperidone. Int Clin Psychopharmacol. 2005;20:213-21.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 1
Names of Sponsor Personnel
Otsuka Pharmaceutical Development & Commercialization, Inc.
508 Carnegie Center 
Princeton, NJ 08540
Phone: 
Fax: 
Otsuka Pharmaceutical Development & Commercialization, Inc.
508 Carnegie Center 
Princeton, NJ 08540
Phone: 
Fax: 
Otsuka Pharmaceutical Development & Commercialization, Inc.
508 Carnegie Center 
Princeton, NJ 08540
Phone: 
Fax: 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Appendix 2
Institutions Concerned With the Trial
Clinical Research Organization
Covance Inc,
210 Carnegie Center
Princeton, NJ 08540
Phone: 
Safety Reporting
Please report SAEs, AEs requiring discontinuation of the study drug, and pregnancies to:
Covance Drug Safety Services
Phone: 
Fax: 
Clinical Lab – ECG Central Reader
eResearch Technology
30 South 17th St.
Philadelphia, PA 19103
Phone: 
Central Laboratory
Covance Central Laboratory Services
8211 SciCor Drive
Indianapolis, IN 46214
Phone: 
Toll free: 
Fax: 
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PPD
PPD
PPD
PPD
PPD
PPD
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PPD


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Appendix 3
Criteria for Identifying Vital Signs of 
Potential Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Heart rateb
> 120 bpm
< 50 bpm
15 bpm increase
15 bpm decrease
Systolic Blood Pressureb
> 180 mm Hg
< 90 mm Hg
20 mm Hg increase
20 mm Hg decrease 
Diastolic Blood Pressureb
> 105 mm Hg
< 50 mm Hg
15 mmHg increase
15 mmHg decrease
Orthostatic Hypotension
20 mmHg decrease in systolic 
blood and a 25 bpm increase in 
heart rate from supine to 
sitting/standing 
Not applicable
(baseline status not considered)
Weight
-
7% increase
7% decrease
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information 
in an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA 
Division of Neuropharmacological Drug Products draft (2/27/87).
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Appendix 4
Criteria for Identifying Laboratory Values of 
Potential Clinical Relevance
Laboratory Tests
Criteria
Chemistrya
AST (SGOT)
3 x upper limit of normal (ULN)
ALT (SGPT)
3 x ULN
Alkaline phosphatase
3 x ULN
LDH
3 x ULN
BUN
30 mg/dL
Creatinine
2.0 mg/dL
Uric Acid
Men
10.5 mg/dL
Women
8.5 mg/dL
Bilirubin (total)
2.0 mg/dL
CPK
3 x ULN
Prolactin
> ULN
Hematologya
Hematocrit
Men
37 % and decrease of 3 percentage points from baseline
Women
32 % and decrease of 3 percentage points from baseline
Hemoglobin
Men
11.5 g/dL
Women
9.5 g/dL
White blood count
2,800 mm3 or 16,000 mm3
Eosinophils
10%
Neutrophils
15%
Platelet count
75,000/ mm3 or 700,000/ mm3
Urinalysisa
Protein
Increase of 2 units
Glucose
Increase of 2 units
Casts
Increase of 2 units
Additional Criteria
Chloride
90 mEq/L or 118 mEq/L
Potassium
2.5 mEq/L or 6.5 mEq/L
Sodium
126 mEq/L or 156 mEq/L
Calcium
8.2 mg/dL or 12 mg/dL
Glucose
Fasting
115 mg/dL 
Non-Fasting
200 mg/dL
Total Cholesterol, Fasting
240 mg/dL 
LDL Cholesterol, Fasting
160 mg/dL 
HDL Cholesterol, Fasting
30 mg/dL 
Triglycerides, Fasting
Men
160 mg/dL
Women
120 mg/dL
aAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information 
in an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA 
Division of Neuropharmacological Drug Products draft (2/27/87).
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Appendix 5
Criteria for Identifying ECG Measurements of 
Potential Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rate
Tachycardia
120 bpm
increase of  15 bpm
Bradycardia
50 bpm
decrease of 15 bpm
Rhythm
Sinus tachycardiab
120 bpm
increase of 15 bpm
Sinus bradycardiac
50 bpm
decrease of 15 bpm
Supraventricular premature beat
all
not present present
Ventricular premature beat
all
not present present
Supraventricular tachycardia
all
not present present
Ventricular tachycardia
all
not present present
Atrial fibrillation
all
not present present
Atrial flutter
all
not present present
Conduction
1atrioventricular block
PR 0.20 second
increase of  0.05 second
2atrioventricular block
all
not present present
3atrioventricular block
all
not present present
Left bundle-branch block
all
not present present
Right bundle-branch block
all
not present present
Pre-excitation syndrome
all
not present present
Other intraventricular conduction 
blockd
QRS 0.12 second
increase of 0.02 second
Infarction
Acute or subacute
all
not present present
Old
all
not present present
12 weeks post study entry
ST/T Morphological
Myocardial Ischemia
all
not present present
Symmetrical T-wave inversion
all
not present present
Increase in QTc
QTc 450 msec
10% increase
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
dNo current diagnosis of left bundle branch block or right bundle branch block.
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Appendix 6
Clinical Global Impression Severity (CGI-S) Scale
Circle the appropriate number for item below.
SEVERITY OF ILLNESS
Considering your total clinical experience with this particular population, how mentally 
ill is the patient at this time? 
0 = Not assessed
4 = Moderately ill
1 = Normal, not at all ill
5 = Markedly ill
2 = Borderline mentally ill
6 = Severely ill
3 = Mildly ill
7 = Among the most extremely ill patients
Adapted from 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.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 7
Abnormal Involuntary Movement Scale (AIMS)
This scale consists of 10 items, each to be rated on a 4-point scale of severity, and two 
questions to be answered by yes or no.  To complete the scale, observe the patient 
unobtrusively at rest (eg, in waiting room).  The chair to be used for this examination 
should be a hard, firm one without arms.
For each item, please mark in the right column, the rating which best describes the 
patient's present condition.
Instructions for Rating Items 1 to 9:  0 = none,    1 = minimum,    2 = mild,    3 = moderate,    4 = severe
Instructions for Rating  Item  10:  0 = no awareness; 1 = aware, no distress ; 2 = aware, mild distress ; 3 = 
aware, moderate distress ; 4 = aware, severe distress
SYMPTOMS
DESCRIPTION OF SYMPTOMS
RATING
FACIAL
AND ORAL
MOVEMENTS
1.
Muscles of facial expression - eg, movements of forehead, 
eyebrows, periorbital area, cheeks; include frowning, blinking, 
smiling, grimacing
2.
Lips and perioral area - eg, puckering, pouting, smacking.
3.
Jaw - eg biting, clenching, chewing, mouth opening, lateral 
movement.
4.
Tongue - Rate only increase in movement both in and out of 
mouth, NOT inability to sustain movement.
EXTREMITY  
MOVEMENTS
5.
Upper (arms, wrists, hands, fingers) - Include choreic movements 
(eg: rapid, objectively purposeless, irregular, spontaneous); 
athetoid movements (eg, slow, irregular, complex, serpentine).  
DO NOT include tremor (eg, repetitive, regular, rhythmic).
6.
Lower (legs, knees, ankles, toes) - eg, lateral knee movement, foot 
tapping, heel dropping, foot squirming, inversion and of foot
TRUNK
MOVEMENTS
7.
Neck, shoulders, hips - eg, rocking, twisting, squirming, pelvic 
gyrations
GLOBAL  
JUDGEMENTS
8.
Severity of abnormal movements.
9.
Incapacitation due to abnormal movements
10. Patient's awareness of abnormal movements
DENTAL  
STATUS
Current problems with teeth and/or dentures        0 = no ; 1 = yes
Does patient usually wear dentures ?                   0 = no ; 1 = yes
Adapted from 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.
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Appendix 8
The Simpson-Angus Neurologic Rating Scale (SAS)
This scale consists of a list of 10 symptoms, each to be rated on a 5-point scale of 
severity.  For each symptom, please mark the rating which best describes the patient's 
present condition.
1. GAIT - The patient is examined as he walks into the examining room - his gait, the 
swing of his arms, his general posture, all form the basis for an overall score for this item.
1 = 
Normal
2 = 
Mild diminution in swing while the patient is walking 
3 = 
Obvious diminution in swing suggesting shoulder rigidity
4 = 
Stiff gait with little or no arm swing noticeable
5 = 
Rigid gait with arms slightly pronated; or stooped-shuffling gait with 
propulsion and retropulsion
9 =
Not ratable
2. ARM DROPPING - The patient and the examiner both raise their arms to shoulder 
height and let them fall to their sides.  In a normal patient, a stout slap is heard as the 
arms hit the sides.  In the patient with extreme Parkinson's syndrome, the arms fall very 
slowly:
1 = 
Normal, free fall with loud slap and rebound
2 = 
Fall slowed slightly with less audible contact and little rebound
3 = 
Fall slowed, no rebound
4 = 
Marked slowing, no slap at all
5 = 
Arms fall as though against resistance; as though through glue
9 = 
Not ratable
3. SHOULDER SHAKING - The patient's arms are bent at a right angle at the elbow 
and are taken one at a time by the examiner who grasps one hand and also clasps the 
other around the patient's elbow.  The patient's upper arm is pushed to and fro and the 
humerus is externally rotated.  The degree of resistance from normal to extreme rigidity 
is scored as detailed.  The procedure is repeated with one hand palpating the shoulder 
cuff while rotation takes place.
1 = 
Normal
2 = 
Slight stiffness and resistance
3 = 
Moderate stiffness and resistance
4 = 
Marked rigidity with difficulty in passive movement
5 = 
Extreme stiffness and rigidity with almost a frozen joint
9 =
Not ratable
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4. ELBOW RIGIDITY - The elbow joints are separately bent at right angles and 
passively extended and flexed, with the patient's biceps observed and simultaneously 
palpated.  The resistance to this procedure is rated.
1 = 
Normal
2 = 
Slight stiffness and resistance
3 = 
Moderate stiffness and resistance
4 = 
Marked rigidity with difficulty in passive movement
5 = 
Extreme stiffness and rigidity with almost a frozen joint
9 =
Not ratable
5. WRIST RIGIDITY - The wrist is held in one hand and the fingers held by the 
examiner's other hand, with the wrist moved to extension, flexion, and ulnar and radial 
deviation or the extended wrist is allowed to fall under its own weight, or the arm can be 
grasped above the wrist and shaken to and fro.  A "1" score would be a hand that extends 
easily, falls loosely, or flaps easily upwards and downwards.
1 =
Normal
2 =
Slight stiffness and resistance
3 =
Moderate stiffness and resistance
4 = 
Marked rigidity with difficulty in passive movement
5 = 
Extreme stiffness and rigidity with almost a frozen wrist
9 =
Not ratable
6. HEAD ROTATION - The patient sits or stands and is told that you are going to move  
his head from side to side, that it will not hurt and that he should try and relax.  
(Questions about pain in the cervical area or difficulty in moving his head should be 
obtained to avoid causing any pain).  Clasp the patient's head between the two hands with 
the fingers on the back of the neck.  Gently rotate the head in a circular motion 3 times 
and evaluate the muscular resistance to this movement.
1 =
Loose, no resistance
2 =
Slight resistance to movement although the time to rotate may be normal
3 = 
Resistance is apparent and the time of rotation is shortened
4 =
Resistance is obvious and rotation is slowed
5 =
Head appears stiff and rotation is difficult to carry out
9 = 
Not ratable
7. GLABELLA TAP - Patient is told to open his eyes wide and not to blink.  The 
glabella region is tapped at a steady, rapid speed.  Note number of times patient blinks in 
succession.  Take care to stand behind the patient so that he does not observe the 
movement of the tapping finger.  A full blink need not be observed; there may be a 
contraction of the infraorbital muscle producing a twitch each time a stimulus is 
delivered.  Vary speed of tapping to assure that muscle contraction is related to the tap.
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1 = 
0 to 5 blinks
2 = 
6 to 10 blinks
3 = 
11 to 15 blinks
4 = 
16 to 20 blinks
5 = 
21 and more blinks
9 = 
Not ratable
8. TREMOR - Patient is observed walking into examining room and then is re-examined 
for this item with arms extended at right angles to the body and the fingers spread out as 
far as possible.
1 = 
Normal
2 = 
Mild finger tremor, obvious to sight and touch
3 = 
Tremor of hand or arm occurring spasmodically
4 = 
Persistent tremor of one or more limbs
5 = 
Whole body tremor
9 = 
Not ratable
9. SALIVATION - Patient is observed while talking and then asked to open his mouth 
and elevate his tongue.
1 = 
Normal
2 = 
Excess salivation so that drooling takes place if mouth is opened and tongue 
raised 
3 = 
Excess salivation is present and might occasionally result in difficulty in 
speaking
4 = 
Speaking with difficulty because of excess salivation
5 = 
Frank drooling
9 =
Not ratable
10. AKATHISIA - Patient is observed for restlessness.  If restlessness is noted, ask: "Do 
you feel restless or jittery inside; is it difficult to sit still?" Subjective response is not 
necessary for scoring but patient report can help make the assessment.
1 = 
No restlessness reported or observed
2 =
Mild restlessness observed, eg, occasional jiggling of the foot occurs when 
patient is seated
3 =
Moderate restlessness observed, eg, on several occasions, jiggles foot, crosses 
and uncrosses legs or twists a part of the body
4 =
Restlessness is frequently observed, eg, the foot or legs moving most of the 
time
5 =
Restlessness persistently observed, eg, patient cannot sit still, may get up and 
walk
9 =
Not ratable
Adapted from Simpson GM and Angus JWS. Acta Psychiatr Scand. 1970;212:S11-S19.
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Appendix 9
Barnes Akathisia Rating Scale (BARS)
Patients should be observed while they are seated and then standing (for a minimum of 
two minutes in each position).  Symptoms observed in other situations (eg, while engaged 
in neutral conversation, engaged in activity on the ward) may also be rated.  
Subsequently, the subjective phenomena should be elicited by direct questioning.
1. OBJECTIVE
0 =
Normal, occasional fidgety movements of the limbs
1 =
Presence of characteristic restless movements: Shuffling or tramping 
movements of the legs/feet, or swinging one leg while sitting, and/or rocking 
from foot to foot or "walking-on-the-spot" when standing, but movement 
present for less than half the time observed
2 = 
Observed phenomena as described in (1) above, which are present for at least 
half the observation period
3 =
The patient is constantly engaged in characteristic restless movements, and/or 
has the inability to remain seated or standing without walking or pacing, 
during the time observed
2. SUBJECTIVE - AWARENESS OF RESTLESSNESS
0 =
Absence of inner restlessness
1 =
Non-specific sense of inner restlessness
2 = 
The patient is aware of inability to keep the legs still, or a desire to move legs 
and/or complains of inner restlessness associated specifically by being 
required to stand still
3 =
Awareness of an inner compulsion to move most of the time and/or reports a 
strong desire to walk or pace most of the time
3. SUBJECTIVE - DISTRESS RELATED TO RESTLESSNESS
0 = 
No distress
1 = 
Mild
2 =
Moderate
3 = 
Severe
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4. GLOBAL CLINICAL ASSESSMENT OF AKATHISIA
0 = 
Absent - No evidence of awareness of restlessness.  Observation of 
characteristic movement of akathisia in the absence of a subjective report of 
inner restlessness or compulsive desire to move the legs should be classified 
as pseudoakathisia
1 = 
Questionable - Non specific inner tension and fidgety movements
2 = 
Mild akathisia - Awareness of restlessness in the legs and/or inner restlessness 
worse when required to stand still.  Fidgety movement present, but 
characteristic restless movements of akathisia not necessarily observed.  
Condition causes little or no distress.
3 = 
Moderate akathisia - Awareness of restlessness as described for mild akathisia 
above, combined with characteristic restless movements; finds the condition 
distressing
4 = 
Marked akathisia - Subjective experience of restlessness includes a 
compulsive desire to walk or pace.  However, the patient is able to remain 
seated for at least five minutes.  Constant restlessness which is associated with
intense distress and insomnia
5 = 
Severe akathisia - The patient reports a strong compulsion to pace up and 
down most of the time.  Unable to sit or lie down for more than a few minutes.  
Constant restlessness which is associated with intense distress and insomnia.
Adapted from Barnes TR. Br J Psychiatry. 1989;154:672-6.
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Appendix 10
Suicide Severity Rating Scale (C-SSRS)
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Baseline
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended for use by trained clinicians. The questions contained in the 
Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the 
determination of the presence of suicidality depends on clinical judgment.
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the 
Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside 
Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal 
behavior: utility and limitations of research instruments. In M.B. First [Ed.] Standardized Evaluation 
in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact 
 New York State Psychiatric Institute, 1051 
Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
 
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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SUICIDAL IDEATION
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the 
answer to question 2 is “yes,” ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is 
“yes”, complete “Intensity of Ideation” section below.
Lifetime: 
Time He/She 
Felt Most 
Suicidal
1.  Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe:
Yes       No
□    □
2.  Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve thought about killing myself”) 
without thoughts of ways to kill oneself/associated methods, intent, or plan. 
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes      No
 □    □
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is 
different than a specific plan with time, place or method details worked out (e.g.  thought of method to kill self but not 
a specific plan).  Includes person who would say, “I thought about taking an overdose but I never made a specific plan 
as to when, where or how I would actually do it…..and I would never go through with it”.
Have you been thinking about how you might do this?
If yes, describe:
Yes      No
 □    □
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed 
to “I have the thoughts but I definitely will not do anything about them”.
Have you had these thoughts and had some intention of acting on them? 
If yes, describe:
Yes       No
 □    □
5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?
  
If yes, describe:
Yes      No
 □    □
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INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, 
with 1 being the least severe and 5 being the most severe ). Ask about time he/she was feeling the  most 
suicidal.
                                            
Most Severe Ideation:             _____      _______________________________________________
                                                                                                      Type # (1-5)                             Description of  Ideation
Most 
Severe
Frequency
How many times have you had these thoughts?
(1) Less than once a week  (2) Once a week  (3) 2-5 times in week  (4) Daily or almost daily (5) Many times each day
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes                                          (4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time                                          (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time                                                                   
____
Controllability
Could /can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts                                               (4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty                              (5) Unable to control thoughts
(3) Can control thoughts with some difficulty                             (0) Does not attempt to control thoughts
____
Deterrents
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from 
wanting to die or acting on thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide     (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you                                             (5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you                                     (0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to 
end the pain or stop the way you were feeling (in other words you couldn’t go on living with this pain 
or how you were feeling) or was it to get attention, revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others.  
(2) Mostly to get attention, revenge or a reaction from others.                    
(3) Equally to get attention, revenge or a reaction from others and to end/stop the pain.
(4) Mostly to end or stop the pain (you couldn’t go on living with the pain or how you were feeling).
(5) Completely to end or stop the pain (you couldn’t go on living with the pain or how you were feeling).
(0) Does not apply.
____
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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Lifetime
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part 
thought of as method to kill oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated 
with the act, then it can be considered an actual suicide attempt. There does not have to be any injury or 
harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no 
injury results, this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be 
inferred (e.g. gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, 
but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to 
relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious Behavior 
without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes      No
□   □
Total # of
Attempts
______
Yes     No
□   □
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not 
for that, actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an 
attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by 
someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, 
it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has 
noose around neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of 
interrupted
______
Aborted Attempt:  
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have 
engaged in any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual 
stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization 
or thought, such as assembling a specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death 
by suicide (e.g. giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such 
as collecting pills, getting a gun, giving valuables away or writing a suicide note)?
If yes, describe:
Yes      No
□   □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes      No
□   □
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Answer for Actual Attempts Only
Most Recent 
Attempt
Date:
Most Lethal          
Attempt
Date:
Initial/First 
Attempt
Date:
Actual Lethality/Medical Damage:  
0.  No physical damage or very minor physical damage (e.g. 
surface scratches).
1.  Minor physical damage (e.g. lethargic speech; first-degree 
burns; mild bleeding; sprains).
2.  Moderate physical damage; medical attention needed (e.g. 
conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel).
3.  Moderately severe physical damage; medical hospitalization 
and likely intensive care required (e.g. comatose with 
reflexes intact; third-degree burns less than 20% of body; 
extensive blood loss but can recover; major fractures).
4.  Severe physical damage; medical hospitalization with intensive 
care required (e.g. comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable 
vital signs; major damage to a vital area).
5.  Death
Enter Code
______
Enter Code
______
Enter Code
______
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the 
following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled 
the trigger but gun fails to fire so no medical damage; laying on 
train tracks with oncoming train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical 
care 
Enter Code
______
Enter Code
______
Enter Code
______
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COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Since Last Visit
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended for use by trained clinicians. The questions contained in the 
Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the 
determination of the presence of suicidality depends on clinical judgment.
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the 
Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside 
Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal 
behavior: utility and limitations of research instruments. In M.B. First [Ed.] Standardized Evaluation 
in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact 
 New York State Psychiatric Institute, 1051 
Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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SUICIDAL IDEATION
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the 
answer to question 2 is “yes,” ask questions 3, 4 and 5.  If the answer to question 1 and/or 
2 is “yes”, complete “Intensity of Ideation” section below.
Since Last 
Visit
1.  Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe:
Yes       No
□    □
2.  Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve thought about killing 
myself”) without thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes      No
 □    □
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is 
different than a specific plan with time, place or method details worked out (e.g.  thought of method to kill self but 
not a specific plan).  Includes person who would say, “I thought about taking an overdose but I never made a 
specific plan as to when, where or how I would actually do it…..and I would never go through with it”.
Have you been thinking about how you might do this?
If yes, describe:
Yes      No
 □    □
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as 
opposed to “I have the thoughts but I definitely will not do anything about them”.
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
Yes       No
 □    □
5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it 
out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this 
plan?
  
If yes, describe:
Yes      No
 □    □
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INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from 
above, with 1 being the least severe and 5 being the most severe ). 
                                            
Most Severe Ideation:             _____                      
_________________________________________________
                                             
                                                                                                           Type # (1-5)                                         Description of  Ideation
Most Severe
Frequency
How many times have you had these thoughts?
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many 
times each day
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or 
continuous
(3) 1-4 hours/a lot of time                                                                   
____
Controllability
Could /can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of 
difficulty
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts
____
Deterrents
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you 
from wanting to die or acting on thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop 
you 
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you                                             (0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was 
it to end the pain or stop the way you were feeling (in other words you couldn’t go on living 
with this pain or how you were feeling) or was it to get attention, revenge or a reaction from 
others? Or both?
(1) Completely to get attention, revenge or a reaction from others      
(2) Mostly to get attention, revenge or a reaction from others                     
(3) Equally to get attention, revenge or a reaction from others and to end/stop the pain              
(4) Mostly to end or stop the pain (you couldn’t go on living with the pain or how you were feeling)
(5) Completely to end or stop the pain (you couldn’t go on living with the pain or  how you were feeling)
(0) Does not apply
____
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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Since Last 
Visit
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part 
thought of as method to kill oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated 
with the act, then it can be considered an actual suicide attempt. There does not have to be any injury or 
harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no 
injury results, this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be 
inferred (e.g. gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, 
but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to 
relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious Behavior 
without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes      No
□   □
Total # of
Attempts
______
Yes     No
□   □
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not 
for that, actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an 
attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by 
someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, 
it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has 
noose around neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of 
interrupted
______
Aborted Attempt:  
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have 
engaged in any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual 
stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything?
If yes, describe:
Yes      No
□   □
Total # of
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization 
or thought, such as assembling a specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death 
by suicide (e.g. giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such 
as collecting pills, getting a gun, giving valuables away or writing a suicide note)?
If yes, describe:
Yes      No
□   □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes      No
□   □
Completed Suicide:
   Yes    No
□   □
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Answer for Actual Attempts Only
Most Lethal 
Attempt
Actual Lethality/Medical Damage:  
0.  No physical damage or very minor physical damage (e.g. surface scratches).
1.  Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains).
2.  Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat responsive; 
second-degree burns; bleeding of major vessel).
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. 
comatose with reflexes intact; third-degree burns less than 20% of body; extensive blood loss but 
can recover; major fractures).
4.  Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without 
reflexes; third-degree burns over 20% of body; extensive blood loss with unstable vital signs; major 
damage to a vital area).
5.  Death
Date
Enter 
#
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual 
medical damage, had potential for very serious lethality: put gun in mouth and pulled the trigger but gun 
fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away before run 
over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Date
Enter 
#
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Appendix 11
Visual Analog Scale (VAS) for Subject-reported Rating of Pain 
at Most Recent Injection Site
Date: ______________________
Time of Assessment: _____________
Patient evaluation of pain at the most recent injection site via visual analog scale:
Note: VAS is 100 mm line; current sample is not to scale
Adapted from Kane et al. Am J Psychiatry. 2003;160:1125-32.
Unbearably painful
No pain
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Appendix 12
Investigator’s Assessment of Most Recent Injection Site
Date: ______________________
Time of Assessment: _____________
The subject and most recent injection site should be observed and evaluated by the 
investigator on a 4-point categorical scale (absent, mild, moderate, severe) for the 
presence or absence of any of the following symptoms.
ITEM
Absent
Mild
Moderate
Severe
PAIN
0 
1  
2  
3  
SWELLING
0 
1  
2  
3  
REDNESS
0 
1  
2  
3  
INDURATION
0 
1  
2  
3  
Adapted from Kane et al. Am J Psychiatry. 2003;160:1125-32 and Lindenmayer JP et al. Int Clin 
Psychopharmacol. 2005;20:213-21.
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Appendix 13
Product Labels
ABILIFY (aripiprazole) US Prescribing Information (USPI)
Please see current US Prescribing Information in the Investigator Site File (ISF) and/or 
the Trial Master File (TMF).
ABILIFY (aripiprazole) EU Summary of Product Characteristics (SmPC)
Please see current SmPC in the Investigator Site File (ISF) and/or the Trial Master File 
(TMF).
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Appendix 14
Protocol Amendment(s)/Administrative Change(s)
Amendment Number:
Amendment 4
Issue Date:
08 Jul 2015
PURPOSE:
In this protocol amendment, the number and types of assessments obtained during the 
trial have been reduced to decrease the burden on study subjects.  Subjects being treated 
with aripiprazole IM Depot in Trial 31-10-270 may continue treatment until the trial ends 
as described in the protocol.  
If the sponsor terminates the study prior to 31 Dec 2018 for any reason other than 
commercial availability, investigators in some countries where the sponsor has limited or 
delayed commercialization plans, or where no commercialization activity is anticipated, 
may be eligible to participate in a managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.  Availability and 
requirements of such a program varies by jurisdiction, and would only be an option for 
subjects who were receiving aripiprazole IM Depot in the current study, and who in the 
physician’s opinion, may benefit from continued treatment with aripiprazole.  To gain 
access to aripiprazole IM Depot for eligible subjects via a managed access program, each 
physician will be responsible for gaining appropriate local regulatory approvals, which 
will be granted by authorities on a case-by-case basis.  The sponsor makes no guarantee 
that such a program is available or approvable in all of the jurisdictions where the study is 
conducted.
BACKGROUND:
The well-established safety profile of both oral aripiprazole and aripiprazole IM Depot 
across the completed double-blind and long-term Phase 3 trials allows this reduction in 
required study assessments for subjects enrolled under Amendment 4, while maintaining 
appropriate safety monitoring.  
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MODIFICATIONS TO PROTOCOL:

The frequency has been reduced for these assessments: CGI-S, EPS assessments 
(AIMS, BARS, SAS), vital signs, BMI, physical exam, ECGs, urine drug screen and 
blood alcohol tests, and assessments by the investigator and subject of injection site 
reactions.  Although these assessments are not required at specific time points, any of 
these assessments may be obtained at any study visit at the discretion of the 
investigator.  Details are provided in Table 3.6-1.

Added information about a managed access program.

Updated the Introduction.

Updated titles for specific sponsor representatives and updated the sponsor’s mailing 
address.

Fixed typographical errors and made minor changes to reflect current styles (not 
displayed in the table below).
Sectional Revisions:
Details of the by-section changes that were updated are shown in the table that follows.
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Updated Text
Title Page
Title Page
(New Text)
Date of Amendment 4: 
08 Jul 2015
Synopsis/
Trial Design
...
Subjects will continue to receive aripiprazole IM Depot 
every month (study months are every 4 weeks which is 
defined as 28 [-2/+10]  days) as a continuation of their 
previous monthly dose in Study  248. ...
...
Following the Baseline visit, the Columbia Suicide Severity 
Rating Scale (C-SSRS), adverse events and concomitant 
medications will be assessed at the monthly injection study 
visit.  The Clinical Global Impression - Severity (CGI-S) 
scale, vital signs, and urine pregnancy test (for women of 
childbearing potential [WOCBP] only; see Section 5.4 for 
definition of WOCBP) will be assessed every 3 months.  
Urine drug screening and blood alcohol testing, at the 
investigator’s discretion, can be performed every 3 months.  
Visual Analog Scale (VAS) for subject-reported rating of 
pain at the most recent injection site and the investigator’s 
assessment for pain, redness, induration, and swelling of 
most recent injection site will be performed every 6 months.  
The following scales will be used to assess extrapyramidal 
symptoms (EPS) every 6 months (more frequently if 
warranted, see Table 3.6-1):  Abnormal Involuntary 
Movement Scale (AIMS), Simpson-Angus Scale (SAS), 
and Barnes Akathisia Rating Scale (BARS).  These EPS 
scales can be administered at any visit at the discretion of 
the investigator if warranted by the presence of symptoms.  
Clinical laboratory tests, physical examination, and 
electrocardiogram (ECG) will be performed annually.  For 
each visit, all assessments, except for post-injection 
assessments, should be performed prior to the aripiprazole 
IM Depot injection.
...
Subjects in this study will continue to receive aripiprazole 
IM Depot every month (study months are every 4 weeks 
which is defined as 28 [−2/+10]  days) as a continuation of 
their previous monthly dose in Study  248. ...
...
Following the baseline visit, subjects will receive monthly 
injections and at the same visit, adverse events (AEs) and 
concomitant medications will be recorded and the Columbia 
Suicide Severity Rating Scale (C-SSRS) will be completed.  
Every 3 months, all of the monthly assessment will be 
completed along with a urine pregnancy test for women of 
childbearing potential (WOCBP).  Every 6 months, all of the 
3-month assessments will be completed along with the 
Clinical Global Impression - Severity (CGI-S) scale, vital 
signs, and extrapyramidal symptoms (EPS) assessments 
(including the Abnormal Involuntary Movement Scale 
[AIMS], Simpson-Angus Scale [SAS], and Barnes Akathisia 
Rating Scale [BARS]).  At the 12-month visit, all of the 
6-month assessments will be completed along with clinical 
laboratory tests and assessments of body weight, height, and
waist circumference.  
Urine drug screening and blood alcohol testing will be 
obtained at baseline and can be re-obtained at the 
investigator’s discretion at any time during the study.  A 
Visual Analog Scale (VAS) for subject-reported rating of 
pain at the most recent injection site and the investigator’s 
assessment for pain, redness, induration, and swelling of the 
most recent injection site will be performed at baseline and 
may be reassessed at the discretion of the investigator.  
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A Study Completion Visit or Early Termination Visit 
(-2/+10 days) will be performed and include the following 
assessments: CGI-S; C-SSRS; injection site assessment by 
the subject using VAS and by the investigator for pain, 
redness, induration, and swelling; AEs; EPS (AIMS, SAS, 
and BARS); clinical laboratory tests; vital signs, body 
height and weight; BMI; physical examination; ECG; urine 
pregnancy test for WOCBP; and concomitant medications.
A 30-Day Post Treatment Follow-up phone call will be 
performed 30 days (3 days) after it has been determined 
that the subject will no longer participate in this study and 
include the recording of AEs that have occurred and any 
concomitant medications taken since the last visit.
...
Aripiprazole IM Depot treatment in this open-label rollover 
study will continue until there are clinical and/or 
administrative reasons for discontinuation of the subject’s 
study treatment or through the end of study date of 
31 Dec 2018 is reached.
... Administrative reasons for discontinuing study treatment 
include, but are not limited to: aripiprazole IM Depot is
commercially available in any dosage (including a generic 
formulation) in the country where the study is being 
conducted, the commercial availability of aripiprazole 
IM Depot is terminated by the sponsor, or until the study 
end date of 31 Dec 2018 is reached, which ever occurs first.
Once aripiprazole IM Depot becomes commercially 
available in any dosage (including generic formulations) in 
the country where the subject is participating in the study or 
the commercial availability of aripiprazole IM Depot is 
terminated by the sponsor, study treatment will be 
discontinued within 6 weeks of the subject’s previous 
injection for clinical transition purposes.
Clinical laboratory tests, physical examination, and 
electrocardiogram (ECG) obtained at baseline may also be 
performed at the discretion of the investigator based on 
clinical necessity.  
A Study Completion visit or Early Termination visit 
(−2/+10 days) will include the following assessments: 
C-SSRS, AEs, concomitant medications, a urine pregnancy 
test for WOCBP, CGI-S, vital signs, EPS assessments 
(AIMS, BARS, SAS), clinical laboratory tests, and body 
height and weight.
A 30-Day Post Treatment Follow-up phone call will be made 
30 days (3 days) after it has been determined that the 
subject will no longer participate in this study and will 
include questions about any AEs that have occurred and any 
concomitant medications taken since the last visit.
...
Aripiprazole IM Depot treatment in this open-label rollover 
study will continue until there are clinical and/or 
administrative reasons for discontinuation of the subject’s 
study treatment or until the study end date of 31 Dec 2018 is 
reached, whichever occurs first.  
... Administrative reasons for discontinuing study treatment 
include, but are not limited to: aripiprazole IM Depot 
becomes commercially available in any dosage (including a 
generic formulation) in the country where the study is being 
conducted, the commercial availability of aripiprazole 
IM Depot is terminated by the sponsor, or until the study end 
date of 31 Dec 2018 is reached, whichever occurs first.
Once aripiprazole IM Depot becomes commercially 
available in any dosage (including generic formulation[s]) in 
the country where the subject is participating in the study or 
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the commercial availability of aripiprazole IM Depot is 
terminated by the sponsor, study treatment will be 
discontinued within approximately 6 weeks of the subject’s 
previous injection for clinical transition purposes.
If the sponsor terminates the study prior to 31 Dec 2018 for 
any reason other than commercial availability, investigators 
in some countries where the sponsor has limited or delayed 
commercialization plans, or where no commercialization 
activity is anticipated, may be eligible to participate in a 
managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.
Synopsis/
Trial Assessments
Safety:  Safety will be assessed by adverse event reporting, 
every month (study months are every 4 weeks which is 
defined as 28 [-2/+10] days).  The C SSRS will be used to 
assess suicidality every month.  VAS for subject-reported 
rating of pain at the most recent injection site and the 
investigator’s assessment for pain, redness, induration, and 
swelling of the most recent injection site will be performed 
every 6 months.  Extrapyramidal symptoms will be 
assessed every 6 months using the AIMS, SAS, and BARS 
assessments.  Vital signs will be assessed every 3 months 
and clinical laboratory tests, ECG, physical examinations, 
body height and weight, BMI, and waist circumference will 
be assessed every 12 months.
Efficacy:  Efficacy will be evaluated using the CGI-S and 
administered every 3 months.
Safety:  Safety will be assessed by adverse event and 
concomitant medication reporting at baseline (post-IM 
administration) and at each subsequent monthly injection 
visit (study months are every 4 weeks which is defined as 
28 [−2/+10] days).  The C-SSRS will be used to assess 
suicidality at baseline and at each subsequent monthly 
injection visit.  Extrapyramidal symptoms will be assessed 
using the AIMS, SAS, and BARS assessment questionnaires 
at baseline, every 6 months, at the discretion of the 
investigator at any subsequent visit, and at Study Completion 
or the Early Termination visit.  Clinical laboratory tests will 
be performed at baseline, every 12 months, and at Study 
Completion or the Early Termination visit.  Vital signs will 
be assessed every 6 months and at Study Completion or the 
Early Termination visit.  Body height and weight, body mass 
index (BMI), and waist circumference will be assessed at 
baseline; body height, weight, and waist circumference will 
be reassessed every 12 months; and body height and weight 
will be assessed at Study Completion or the Early 
Termination visit.  For WOCBP, a urine pregnancy test will 
be administered at baseline, every 3 months, and at Study 
Completion or the Early Termination visit. 
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Efficacy:  Efficacy will be evaluated using the CGI-S 
administered every 6 months.
Synopsis/
Criteria for Evaluation
Safety Endpoints:  
...

The incidence of clinically significant changes will be 
calculated for vital signs and routine laboratory tests.  
Mean change from baseline and incidence of clinically 
significant changes will be calculated for ECG 
parameters and body weight.  By-patient listings of 
physical findings will be reviewed as a further 
assessment of safety.
Safety Endpoints:  
...

The incidence of clinically significant changes will be 
calculated for vital signs.  Mean change from baseline 
and incidence of clinically significant changes will be 
calculated for body weight and waist circumference.  
Synopsis/
Trial Duration
Subjects will continue to receive aripiprazole IM Depot in 
this open-label rollover study until there are clinical and/or 
administrative reasons for discontinuation of the subject’s 
study treatment or the end of study date of 31 Dec 2018 is 
reached (see “Trial Design” section above).  
Once aripiprazole becomes available commercially at any
dosage [including generic formulation(s)] in the country 
where the study is being conducted, the commercial 
availability of aripiprazole IM Depot is terminated by the 
sponsor, or until the study end date of 31 Dec 2018 is 
reached, treatment will be discontinued. If aripiprazole 
IM Depot is commercially available or if the availability of 
aripiprazole IM Depot is terminated by the sponsor, then 
the subject will discontinue treatment within 6 weeks of last 
injection for clinical transition purposes.
Subjects will continue to receive aripiprazole IM Depot in 
this open-label rollover study until there are clinical and/or 
administrative reasons for discontinuation of the subject’s 
study treatment or until the study end date of 31 Dec 2018 is 
reached, whichever occurs first (see “Trial Design” section 
above).  
Once aripiprazole becomes available commercially at any 
dosage (including generic formulation[s]) in the country 
where the study is being conducted, the commercial 
availability of aripiprazole IM Depot is terminated by the 
sponsor, or until the study end date of 31 Dec 2018 is 
reached, treatment will be discontinued.  If aripiprazole 
IM Depot is commercially available or if the availability of 
aripiprazole IM Depot is terminated by the sponsor, then the 
subject will discontinue treatment within approximately 
6 weeks of last injection for clinical transition purposes.
1 Introduction
ABILIFY(aripiprazole) oral tablets are approved in the 
United States (US) for the treatment of adults and 
adolescents with acute schizophrenia, maintenance of 
stability in adults with schizophrenia, treatment of acute 
manic episodes associated with Bipolar I Disorder in adults 
and pediatric patients, maintenance of efficacy in adults 
with Bipolar I Disorder, and as adjunctive treatment of 
ABILIFY(aripiprazole, OPC-14597, BMS-337039), a 
second generation antipsychotic, which exhibits partial 
agonism (agonism/antagonism) at dopamine D2 and 
serotonin 5-HT1A receptors and antagonism at serotonin 
5-HT2 receptors, is approved and marketed in the United 
States (US) for use in the following indications.9
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major depressive disorder (MDD).  Aripiprazole is also 
approved for the treatment of schizophrenia in the European 
Union (EU), Australia, and a number of countries in Asia, 
Europe, and Latin America.  The aripiprazole 
immediate-release IM formulation is approved for the 
treatment of agitation in patients with schizophrenia and 
bipolar mania in the US and EU.  In addition, an oral 
solution formulation and orally disintegrating (dispersible) 
tablets have been approved and marketed in the US and EU.  
The favorable side effect profile of oral aripiprazole, 
including its low incidence of EPS, low risk of prolactin 
elevation, decreased adrenergic and anticholinergic side 
effects, and minimal weight gain, makes it an excellent 
candidate for a long-acting depot formulation.  The 
efficacy, safety, and tolerability of an IM depot formulation 
of aripiprazole are being examined for the treatment of 
schizophrenia in 2 pivotal Phase 3 studies (31-07-246 and 
31-07-247).  Study 31-08-248 is included in the 
development plan for aripiprazole IM Depot to supplement 
the safety data that will be generated as part of the Phase 3 
program and to provide additional efficacy data for the 
maintenance treatment of patients with schizophrenia.  The 
current study (31-10-270, hereafter referred to as Study 
270), will allow subjects who completed Study 31-08-248 
(hereafter referred to as Study 248) to continue treatment 
with aripiprazole IM Depot until it is commercially 
available in any dosage [including generic formulation(s)] 
in the country where the study is being conducted, the 
commercial availability of aripiprazole IM Depot is 
terminated by the sponsor, or until the study end date of 
31 Dec 2018 is reached.  This study will provide additional 
long-term safety information.
In adults, aripiprazole is indicated:

for treatment of schizophrenia and manic or mixed 
episodes associated with bipolar I disorder as 
monotherapy or adjunctive to lithium or valproate.

for adjunctive treatment of major depressive disorder 
(MDD) in adults.

as an injection for treatment of adults with agitation 
associated with schizophrenia or bipolar I disorder, 
manic or mixed episodes.

as an IM depot formulation for treatment of 
schizophrenia.
In pediatrics, aripiprazole is indicated:

for treatment of schizophrenia (ages 13 to 17 years). 

for treatment of manic or mixed episodes associated 
with bipolar I disorder as monotherapy or adjunctive to 
lithium or valproate (ages 10 to 17 years). 

for treatment of irritability associated with autistic 
disorder in children and adolescents (ages 6 to 17 years).
In the European Union (EU), aripiprazole is also approved 
for the treatment of moderate to severe manic episodes in 
bipolar I disorder and for the prevention of new manic 
episodes in those patients who experienced predominantly 
manic episodes and whose manic episodes responded to 
aripiprazole treatment, as well as for the treatment of 
schizophrenia in adults and adolescents (Appendix 13).  The 
aripiprazole immediate-release IM injection formulation is 
approved for the treatment of agitation associated with 
schizophrenia or bipolar mania in the US and EU.  In 
addition, an oral solution formulation and orally 
disintegrating (dispersible) tablets have been approved and 
marketed in the US and EU.  
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The favorable side effect profile of oral aripiprazole, 
including its low incidence of EPS, low risk of prolactin 
elevation, decreased adrenergic and anticholinergic side 
effects, and minimal weight gain, makes it an excellent 
candidate for a long-acting depot formulation.  Aripiprazole 
IM depot formulation is currently being developed for 
maintenance treatment of schizophrenia and bipolar I 
disorder, and was approved for the treatment of 
schizophrenia in the US in February 2013.  Its efficacy was 
demonstrated in a pivotal phase 3 registrational trial (Study 
31-07-246) designed to evaluate the efficacy, safety, and 
tolerability of the long-acting IM depot formulation of 
aripiprazole administered to adult subjects with a diagnosis 
of schizophrenia as defined by the Diagnostic and Statistical 
Manual of Mental Disorders, Fourth Edition, Text Revision 
(DSM-IV-TR).  A marketing application was submitted in 
September 2011 to the Food and Drug Administration (FDA) 
for use of the aripiprazole IM depot formulation as 
maintenance treatment in patients with schizophrenia, which 
was approved in February 2013 (Appendix 13).  A marketing 
application was submitted in December 2012 to the 
European Medicines Agency.
Study 31-08-248 is included in the development plan for 
aripiprazole IM Depot to supplement the safety data that will 
be generated as part of the phase 3 program and to provide 
additional efficacy data for the maintenance treatment of 
patients with schizophrenia.  The current study (31-10-270, 
hereafter referred to as Study 270), will allow subjects who 
completed Study 31-08-248 (hereafter referred to as Study 
248) to continue treatment with aripiprazole IM Depot until 
it is commercially available in any dosage (including generic 
formulation[s]) in the country where the study is being 
conducted, the commercial availability of aripiprazole IM 
Depot is terminated by the sponsor, or until the study end 
date of 31 Dec 2018 is reached.  This study will provide 
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additional long term safety information.
If the sponsor terminates the study prior to 31 Dec 2018 for 
any reason other than commercial availability, investigators 
in some countries where the sponsor has limited or delayed 
commercialization plans, or where no commercialization 
activity is anticipated, may be eligible to participate in a 
managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.  
Availability and requirements of such a program varies by 
jurisdiction, and would only be an option for subjects who 
were receiving aripiprazole IM Depot in the current study, 
and who in the physician’s opinion, may benefit from 
continued treatment with aripiprazole.  To gain access to 
aripiprazole IM Depot for eligible subjects via a managed 
access program, each physician will be responsible for 
gaining appropriate local regulatory approvals, which will be 
granted by authorities on a case-by-case basis.  The sponsor 
makes no guarantee that such a program is available or 
approvable in all of the jurisdictions where the study is 
conducted.
1.2 Clinical Data
A comprehensive clinical program to evaluate the 
effectiveness of aripiprazole was conducted.  The studies of 
subjects with an acute exacerbation of schizophrenia 
established the effectiveness of aripiprazole in the treatment 
of schizophrenia, including positive and negative 
symptoms.  These studies also demonstrated its early onset 
of action.  The long-term studies showed that aripiprazole 
treatment maintained stability in subjects with 
schizophrenia.
A comprehensive clinical program to evaluate the 
effectiveness of aripiprazole was conducted.  The studies of 
subjects with an acute exacerbation of schizophrenia 
established the effectiveness of aripiprazole in the treatment 
of schizophrenia, including positive and negative symptoms.  
These studies also demonstrated its early onset of action.  
The long-term studies showed that aripiprazole treatment 
maintained stability in subjects with schizophrenia.  The 
Investigator’s Brochure provides additional safety data on 
studies not described below.9
1.3 Known and Potential Risks 
and Benefits
As of 16 Apr 2007, 14,632 patients had been treated with 
aripiprazole oral-tablet formulation in Phase 2/3/4 studies 
(representing 8102 patient-exposure years).  Of these, 3774 
(25.8%) patients were treated with aripiprazole for 180 days 
or longer; 2063 (14.1%) patients received aripiprazole for at 
As of 01 Jun 2014, all voluntary reports of adverse events 
(AEs) in patients taking aripiprazole received since market 
introduction that were considered by the sponsor as 
medically relevant have been listed in the USPI and EU 
SmPC (Appendix 13).  The USPI and EU SmPC also contain 
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least 360 days, with 908 (6.2%) patients continuing 
aripiprazole treatment for at least 720 days.9
the currently available phase 2/3/4 clinical safety information 
(Appendix 13).
2.1 Trial Rationale
The current study (31-10-270) will allow the long-term 
patients who completed Study 248 to continue to receive 
aripiprazole IM Depot treatment until aripiprazole 
IM Depot is either commercially available in any dosage 
[including generic formulation(s)] in the country where the 
study is being conducted, the commercial availability of 
aripiprazole IM Depot is terminated by the sponsor, or until 
the study end date of 31 Dec 2018 is reached.  
The current study (31-10-270) will allow the long-term 
subjects who completed Study 248 to continue to receive 
aripiprazole IM Depot treatment until aripiprazole IM Depot 
is either commercially available in any dosage (including 
generic formulation[s]) in the country where the study is 
being conducted, the commercial availability of aripiprazole 
IM Depot is terminated by the sponsor, or until the study end 
date of 31 Dec 2018 is reached.
If the sponsor terminates the study prior to 31 Dec 2018 for 
any reason other than commercial availability, investigators 
in some countries where the sponsor has limited or delayed 
commercialization plans, or where no commercialization 
activity is anticipated, may be eligible to participate in a 
managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.  
Availability and requirements of such a program varies by 
jurisdiction and would only be an option for subjects who 
were receiving aripiprazole IM Depot in the current study, 
and who in the physician’s opinion, may benefit from 
continued treatment with aripiprazole.  To gain access to 
aripiprazole IM Depot for eligible subjects via a managed 
access program, each physician will be responsible for 
gaining appropriate local regulatory approvals, which will be 
granted by authorities on a case-by-case basis.  The sponsor 
makes no guarantee that such a program is available or 
approvable in all of the jurisdictions where the study is 
conducted.
3.1 Type/ Design of Trial
...
Following the Baseline visit, the Columbia Suicide Severity 
Rating Scale (C-SSRS), adverse events and concomitant 
medications will be assessed at the monthly injection study 
visit.  The CGI-S scale, vital signs, and urine pregnancy test 
(for women of child-bearing potential [WOCBP] only; see 
...
Following the baseline visit (described in detail in Section 
3.6.1.1), subjects will receive monthly injections and at the 
same visit, AEs and concomitant medications will be 
recorded and the Columbia Suicide Severity Rating Scale 
(C-SSRS) will be completed (Section 3.6.1.2).  Every 
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Section 5.4 for definition of WOCBP) will be assessed 
every 3 months.  Urine drug screening and blood alcohol 
testing, at the investigator’s discretion, can be performed 
every 3 months.  Visual Analog Scale (VAS) for 
subject-reported rating of pain at the most recent injection 
site and the investigator’s assessment for pain, redness, 
induration, and swelling of most recent injection site will be 
performed every 6 months.  The following scales will be 
used to assess EPS every 6 months (more frequently if 
warranted, see Table 3.6-1):  Abnormal Involuntary 
Movement Scale (AIMS), Simpson-Angus Scale (SAS), 
and Barnes Akathisia Rating Scale (BARS).  These EPS 
scales can be administered at any visit at the discretion of 
the investigator if warranted by the presence of symptoms.  
Clinical laboratory tests, a physical examination, an ECG, 
body height and weight, BMI, and waist circumference will 
be performed annually.  For each visit, all the assessments, 
except for post-injection assessments, should be performed 
prior to the aripiprazole IM Depot injection.
A Study Completion Visit or Early Termination Visit 
(-2/+10 days) will be performed and include the following 
assessments: CGI-S; C-SSRS; injection site assessment by 
the subject using VAS and by the investigator for pain, 
redness, induration, and swelling; AEs; EPS (AIMS, SAS, 
and BARS); clinical laboratory tests; vital signs, body 
height and weight; BMI; physical examination; ECG; urine 
pregnancy test for WOCBP; and concomitant medications.  
...
Aripiprazole IM Depot treatment in this open-label rollover 
study will continue until there are clinical and/or 
administrative reasons for discontinuation of the subject’s 
study treatment or the end of study date of 31 Dec 2018 is 
reached. ...
Once aripiprazole IM Depot becomes commercially 
3 months (Section 3.6.1.3), all of the monthly assessments 
will be completed along with a urine pregnancy test for 
women of childbearing potential (WOCBP) (see Section 5.4 
for the definition of WOCBP).  Every 6 months (Section 
3.6.1.4), all of the 3-month assessments will be completed 
along with the CGI-S scale, vital signs, and EPS assessments 
(Abnormal Involuntary Movement Scale [AIMS], 
Simpson-Angus Scale [SAS], and Barnes Akathisia Rating 
Scale [BARS]).  Every 12 months (Section 3.6.1.5), all of the 
6-month assessments will be completed along with clinical 
laboratory tests and assessments of body height, weight, and 
waist circumference.  
At the discretion of the investigator, the baseline assessments 
for clinical chemistry and hematology, urine drug screening,
and blood alcohol testing may be repeated at any subsequent 
study visit.  For each visit, all the assessments, except for 
those specified as post-injection assessments, should be 
performed prior to the aripiprazole IM Depot injection.
A Study Completion visit or Early Termination visit 
(−2/+10 days) will include the following assessments  
(Section 3.6.1.6): C-SSRS, AEs, concomitant medications, a 
urine pregnancy test for WOCBP, CGI-S, vital signs, EPS 
assessments (AIMS, BARS, SAS), clinical laboratory tests, 
and body height and weight.  
...
Aripiprazole IM Depot treatment in this open-label rollover 
study will continue until there are clinical and/or 
administrative reasons for discontinuation of the subject’s 
study treatment or until the study end date of 31 Dec 2018 is 
reached, whichever occurs first. ...
If the sponsor terminates the study prior to 31 Dec 2018 for 
any reason other than commercial availability, investigators 
in some countries where the sponsor has limited or delayed 
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available in the country where the subject is participating in 
the study [including generic formulation(s)] or the 
commercial availability of aripiprazole IM Depot is 
terminated by the sponsor, study treatment will be 
discontinued within 6 weeks of the subject’s previous 
injection for clinical transition purposes.
commercialization plans, or where no commercialization
activity is anticipated, may be eligible to participate in a 
managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.  
Availability and requirements for such a program varies by 
jurisdiction, and would only be an option for subjects who 
were receiving aripiprazole IM Depot in the current study, 
and who in the physician’s opinion, may benefit from 
continued treatment with aripiprazole.  To gain access to 
aripiprazole IM Depot for eligible subjects via a managed 
access program, each physician will be responsible for 
gaining appropriate local regulatory approvals, which will be 
granted by authorities on a case-by-case basis.  The sponsor 
makes no guarantee that such a program is available or 
approvable in all of the jurisdictions where the study is 
conducted.
Once aripiprazole IM Depot becomes commercially 
available in the country where the subject is participating in 
the study (including generic formulation[s]) or the 
commercial availability of aripiprazole IM Depot is 
terminated by the sponsor, study treatment will be 
discontinued within approximately 6 weeks of the subject’s 
previous injection for clinical transition purposes.
Figure 3.1-1 Study 31-10-270 
Trial Design Schema
Both Figures are displayed below
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Amendment 3 
Figure 3.1-1
Study 31-10-270 Trial Design Schema
AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; BMI = body mass index; CGI-S = Clinical 
Global Impression – Severity; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EPS = extrapyramidal symptoms; 
IM = intramuscular; PE = physical examination; SAS = Simpson-Angus Scale.
Study Entry
Open Label IM Depot Treatment
Follow-up
Study 248 
Completers only
Week 52 Visit of 
Study 248 = 
Baseline for Study 
270
±3 days
Every Month:
Injection visits, C -SSRS, AEs, & 
concomitant medications
Every 3 months:
CGI-S, vital signs, urine pregnancy 
test, optional drug and alcohol 
testing
Every 6 months:
Injection site assessments and EPS 
(AIMS, SAS, & BARS)
Every 12 months: Clinical laboratory tests, PE, ECG, 
body height & weight, BMI, and 
waist circumference
One 30-day post
End of Study
Injection visit window  =  28 ( -2/+10) days
Assessment visit windows  = 
-2/+10 days
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Amendment 4 
Study Entry
Open-label IM Depot Treatment
Follow-up
Study 248 
Completers only
Every month:
Injection, C-SSRS, AEs, and 
concomitant medications
One 30-day post 
End of Study phone 
call - AEs and 
concomitant 
medications 
Every 3 monthsa:
Urine pregnancy test for WOCBP
Every 6 monthsa:
CGI-S, vital signs, and EPS 
assessments (AIMS, BARS, SAS)
Every 12 monthsa:
Clinical laboratory tests, body weight 
and height, and waist circumference
Week 52 Visit of 
Study 248 = 
Baseline for 
Study 270
Injection visit window = 28 (−2/+10) days
Assessment visit window = −2/+10 days
± 3 days
Figure 3.1-1
Study 31-10-270 Trial Design Schema
BMI = body mass index.
aThe 3-month, 6-month, and 12-month visits include assessments from the previous visit.  For example, the 3-month visit includes all of the monthly visit 
assessments in addition to the 3-month visit assessments.  A Study Completion or Early Termination visit will also be performed.  Refer to Table 3.6-1 for 
a comprehensive Schedule of Assessments at each visit. 
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3.2 Treatments
Needle length for injection of aripiprazole IM Depot will be 
selected based on body mass index (BMI) as follows: 21
gauge, 1.5 inch for BMI ≤28 kg/m2; 21 gauge, 2 inch for 
BMI > 28 kg/m2.  
Needle length for injection of aripiprazole IM Depot will be 
selected based on body mass index (BMI) obtained at 
baseline as follows: 21 gauge, 1.5 inch for BMI ≤ 28 kg/m2; 
21 gauge, 2 inch for BMI > 28 kg/m2.  
Table 3.4.3-1 Exclusion Criteria
... If employing birth control, two of the following 
precautions must be used: vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device (IUD), birth control 
pill, birth control implant, condom, or sponge with 
spermicide.
... If employing birth control, two of the following 
precautions must be used: vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device (IUD), birth control pill, birth 
control implant, condom with spermicide, or sponge with 
spermicide.
3.5.1 Safety Endpoints
AEs will be examined by frequency, severity, seriousness, 
and discontinuation due to AEs.  The Columbia Suicide 
Severity Rating Scale (C-SSRS) will be completed at 
baseline and every month to assess the risk of suicide 
events and to classify reported suicide events.  Injection site 
pain will be evaluated by mean VAS scores as reported by 
the subject once every 6 months before and after injection.  
Extrapyramidal symptoms will be evaluated by calculating 
mean change from baseline in AIMS, SAS, and BARS 
every 6 months (more frequently if warranted, see 
Table 3.6.-1).  The investigator rating of localized pain, 
redness, induration, and swelling at the injection site will 
also be tabulated every 6 months.  Vital signs will be 
assessed every 3 months and clinical laboratory tests, ECG, 
and physical examinations will be assessed every 12 
months.
Adverse events will be examined by frequency, severity, 
seriousness, and discontinuation due to AEs.  The C-SSRS 
will be completed at baseline and every subsequent monthly 
visit to assess the risk of suicide events and to classify 
reported suicide events.  Extrapyramidal symptoms will be 
evaluated by calculating mean change from baseline in 
AIMS, SAS, and BARS every 6 months (more frequently if 
warranted, see Table 3.6.-1) and at Study Completion or the 
Early Termination visit.  Clinical laboratory tests will be 
performed at baseline, every 12 months, and at Study 
Completion or the Early Termination visit.  Vital signs will 
be assessed every 6 months and at Study Completion or the 
Early Termination visit. Body weight, height, and waist 
circumference will be assessed every 12 months; body 
weight and height will also be assessed at Study Completion 
or the Early Termination visit.
3.5.2 Efficacy Endpoint
CGI-S will be evaluated by calculating mean change from 
baseline every 3 months over the course of the study.
CGI-S will be evaluated by calculating mean change from 
baseline every 6 months over the course of the study.
Table 3.6-1 Schedule of 
Assessments (Study 31-10-270)
Both Tables are presented below
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Table 3.6-1
Schedule of Assessments (Study 31-10-270)
Assessment
Baseline
(Week 52 Visit 
of previous 
Otsuka 
31 08-248 
study)a
Study Visits
Study 
Completion or 
Early 
Termination
30-Day Post 
Treatment 
Follow-up 
Phone Callc
Every 
Monthb
Every 3 
Monthsb
Every 6 
Monthsb
Every 12 
Monthsb
(-2/+10 days)
(-2/+10 days)
(-2/+10 days)
(-2/+10 days)
(-2/+10 days)
(3 days)
STANDARD
Informed consent
X
Inclusion/exclusion criteria
X
Medical history
X
STUDY ASSESSMENTS
CGI-S
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
AIMSd
X
<-------------------------------------->
X
X
X
SASd
X
<-------------------------------------->
X
X
X
BARSd
X
<-------------------------------------->
X
X
X
VAS pain at injection sitee
X
X
X
X
Investigator rating of injection sitee
X
X
X
X
Body height and weight
X
X
X
BMIf
X
X
X
Waist circumference
X
X
Adverse eventsg
X
X
X
X
X
X
X
Clinical laboratory tests (hematology, 
serum chemistry, and urinalysis)
X
X
X
Vital signs
X
X
X
X
X
Physical exam
X
X
X
ECG
X
X
X
Urine pregnancy test
(WOCBP only)h
X
X
X
X
X
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Table 3.6-1
Schedule of Assessments (Study 31-10-270)
Assessment
Baseline
(Week 52 Visit 
of previous 
Otsuka 
31 08-248 
study)a
Study Visits
Study 
Completion or 
Early 
Termination
30-Day Post 
Treatment 
Follow-up 
Phone Callc
Every 
Monthb
Every 3 
Monthsb
Every 6 
Monthsb
Every 12 
Monthsb
(-2/+10 days)
(-2/+10 days)
(-2/+10 days)
(-2/+10 days)
(-2/+10 days)
(3 days)
Urine drug screen and blood alcohol 
testi
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
STUDY MANAGEMENT
Administer open-label IM Depotj
X
X
X
X
X
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Table 3.6-1
Schedule of Assessments (Study 31-10-270)
Assessment
Baseline
(Week 52 Visit 
of previous 
Otsuka 
31-08-248 
study)a
Study Visits
Study 
Completion 
or 
Early 
Termination
30-Day 
Post 
Treatment 
Follow-up 
Phone 
Callc
Every 
Monthb
Every 3 
Monthsb
Every 6 
Monthsb
Every 12 
Monthsb
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(3 days)
STANDARD
Informed consent
X
Inclusion/exclusion criteria
X
Medical history
X
STUDY ASSESSMENTS
CGI-S
X
X
X
X
C-SSRS
X
X
X
X
X
X
AIMSd
X
X
X
X
SASd
X
X
X
X
BARSd
X
X
X
X
VAS pain at injection sitee
X
At the discretion of the investigator
Investigator rating of injection sitee
X
At the discretion of the investigator
Body height and weightf
X
X
X
BMIf
X
At the discretion of the investigator
Waist circumferencef
X
X
Adverse eventsg
X
X
X
X
X
X
X
Clinical laboratory tests (hematology, serum chemistry, 
and urinalysis)
X
At the discretion of the investigator
X
X
Vital signs
X
X
X
X
Physical exam
X
At the discretion of the investigator
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Table 3.6-1
Schedule of Assessments (Study 31-10-270)
Assessment
Baseline
(Week 52 Visit 
of previous 
Otsuka 
31-08-248 
study)a
Study Visits
Study 
Completion 
or 
Early 
Termination
30-Day 
Post 
Treatment 
Follow-up 
Phone 
Callc
Every 
Monthb
Every 3 
Monthsb
Every 6 
Monthsb
Every 12 
Monthsb
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(−2/+10 
days)
(3 days)
ECG
X
At the discretion of the investigator
Urine pregnancy testh
X
X
X
X
X
Urine drug screen and blood alcohol testi
X
At the discretion of the investigator
Concomitant medications
X
X
X
X
X
X
X
STUDY MANAGEMENT
Administer open-label IM Depotj
X
X
X
X
X
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Table 3.6-1 Schedule of 
Assessments (Study 31-10-270), 
Footnotes
...
d  Extrapyrimidal symptoms (EPS) will be assessed using 
AIMS, SAS, and BARS at least every 6 months, but these 
EPS scales can be administered at any visit at the discretion 
of the investigator if warranted by the presence of 
symptoms.
e  The subject will complete the pain evaluation and the 
investigator (or qualified designee) will assess the most 
recent injection site for localized pain, redness, swelling, 
and induration.  These assessments will occur as the last 
evaluations prior to the IM Depot injection.  Approximately 
30 minutes prior to the injection, the investigator and 
subject will complete the injection site evaluation and VAS 
pain assessment, respectively, with the most recent 
injection site as the basis for the evaluation (ie, the site from 
the last injection).  These assessments will be repeated at 1 
hour (± 15 min) after the injection is administered with 
focus again on the most recent injection site, which is now 
the new injection site from the latest injection.  The pre-
and post-injection evaluations must be completed on the 
same day (ie, the day the injection is administered).  The 1-
hour post injection follow-up is to assess the injection site 
and any reaction to medication.
f  Needle length for injection of aripiprazole IM Depot will 
be selected based on BMI (21 gauge, 1.5 inch for BMI 
≤28 kg/m2; 21 gauge, 2 inch for BMI > 28 kg/m2).  The 
BMI, which will be calculated in kg/m2 from the baseline 
height and weight at the baseline visit using one of the 
following formulae, as appropriate: Weight (kg) ÷ [Height 
(m)]2 or Weight (lb) ÷ [Height (in)]2 x 703.  If a noticeable 
fluctuation in body height and weight has occurred during 
the study, at the investigator’s discretion, body weight can 
...
d  Extrapyramidal symptoms (EPS) will be assessed using 
AIMS, SAS, and BARS at baseline, every 6 months, at Study 
Completion or the Early Termination visit, and at any other 
study visit at the discretion of the investigator if warranted 
by the presence of symptoms.
e  At baseline (Week 52 visit of the previous Otsuka 
31-08-248 study), each subject will complete the pain 
evaluation and the investigator (or qualified designee) will 
assess the most recent injection site for localized pain, 
redness, swelling, and induration.  These assessments will 
occur as the last evaluations prior to the IM Depot injection.  
Approximately 30 minutes prior to the injection, the 
investigator and subject will complete the injection site 
evaluation and VAS pain assessment, respectively, with the 
most recent injection site as the basis for the evaluation (ie, 
the site from the last injection).  These assessments will be 
repeated at 1 hour (± 15 min) after the injection is 
administered with focus again on the most recent injection 
site.  The pre- and post-injection evaluations must be 
completed on the same day (ie, the day the injection is 
administered).  The 1-hour post injection follow-up is to 
assess the injection site and any reaction to medication.  This 
assessment may be repeated at the discretion of the 
investigator.
f  Needle length for injection of aripiprazole IM Depot will 
be selected based on BMI (21 gauge, 1.5 inch for BMI 
≤28 kg/m2; 21 gauge, 2 inch for BMI > 28 kg/m2).  The BMI 
will be calculated in kg/m2 from the baseline height and 
weight at the baseline visit using one of the following 
formulae, as appropriate: Weight (kg) ÷ [Height (m)]2 or 
Weight (lb) ÷ [Height (in)]2 x 703.  If a noticeable 
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be remeasured and BMI recalculated and used for the next 
aripiprazole IM Depot injection.
...
h  A urine pregnancy test is required for all women of 
childbearing potential (WOCBP) at the designated times, 
but can be performed at any point during the trial if 
pregnancy is suspected.  All positive urine pregnancy test 
results must be confirmed by a serum test.  WOCBP is 
defined as ALL women unless they have had an 
oophorectomy and/or hysterectomy or have been 
menopausal for at least 12 consecutive months.  This should 
be documented in their medical history.  Subjects with 
positive serum test results will be excluded from the study.  
Treated subjects with a positive serum pregnancy test must 
discontinue treatment, be withdrawn from the study, and an 
IRE form should be completed.
i  Urine drug screen and blood alcohol test are required at 
Baseline and optional every 3 months afterwards, at the 
investigator’s discretion.
fluctuation in body height and weight has occurred during 
the study, at the investigator’s discretion, body weight can be 
remeasured and BMI recalculated and used for the next 
aripiprazole IM Depot injection.  Body weight, height, and 
waist circumference will be reassessed annually, and body 
weight and height will also be assessed at Study Completion 
or the Early Termination visit.
...
h  A urine pregnancy test is required for all WOCBP at 
baseline, every 3 months, and at Study Completion or the 
Early Termination visit, but can be performed at any point 
during the trial if pregnancy is suspected.  All positive urine 
pregnancy test results must be confirmed by a serum test.  
WOCBP is defined as ALL women unless they have had an 
oophorectomy and/or hysterectomy or have been menopausal 
for at least 12 consecutive months.  This should be 
documented in their medical history.  Subjects with positive 
serum test results will be excluded from the study.  Treated 
subjects with a positive serum pregnancy test must 
discontinue treatment, be withdrawn from the study, and an 
immediately reportable event (IRE) form should be 
completed.
i  Urine drug screen and blood alcohol test are required at 
baseline and anytime at the investigator’s discretion.
3.6.1.1 Baseline
The baseline visit for Study 270 (which is the Week 52 visit 
of Study 248) and the first injection for Study 270 must 
occur within 4 weeks (which is defined as 28 [-2/+10] days) 
of the last injection in Study 248.  The Week 52 
assessments for Study 248 include the necessary 
assessments for Study 270 baseline: CGI-S; C-SSRS; 
AIMS; SAS; BARS; injection site pain assessed by the 
subject using VAS; investigator’s injection site assessment 
for pain, redness, swelling, and induration; body weight and 
height; BMI; waist circumference; AEs; clinical laboratory 
tests; vital signs; physical exam; ECG; urine pregnancy test 
The baseline visit for Study 270 (which is the Week 52 visit 
of Study 248) and the first injection for Study 270 must 
occur within 4 weeks (which is defined as 28 [−2/+10] days) 
of the last injection in Study 248.  At this visit, subjects will 
sign an Informed Consent for Study 270 and their eligibility 
will be confirmed.
The Study 248 Week 52 assessments will also serve as the 
baseline assessments for Study 270: CGI-S; C-SSRS; EPS 
assessments (AIMS, SAS, BARS); injection site pain 
assessed by the subject using VAS; investigator’s injection 
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for WOCBP (see Section 5.4 for definition of WOCBP); 
urine drug screen; blood alcohol test; and concomitant 
medications (see Table 3.6-1).  All ongoing AEs and 
clinically significant AEs from Study 248 will be recorded 
as Medical History of Study 270; please refer to the 
Operations Manual or CRF Completion Guidelines for 
additional detail.  
site assessment for pain, redness, swelling, and induration; 
body weight and height; BMI; waist circumference; AEs; 
clinical laboratory tests; vital signs; physical exam; ECG; 
urine pregnancy test for WOCBP (see Section 5.4 for the 
definition of WOCBP); urine drug screen; blood alcohol test; 
and concomitant medications (see Table 3.6-1).  All ongoing 
AEs and clinically significant AEs from Study 248 will be 
recorded as Medical History of Study 270; please refer to the 
Operations Manual or case report form (CRF) Completion 
Guidelines for additional detail.
3.6.1.2 Injection and Assessments 
Performed Every Month
−
3.6.1.3 Assessments Performed 
Every 3 Months
In addition to the monthly assessments, every 3 months 
(study months are every 4 weeks which is defined as 28 
[-2/+10] days) CGI-S, vital signs, and urine pregnancy test 
for WOCBP will also be performed or assessed.  In addition 
to these assessments, urine drug screening and blood 
alcohol testing, at the investigator’s discretion, can be 
performed every 3 months.  
Every 3 months (study months are every 4 weeks which is 
defined as 28 [−2/+10] days), the following assessments will 
be performed: injection, C-SSRS, AEs, concomitant 
medications, and a urine pregnancy test for WOCBP.  
3.6.1.4 Assessments Performed 
Every 6 Months
In addition to the monthly and 3-month assessments, every 
6 months (study months are every 4 weeks which is defined 
as 28 [2/+10] days) injection pain will be assessed by the 
subject using VAS, and the investigator injection site 
assessment for pain, redness, induration, and swelling at the 
most recent injection site will also be performed.  
Extrapyramidal symptoms will be assessed every 6 months 
(more frequently if warranted, see Table 3.6-1) using the 
AIMS, SAS, and BARS assessments.  
Every 6 months (study months are every 4 weeks which is 
defined as 28 [−2/+10] days) the following assessments will 
be performed:  injection, C-SSRS, AEs, concomitant 
medications, a urine pregnancy test for WOCBP, CGI-S, 
vital signs, and EPS assessments (AIMS, BARS, SAS).  
3.6.1.5 Assessments Performed 
Every 12 Months
In addition to the monthly, 3-month, and 6-month 
assessments, every 12 months (study months are every 
4 weeks which is defined as 28 [-2/+10] days) clinical 
laboratory tests, a physical examination, and an ECG will 
also be performed.  Every 12 months, body height and 
weight and waist circumference will be measured and BMI 
calculated.  
Every 12 months (study months are every 4 weeks which is 
defined as 28 [−2/+10] days) the following assessments will 
be performed:  injection, C-SSRS, AEs, concomitant 
medications, a urine pregnancy test for WOCBP, CGI-S, 
vital signs, and EPS assessments (AIMS, BARS, SAS), 
clinical laboratory tests, body height and weight, and waist 
circumference.  
3.6.1.6 Study Completion or Early 
A Study Completion Visit or Early Termination Visit 
A Study Completion visit or Early Termination visit 
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Termination Visit
(-2/+10 days) will be performed and include the following 
assessments: CGI-S; C -SSRS; EPS (AIMS, SAS, and 
BARS), injection site assessment by the subject using VAS 
and by the investigator for pain, redness, induration, and 
swelling; AEs, clinical laboratory tests, vital signs, body 
height and weight, BMI, ECG, physical examination, urine 
pregnancy test for WOCBP, and concomitant medications.  
(−2/+10 days) will be performed and will include the 
following assessments:  C-SSRS, AEs, concomitant 
medications, a urine pregnancy test for WOCBP, CGI-S, 
vital signs, and EPS assessments (AIMS, BARS, SAS), 
clinical laboratory tests, and body height and weight. 
3.6.1.7 30-Day Post Treatment 
Follow-up Phone Call
A 30-Day Post Treatment Follow-up phone call will be 
performed 30 days (3 days) after it has been determined 
that the subject will no longer participate in this study and 
include the recording of AEs that have occurred and any 
concomitant medications taken since the last visit.
A 30-Day Post Treatment Follow-up phone call will be 
performed 30 days (3 days) after it has been determined 
that the subject will no longer participate in this study and 
will include the recording of AEs that have occurred since 
the last visit and any concomitant medications taken since 
the last visit.
3.6.3.2 Clinical Laboratory 
Assessments
A central laboratory designated by the sponsor will be used 
for all laboratory testing required during the study.  The 
central laboratory should be used for all laboratory testing 
whenever possible (including unscheduled and follow-up 
labs, if needed).  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.
Samples for serum chemistry, hematology, and urinalysis 
will be obtained once every 12 months and at the Study 
Completion visit or the Early Termination visit as specified 
in Table 3.6-1.  Additional urine and blood samples may be 
collected for further evaluation of safety as warranted by 
the investigator’s judgment.
Subjects should be fasting for a minimum of 10 hours prior 
to any blood draws for assessment of safety, including 
baseline.  If a nonfasting blood sample is initially obtained 
and the test results possibly impacted, a fasting blood 
sample should be drawn shortly afterwards and the affected 
lab test(s) repeated.  The laboratory tests to be evaluated in 
this trial are listed in Table 3.6.3.2-1.  To better understand 
A central laboratory designated by the sponsor will be used 
for all laboratory testing required.  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.   
Samples for serum chemistry, hematology, and urinalysis 
will be obtained at baseline, every 12 months (study months 
are every 4 weeks which is defined as 28 [−2/+10] days), and 
at Study Completion or the Early Termination visit as 
specified in Table 3.6-1.  Urine and blood samples may be 
collected for further evaluation of safety as warranted by the 
investigator’s judgment.
Subjects should be fasting for a minimum of 10 hours prior 
to any blood draws for assessment of safety, including 
baseline.  If a nonfasting blood sample is initially obtained 
and the test results possibly impacted, a fasting blood sample 
should be drawn shortly afterwards and the affected lab 
test(s) repeated.  The laboratory tests to be evaluated in this
trial are listed in Table 3.6.3.2-1.  
For Study 270, a urine pregnancy test will be performed at 
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the risk of diabetes mellitus in this subject population, 
hemoglobin A1c will be measured only if fasting glucose is 
≥ 125 mg/dL and/or the urinalysis is positive for glucose.
For Study 270, a urine pregnancy test will be performed at 
baseline and every 3 months for all WOCBP (see Section 
5.4 for the definition of WOCBP) to confirm that the 
subject is not pregnant.  Any positive urine pregnancy test 
result will be confirmed by a serum test.
...
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.  
baseline, every 3 months, at Study Completion or the Early 
Termination visit, and at any time at the discretion of the 
investigator when pregnancy is suspected for all WOCBP 
(see Section 5.4 for the definition of WOCBP) to confirm 
that the subject is not pregnant.  Any positive urine 
pregnancy test result will be confirmed by a serum test.
...
Any baseline 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.  
Table 3.6.3.2-1 Baseline Clinical 
Laboratory Assessments, 
Footnotes
a  A urine pregnancy test will be performed at baseline for 
all WOCBP (see Section 5.4 for the definition of WOCBP) 
to assess eligibility for the study and will be repeated every 
3 months throughout the trial.  All positive urine pregnancy 
test results must be confirmed by a serum test.
b To better understand the risk of diabetes mellitus in this 
subject population, hemoglobin A1c will be measured if the 
subject’s fasting glucose is ≥125 mg/dL and/or the 
urinalysis is positive for glucose.  
a  A urine pregnancy test will be performed at baseline for all 
WOCBP (see Section 5.4 for the definition of WOCBP) to 
assess eligibility for the study and will be repeated every 
3 months throughout the trial, at Study Completion or the 
Early Termination visit, and at any time at the discretion of 
the investigator when pregnancy is suspected.  All positive 
urine pregnancy test results must be confirmed by a serum 
test.
b At the discretion of the investigator, hemoglobin A1c will 
be measured if the subject’s fasting glucose is ≥ 125 mg/dL 
and/or the urinalysis is positive for glucose.  
3.6.3.3.1
Physical Examination
A complete physical examination, including height, will be 
performed at baseline.  The physical examination will be 
repeated once every 12 months and at the Study 
Completion visit or the Early Termination visit (as 
designated in Table 3.6-1). ... Any condition present at the 
post-treatment physical exam that was not present at the 
baseline exam should be documented as an AE and 
followed to a satisfactory conclusion.
A full physical exam will be performed with the exception 
of the genitourinary (GU) body system.  It will be 
A complete physical examination, including height, will be 
performed at baseline.  The physical examination may be 
repeated at the discretion of the investigator at any 
subsequent visit. ... Any condition present at subsequent 
physical exams that was not present at the baseline exam 
should be documented as an AE and followed to a 
satisfactory conclusion.
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mandatory that there is a baseline GU exam, which can 
have been performed up to 1 calendar year prior to the date 
of the ICF being signed; the subject must provide a copy of 
the progress note/details of the exam as the source.  If no 
records of such prior GU exam are provided, a GU exam 
will be done as part of the baseline physical exam by a 
qualified practitioner listed on the FDA Form 1572.  
Postbaseline, a GU exam will be required annually, by 
either the subject’s private practitioner (provision of a copy 
of the documented results of the exam is mandatory) or by a 
qualified practitioner on the 1572.  Medically relevant 
questions about the GU body system should be asked of the 
subject at all protocol-required physical exams, with 
answers recorded accordingly in the source documentation.  
Any documentation received from an exam performed by a 
practitioner not on the 1572 form should be reviewed by the 
investigator or a medically qualified subinvestigator, and a 
note should be written by this investigator or 
subinvestigator confirming the review and documenting any 
necessary follow-up in their opinion. 
3.6.3.3.2Vital Signs
Vital sign measurements will be performed at baseline and 
every 3 months (study months are every 4 weeks which is 
defined as 28 [-2/+10] days) and include body temperature, 
systolic and diastolic blood pressure, and heart rate.
Vital sign measurements will be performed at baseline, every 
6 months (study months are every 4 weeks which is defined 
as 28 [−2/+10] days), and at Study Completion or the Early 
Termination visit, and will include body temperature, 
systolic and diastolic blood pressure, and heart rate.  
3.6.3.3.3 Body Height and Weight 
and Body Mass Index
Body height and weight will be measured at baseline prior 
to the first dose of aripiprazole IM Depot and every 
12 months (study months are every 4 weeks which is 
defined as 28 [-2/+10] days) and at the Study Completion 
visit or the Early Termination visit. ...
...
... If a noticeable fluctuation in body weight has occurred 
during the study, at the investigator’s discretion, body 
height and weight can be remeasured and BMI recalculated 
and used for the next aripiprazole IM Depot injection.  
Body height and weight will be measured at baseline prior to 
the first dose of aripiprazole IM Depot, every 12 months 
(study months are every 4 weeks which is defined as 
28 [−2/+10] days), and at Study Completion or the Early 
Termination visit.  ...
...
... If a noticeable fluctuation in body weight has occurred 
during the study, at the investigator’s discretion, body height 
and weight can be remeasured and BMI recalculated and 
used for the next aripiprazole IM Depot injection.  BMI may 
be calculated at subsequent visits at the discretion of the 
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investigator.  Body height and weight (not BMI) will be 
reassessed annually and at any study visit at the discretion of 
the investigator.  
3.6.3.3.4
Waist Circumference
Waist circumference will be measured at baseline and every 
12 months (study months are every 4 weeks which is 
defined as 28 [-2/+10] days).  
Waist circumference will be measured at baseline and every 
12 months (study months are every 4 weeks which is defined 
as 28 [−2/+10] days), or at other visits at the discretion of the 
investigator.
3.6.3.4
ECG Assessments
Twelve-lead ECGs will be recorded at baseline and every 
12 months (study months are every 4 weeks which is 
defined as 28 [-2/+10] days) and at the Study Completion 
visit or the Early Termination visit as specified in Table 
3.6-1.  The ECG criteria for baseline ECG for Study 270 
(which is the Week 52 visit of Study 248) will be done per 
Study 248 requirements.  At baseline, three ECG recordings 
will be obtained approximately 5 minutes apart.  Additional 
12 lead ECGs may be obtained at the investigator’s 
discretion and should always be obtained in the event of an 
early termination.  ECGs 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.
...
The ECG assessments performed after baseline will be a 
single ECG, not done in triplicate.  Additional ECGs can be 
done if warranted by a clinically significant finding or 
abnormality, an error, or as deemed necessary by the 
investigator.
Twelve-lead ECGs will be recorded at baseline and at the 
discretion of the investigator.  The ECG criteria for baseline 
ECG for Study 270 (which is the Week 52 visit of 
Study 248) will be done per Study 248 requirements.  
At baseline, three ECG recordings will be obtained 
approximately 5 minutes apart.  All ECGs will be evaluated 
at the investigational site to determine the subject’s 
eligibility.  The principal investigator or qualified designee 
will review, sign, and date each ECG reading obtained, 
noting whether or not any abnormal results are of clinical 
significance.  The ECG will be repeated if any results are 
considered to be clinically significant.  As of Amendment 4, 
ECG results will not be obtained centrally after the baseline 
assessment.  Any subsequent ECG assessments will be 
obtained locally at the discretion of the investigator.
3.6.3.5 Extrapyramidal Symptoms
(All text here is new)
Extrapyramidal symptoms are assessed at baseline, every 
6 months (study months are every 4 weeks which is defined 
as 28 [−2/+10] days), and at Study Completion or the Early 
Termination visit.  The EPS symptoms may also be 
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reassessed at the discretion of the investigator using the 
instruments described in Section 3.6.3.5.1, Section 3.6.3.5.2, 
and Section 3.6.3.5.3.  
3.6.3.6 Suicidality
Suicidality will be monitored throughout the study (from 
Study Month 1 through Study Completion or the Early 
Termination visit, if the subject discontinues the study 
before completion) using the C-SSRS at every visit. ... A 
baseline C-SSRS will be completed at baseline.  The 
C-SSRS Since Last Visit form will be completed at all 
subsequent visits.  
Suicidality will be monitored using the C-SSRS at baseline, 
every subsequent monthly visit, and at Study Completion or 
the Early Termination visit. ... A baseline C-SSRS will be 
completed and a C-SSRS Since Last Visit form will be 
completed at all designated visits.  
3.6.3.7 Injection Site Evaluation
Injection site reaction will be assessed by the investigator 
(or qualified designee) and the subject in a manner similar 
to that used for the evaluation of other IM depot 
compounds.5,32  Investigators (or qualified designees) will 
rate localized pain, redness, swelling, and induration at the 
most recent injection site using a 4-point categorical scale 
ranging from absent to severe (Appendix 12).  The subject 
will indicate the degree of pain at the most recent injection 
site using a VAS (Appendix 11).  Ratings will range from 0 
(no pain) to 100 (unbearably painful).  These assessments 
will occur at baseline, every 6 months, and at the Study 
Completion visit or the Early Termination visit.  These 
assessments will be completed both pre- and post-injection.  
The investigator’s rating of the most recent injection site 
(ie, the site of the last injection given) and the subject-rated 
VAS pertaining to this location will be completed after all 
other study assessments, and within 30 minutes prior to the 
IM depot injection
Injection site reaction will be assessed at baseline and at the 
discretion of the investigator (or qualified designee) and the 
subject at any subsequent study visit in a manner similar to 
that used for the evaluation of other IM depot compounds.5,32  
Investigators (or qualified designees) at baseline will rate 
localized pain, redness, swelling, and induration at the most 
recent injection site using a 4-point categorical scale ranging 
from absent to severe (Appendix 12).  The subject will 
indicate the degree of pain at the most recent injection site 
using a VAS (Appendix 11).  Ratings will range from 0 (no 
pain) to 100 (unbearably painful).  If required, these 
assessments will be completed both pre- and post-injection, 
after all other study assessments, and within 30 minutes prior 
to the IM depot injection. ... As of Amendment 4, VAS and 
injection site assessments are no longer required at any 
post-baseline study visits.
3.7.1 Entire Trial of Treatment 
Arm(s)
The sponsor will terminate the study in countries where 
aripiprazole IM Depot becomes commercially available 
[including generic formulation(s)], the commercial 
availability of aripiprazole IM Depot is terminated by the 
sponsor, or if the study end date of 31 December 2018 is 
reached.
The sponsor will terminate the study in countries where 
aripiprazole IM Depot becomes commercially available 
(including generic formulation[s]), the commercial 
availability of aripiprazole IM Depot is terminated by the 
sponsor, or if the study end date of 31 Dec 2018 is reached.
If the sponsor terminates the study prior to 31 Dec 2018 for 
any reason other than commercial availability, investigators 
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in some countries where the sponsor has limited or delayed
commercialization plans, or where no commercialization 
activity is anticipated, may be eligible to participate in a 
managed access program until aripiprazole IM Depot is 
commercially available in their country or until 31 Dec 2018.  
Availability and requirements of such a program varies by 
jurisdiction, and would only be an option for subjects who 
were receiving aripiprazole IM Depot in the current study, 
and who in the physician’s opinion, may benefit from 
continued treatment with aripiprazole.  To gain access to 
aripiprazole IM Depot for eligible subjects via a managed 
access program, each physician will be responsible for 
gaining appropriate local regulatory approvals, which will be 
granted by authorities on a case-by-case basis.  The sponsor 
makes no guarantee that such a program is available or 
approvable in all of the jurisdictions where the study is 
conducted.
3.9 Definition of Completed 
Subjects
... For purposes of this trial, subjects who discontinue due to 
the commercial availability of study drug in the country 
where the study is being conducted will be defined as 
completers.  Protocol-specified post-treatment follow-up 
contacts will not qualify as “last scheduled” visit.
... For purposes of this trial, subjects who discontinue due to 
the commercial availability of study drug in the country 
where the study is being conducted will be defined as 
completers.  In addition, subjects in countries where a 
managed access program is available for continued treatment 
with aripiprazole at the time of trial closure in their 
respective country, regardless of whether they transition to a 
managed access program, will also be defined as completers.  
Protocol-specified post-treatment follow-up contacts will not 
qualify as “last scheduled” visit.
5.4  Pregnancy
Unless the subject and his/her partner(s) are sterile (ie, 
women who have had an oophorectomy and/or 
hysterectomy or have been postmenopausal for at least 
12 consecutive months; or men who have had 
orchidectomy) or remain abstinent, two of the following 
precautions must be used: vasectomy, tubal ligation, 
vaginal diaphragm, IUD, birth control pills, birth control 
implant, condom, or sponge with spermicide.  
Unless the subject and his/her partner(s) are sterile (ie, 
women who have had an oophorectomy and/or hysterectomy 
or have been postmenopausal for at least 12 consecutive 
months; or men who have had orchidectomy) or remain 
abstinent, two of the following precautions must be used: 
vasectomy, tubal ligation, vaginal diaphragm, IUD, birth 
control pills, birth control implant, condom with spermicide, 
or sponge with spermicide.  
14 References
9  Aripiprazole Investigator Brochure, Version No. 13, 
9  Aripiprazole Investigator’s Brochure, edition 18.1. Otsuka 
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BMS Document Control V.15.0 No. 920002092 11.0. 04 
Aug 2009.
27  International Conference on Harmonisation (ICH). E6:  
Good Clinical Practice:  Consolidated Guideline [finalized 
1996 May, corrected 1996 Jun 1996; cited 2005 Dec 6]. 
Available from:  http://www.ich.org/cache/compo/276-254-
1.html.
IB, issued 18 Nov 2014.
27  International Conference on Harmonisation (ICH). E6:  
Good Clinical Practice:  Consolidated Guideline [finalized 
01 May 1996, corrected 10 Jun 1996; cited 06 Dec 2005]. 
Available from:  http://www.ich.org/products/guidelines/ 
efficacy/article/efficacy-guidelines.html.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, [Aripiprazole OPC-14597], the 
concurrent medications, the efficacy and safety parameters and the conduct of the trial in general. 
I am aware that this protocol must be approved by the Institutional Review Board (IRB) or receive 
a favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in 
the clinical trial facility where [Aripiprazole OPC-14597] will be tested prior to commencement of 
this trial. I agree to adhere strictly to the attached protocol (unless amended in the manner set
forth in the sponsor's Clinical Trial Agreement, at which time I agree to adhere strictly to the 
protocol as amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways, such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor and designee monitors and 
auditors full access to all medical records at the research facility for subjects screened or enrolled 
in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
__________________________
__________________________
__________
Sponsor Representative Print Name
Signature
Date
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 31-10-270
16.1.1 Protocol and Protocol Amendments
120


Otsuka Pharmaceutical Development & Commercialization, Inc.
This page is a manifestation of an electronically captured signature
                                                                                                                                
SIGNATURE PAGE
Document Name:
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Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
OPC-14597
Protocol_31-10-270_Long-term Extension_Amend 004
0001157993
2.0
Biostatistics Approval
10-Jul-2015 21:02 GMT+000
Clinical Approval
10-Jul-2015 21:28 GMT+000
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
Clinical Study Report 31-10-270
16.1.1 Protocol and Protocol Amendments
121
PPD

SAP_000.pdf: 
Protocol 31-10-270 
Confidential - Proprietary Information 
Protocol number: 31-10-270
Document title:  An Open-Label, Multicenter, Rollover, Long-term 
Study of Aripiprazole Intramuscular Depot in Patients With 
Schizophrenia
Version number: 1.0
Date of the document: 12 December 2018
NCT number:    NCT01129882


Otsuka Pharmaceutical 
Development & Commercialization, Inc.
Investigational Medicinal Product
Aripiprazole (OPC-14597)
STATISTICAL ANALYSIS PLAN
for
Protocol No. 31-10-270
IND No. 67,380
An Open-Label, Multicenter, Rollover, Long-term Trial of Aripiprazole Intramuscular 
Depot in Patients with Schizophrenia
Version Final 1.0
Date: December 12, 2018
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.


Protocol 31-10-270 Statistical Analysis Plan                                                        
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Table of Contents
Table of Contents...........................................................................................2
List of In-text Tables .....................................................................................4
List of In-text Figures....................................................................................5
List of Appendices..........................................................................................6
1
Introduction ..........................................................................................7
2
Trial Objectives.....................................................................................7
2.1
Primary Objective................................................................................................7
2.2
Secondary Objective............................................................................................7
3
Trial Design...........................................................................................7
4
Sample Size and Power Justification................................................10
5
Statistical Method...............................................................................10
5.1
Data/Data Sets Specifications ...........................................................................10
5.1.1
Data Sets Analyzed.........................................................................................10
5.1.2
Definition of Baseline and Last Visit .............................................................10
5.1.3
Handling Missing Data...................................................................................10
5.2
Disposition of Subjects......................................................................................12
5.3
Demographic and Baseline Characteristics.......................................................12
5.4
Efficacy Analysis ..............................................................................................12
5.5
Safety Analyses .................................................................................................12
5.5.1
Adverse Events ...............................................................................................12
5.5.2
Clinical Laboratory Tests ...............................................................................13
5.5.3
Vital Signs Data..............................................................................................15
5.5.4
Electrocardiograms (ECG) Data.....................................................................15
5.5.5
Physical Examination .....................................................................................16
5.5.6
Other Safety Data Analysis ............................................................................16
5.5.6.1
Special Interested Adverse Events..............................................................16
5.5.6.2
Extrapyramidal Symptoms Rating Scales...................................................17
5.5.6.3
Suicidality ...................................................................................................17
5.5.6.4
Injection Site Reaction and Pain .................................................................18
5.5.7
Other Data Analysis........................................................................................18


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5.5.7.1
Concomitant Medication.............................................................................18
5.5.7.2
Duration of Exposure to Trial Medication..................................................18
5.5.7.3
Compliance of Trial Medication.................................................................19
5.5.7.4
Protocol Deviation ......................................................................................19


Protocol 31-10-270 Statistical Analysis Plan                                                        
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List of In-text Tables
Table 5.1.3-1
Mapping of Trial Months...............................................................11
Table 5.5.2-1
Treatment-emergent Clinically Relevant Changes in Lipids 
Parameters and Glucose.................................................................14


Protocol 31-10-270 Statistical Analysis Plan                                                        
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List of In-text Figures
Figure 3-1
Trial 31-10-270 Trial Design Schema Prior to Amendment 4 ........9
Figure 3-2
Trial 31-10-270 Trial Design Schema in Amendment 4 .................9


Protocol 31-10-270 Statistical Analysis Plan                                                        
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List of Appendices
Appendix 1
Clinical Relevance Criteria for Laboratory Test 
Abnormalities……………………………………………….........20
Appendix 2
Clinical Relevance Criteria for Vital Sign Abnormalities.............21
Appendix 3
Clinical Relevance Criteria for ECG Abnormalities .....................22
Appendix 4
Table of Contents for Tables and Listings.....................................23


Protocol 31-10-270 Statistical Analysis Plan                                                        
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1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for statistical analysis and reporting of 
efficacy and safety data of trial 31-10-270.  The first approved protocol, dated 30 Mar 
2010, and its amendments (amendment 1 - 23 Nov 2010, amendment 2 - 08 Apr 2013, 
amendment 3 - 11 Apr 2013, amendment 4 - 08 Jul 2015) are taken into consideration in 
developing this SAP.  
2
Trial Objectives
2.1
Primary Objective
To continue to provide aripiprazole intramuscular (IM) Depot treatment (400 mg or 300 
mg) to subjects with schizophrenia completing the 52-week, open-label safety and 
tolerability trial 31-08-248 (hereafter referred to as trial 248).  Subjects can receive this 
treatment until aripiprazole IM Depot is commercially available in any dosage [including 
generic formulation(s)] in the country that the trial is being conducted or until the trial
end date of 31 Dec 2018 is reached.
2.2
Secondary Objective
The secondary objective of this trial is to collect long-term safety data on aripiprazole IM 
Depot in addition to what was collected in trial 248 (52-weeks).  
3
Trial Design
This is an open-label, multicenter rollover non-comparative trial. The adult subjects with 
schizophrenia who completed aripiprazole IM Depot treatment in trial 248 are allowed to 
enroll this trial.  No subject who discontinued or did not complete trial 248 are allowed to 
enroll in this trial. The trial design is presented in Figure 3-1 and Figure 3-2.
Eligible subjects enter this trial directly after completing the end of treatment visit (week 
52) of trial 248.  The end of treatment evaluations conducted at the last trial visit for trial 
248 serve as the baseline evaluations for this trial.  Subjects continue to receive 
aripiprazole IM Depot every month as a continuation of their previous monthly dose in 
trial 248.  The monthly dose can be modified, either reduced from 400 mg to 300 mg to 
address tolerability or increased from 300mg to 400mg to address efficacy, at the 
discretion of the investigator.
Following the baseline visit, subjects receive monthly injections and at the same visit, 
adverse events (AEs) and concomitant medications are recorded and the Columbia 


Protocol 31-10-270 Statistical Analysis Plan                                                        
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Suicide Severity Rating Scale (C-SSRS) are completed. Every 3 months, all of the 
monthly assessments are completed along with a urine pregnancy test for women of 
childbearing potential (WOCBP).  Every 6 months, all of the 3-month assessments are 
completed along with the Clinical Global Impression - Severity (CGI-S) scale, vital signs, 
and extrapyramidal symptoms (EPS) assessments (including the Abnormal Involuntary 
Movement Scale [AIMS], Simpson-Angus Scale [SAS], and Barnes Akathisia Rating 
Scale [BARS]).  At the 12-month visit, all of the 6-month assessments are completed 
along with clinical laboratory tests and assessments of body weight, height, and waist 
circumference.  
Urine drug screening and blood alcohol testing are obtained at baseline and can be re-
obtained at the investigator’s discretion at any time during the trial.  A Visual Analog 
Scale (VAS) for subject-reported rating of pain at the most recent injection site and the 
investigator’s assessment for pain, redness, induration, and swelling of the most recent 
injection site are performed at baseline and may be reassessed at the discretion of the 
investigator.  Clinical laboratory tests, physical examination, and electrocardiogram 
(ECG) obtained at baseline may also be performed at the discretion of the investigator 
based on clinical necessity.  
A Trial Completion visit or Early Termination visit (−2/+10 days) includes the following 
assessments: C-SSRS, AEs, concomitant medications, a urine pregnancy test for 
WOCBP, CGI-S, vital signs, EPS assessments (AIMS, BARS, SAS), clinical laboratory 
tests, and body height and weight.
A 30-Day Post Treatment Follow-up phone call is made 30 days (3 days) after it has 
been determined that the subject no longer participates in this trial and includes questions 
about any AEs that have occurred and any concomitant medications taken since the last 
visit
The subject population is comprised of subjects who have completed Trial 248 and in the 
investigator’s judgment may benefit from continued participation in an aripiprazole IM 
Depot trial, in countries where aripiprazole IM Depot is not commercially available. It is 
anticipated that 500 to 800 subjects from estimated 250 sites in trial 248 enroll in this 
trial.


Protocol 31-10-270 Statistical Analysis Plan                                                        
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  Note: The 3-month, 6-month, and 12-month visits include assessments from the previous visit.  For 
example, the 3-month visit includes all of the monthly visit assessments in addition to the 3-month 
visit assessments.   
Figure 3-1
Trial 31-10-270 Trial Design Schema Prior to Amendment 4
Trial Entry
Open-label IM Depot Treatment
Follow-up
Trial 248 
Completers only
Every month:
Injection, C-SSRS, AEs, and 
concomitant medications
One 30-day 
post End of 
Study phone 
call - AEs and 
concomitant 
medications 
Every 3 monthsa:
Urine pregnancy test for WOCBP
Every 6 monthsa:
CGI-S, vital signs, and EPS 
assessments (AIMS, BARS, SAS)
Every 12 monthsa:
Clinical laboratory tests, body 
weight and height, and waist 
circumference
Week 52 Visit of 
Trial 248 = 
Baseline for 
Trial 270
Injection visit window = 28 (−2/+10) days
Assessment visit window = −2/+10 days
± 3 days
aThe 3-month, 6-month, and 12-month visits include assessments from the previous visit.  For example, 
the 3-month visit includes all of the monthly visit assessments in addition to the 3-month visit 
assessments.  A Trial Completion or Early Termination visit will also be performed.  
Figure 3-2
Trial 31-10-270 Trial Design Schema in Amendment 4
Study Entry
Open Label IM Depot Treatment
Follow up
Study 248 
Completers only
Week 52 Visit of 
Study 248 = 
Baseline for Study 
270
-2/+10 days
Every Month:
Injection visits, C-SSRS, AEs, &  
concomitant medications
Every 3 months:
CGI-S, vital signs, urine pregnancy 
test, optional drug and alcohol 
testing
Every 6 months:
Injection site assessments
Every 12 months: Clinical laboratory tests, PE, ECG, 
body height & weight, BMI, and 
waist circumference
One 6-month post 
End of Study
Injection visit window  =>  28 (-2/+10) days
Assessment visit windows  =>   -2/+10 days


Protocol 31-10-270 Statistical Analysis Plan                                                        
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4
Sample Size and Power Justification
In this open-label, single arm rollover trial, no formal sample computations were 
employed.  The anticipated number of subjects from Trial 248 that is predicted to enroll 
in this trial is approximately 500 to 800.
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 the trial.

Safety Sample:  All subjects who receive at least one dose of open-label
aripiprazole IM depot.  

Efficacy Sample:  All subjects who enter and have at least one post-baseline 
efficacy evaluation.
  
Due to the open-label single-arm nature of the trial, all endpoints will be summarized 
using descriptive statistics. Continuing variables will be tabulated for frequency, mean, 
median, standard deviation (SD), maximum and minimum. Categorical variables will be
tabulated for frequency and percentage.  No formal statistical analyses are planned due to 
the open-label nature of this trial.  Subjects who enrolled in this trial rolled over directly
from Trial 248. Subjects who enrolled in Trial 248 either rolled over from Trial 31-07-
246 or Trial 31-07-247, or directly entered Trial 31-08-248 as de novo subjects (i.e., 
subjects never enrolled in Trial 31-07-246 or 31-07-247). The data will be summarized 
by enrollment source into Trial 248 as well for all subjects.
5.1.2
Definition of Baseline and Last Visit
Baseline is defined as the last visit with available data in Trial 248.  The last visit is 
defined as the last visit with available data at the completion or on/before early 
termination.  These definitions apply to all efficacy analysis and safety analysis.  
5.1.3
Handling Missing Data
Due to nature of this trial design, no missing data are imputed.  However, trial days are 
derived using the formula: Trial Day = Date of assessment - Date of first aripiprazole IM 
depot injection in trial 270 + 1.  Based on the number of trial days, assessments will be
mapped into the corresponding trial months in the summary tables as described in Table 
5.1.3-1.  


Protocol 31-10-270 Statistical Analysis Plan                                                        
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Table 5.1.3-1
Mapping of Windows for Trial Months
Trial Month
Range of Trial Day
Month 1
16~44
Month 2
45~74
Month 3
75~105
Month 4
106~135
Month 5
136-165
Month 6
166-196
Month 7
197-226
Month 8
227-256
Month 9
257-287
Month 10
288-317
Month 11
318-347
Month 12
348-379
Month 13
380-409
Month 14
408-439
Month 15
440-470
Month 16
471-500
Month 17
501-530
Month 18
531-561
Month 19
562-591
Month 20
592-621
Month 21
622-652
Month 22
653-682
Month 23
683-712
Month 24
713-744
Month 25
745-774
Month 26
775-804
Month 27
805-835
Month 28
836-865
Month 29
866-895
Month 30
896-926
Month 41
927-956
Month 42
957-987
Month 43
988-1017
Month 44
1018-1047
Month 45
1048-1078
Month 46
1079-1108
Month 47
1109-1138
Month 48
1139-1170
Month 49
1171-1200
Month 50
1201-1230
Month 51
1231-1261
Month 52
1262-1291


Protocol 31-10-270 Statistical Analysis Plan                                                        
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Table 5.1.3-1
Mapping of Windows for Trial Months
Trial Month
Range of Trial Day
Month 53
1292-1321
Month 54
1322-1352
Month 55
1353-1382
Month 56
1383-1412
Month 57
1413-1443
Month 58
1444-1473
Month 59
1474-1503
Month 60
1504~~
5.2
Disposition of Subjects
Disposition of subjects for the enrolled sample will be summarized by region, country
and center. Subject duration by month and reason for discontinuation will be tabulated
for the enrolled sample.  Subjects who are evaluated at last scheduled visit during the 
treatment period are defined as completers. Subjects who are evaluated at the last 
scheduled visit during the treatment period are defined as completers, i.e., subjects who 
have their last scheduled visit, or who discontinue due to the commercial availability of 
trial drug in the country are defined as completers.  
5.3
Demographic and Baseline Characteristics
Baseline and demographic characteristics will be summarized using descriptive statistics
for the enrolled sample. These characteristics including age, race, ethnicity, gender, 
weight, height and body mass index (BMI), will be tabulated for the enrolled sample.
5.4
Efficacy Analysis
Change from baseline in CGI Severity (CGI-S) score will be summarized by scheduled 
visit using descriptive statistics for the efficacy sample.  CGI-S score (range 1-7) are 
directly derived from CGI-S panel.  
5.5
Safety Analyses
5.5.1
Adverse Events
All adverse events (AEs) are coded by system organ class and Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term (Version 21.0 or later). A treatment-
emergent AE (TEAE) is defined as an AE which starts after start of trial medication 
(Aripiprazole IM Depot), or an AE continues from baseline and becomes serious, 
worsening, trial drug-related or results in death, discontinuation, interruption or reduction 
of trial medication during this trial.  All ongoing AEs and clinically significant AEs from 


Protocol 31-10-270 Statistical Analysis Plan                                                        
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Trial 248 are recorded as Medical History for this trial. If the AE increases severity or 
frequency during this trial period, a new AE are recorded.  The incidences of the 
following treatment-emergent adverse events (TEAEs) will be summarized for the safety 
sample:  

TEAEs by severity

Potentially drug-related TEAEs

TEAEs with an outcome of death

Serious TEAEs

Discontinuations due to TEAEs
Listing and incidences of AEs described above are tabulated for the safety sample.  
Deaths, SAEs, and AEs leading to discontinuation from trial or trial treatment are listed 
for the enrolled sample.  In addition, incidences of TEAEs will be provided for the 
following subgroup analyses: region (US, non-US), sex (male, female), race (Caucasian, 
Black or African American, American Indian or Alaska Native, Asian, other), age (< 45 
years old, ≥ 45 years old), ethnicity (Hispanic or Latino, not Hispanic or Latino), and 
BMI at baseline (≤ 28 kg/m2, > 28 kg/m2).  
5.5.2
Clinical Laboratory Tests
Clinical laboratory tests include serum chemistry analysis, hematology analysis, 
urinalyses and other lab analysis.  The potentially clinically relevant laboratory test 
abnormalities will be listed by subject and by test for the safety sample, respectively.  
Criteria for the potentially clinically relevant laboratory test abnormalities per protocol 
are provided in Appendix 1.  Per Hy’s law, the subjects with AST or ALT > 3 x upper 
limit of normal value and total bilirubin > 2 x upper limit of normal values will be listed 
as the potential Hy’s law cases.  The incidences of potentially clinically relevant
laboratory tests abnormalities based on the observation from the scheduled and the 
unscheduled post-baseline visits will be tabulated.  In addition, incidence of potentially 
clinically relevant laboratory tests in potassium (<= 3.0 mEq/L or >= 5.5 mEq/L) and 
neutrophils (<= 1500/mm3) per FDA recommendation will be provided.  Summary 
statistics (frequency, mean, standard deviation, minimum, and maximum) for the clinical 
laboratory measurements at all scheduled visits, and changes from baseline at scheduled 
visit and last visits will be presented for the safety sample.  
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 below or above limit of quantification), these data are not 


Protocol 31-10-270 Statistical Analysis Plan                                                        
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included in the calculations for changes from baseline but included in the calculations for 
incidence.  
The incidence of prolactin level above the upper limit of normal range (potentially 
clinically relevant change) will be tabulated by gender and the designated visits for the 
safety sample.  The change from baseline in prolactin levels will be presented by gender 
at scheduled visit and last visit for the safety sample. 
Additionally, incidence of treatment-emergent clinically relevant changes in fasting lipid 
parameters and glucose (as defined in Table 5.5.2-1) will be summarized for the safety 
sample.
Table 5.5.2-1
Treatment-emergent Clinically Relevant Changes in Lipids 
Parameters and Glucose
Parameters
Baseline
Post-baseline
Total Cholesterol(mg/dL), fasting1
Normal <200        
High >=240               
Borderline 200~<240    
High >=240               
Normal/Borderline <240
High >=240               
Normal <200            
Borderline/High >=200    
Any Value              
Increased >=40           
LDL Cholesterol(mg/dL), fasting 1
Normal <100        
High >=160               
Borderline 100~<160    
High >=160               
Normal/Borderline <160
High >=160               
Normal <100            
Borderline/High >=100    
Any Value              
Increased >=30           
HDL Cholesterol(mg/dL), fasting1
Normal >=40        
Low<40               
Any Value              
Decreased >=20           
Triglycerides(mg/dL), fasting1
Normal <150        
High >=200               
Normal <150        
Very High >=500               
Borderline 150~<200    
High >=200               
Borderline 150~<200    
Very High >=500               
Normal/Borderline <200
High >=200               
Normal/Borderline <200
Very High >=500               
Normal <150            
Borderline/High/Very 
High >=150    
Normal/Borderline /High
>=200
Very High >=500               
Any Value              
Increased >=40           
Glucose(mg/dL), fasting2
Normal <100        
High >=126               


Protocol 31-10-270 Statistical Analysis Plan                                                        
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Table 5.5.2-1
Treatment-emergent Clinically Relevant Changes in Lipids 
Parameters and Glucose
Parameters
Baseline
Post-baseline
Impaired Fasting Glucose 
100~<126
High >=126               
Normal/ Impaired Fasting 
Glucose <126
High >=126               
Any Value              
Increased >=10           
Note: The National Cholesterol Education Program (NCEP) Adult Treatment Program Classifications of lipids 
(refer to fasting lipid measurements) are used for lipid parameters and the American Diabetes Association 
Criteria are used for glucose.
5.5.3
Vital Signs Data
Vital signs include body temperature, respiration rate, pulse, systolic blood pressure, and 
diastolic blood pressure in supine and standing position.  In addition, body weight and 
waist circumference are measured.  The potential clinically relevant vital sign 
abnormalities will be listed by subject.  Criteria for the potentially clinically relevant vital 
sign abnormalities are provided in Appendix 2.  Incidences of clinical relevant vital signs 
abnormalities based on the observation from the scheduled and unscheduled post-baseline 
visits will be tabulated for the safety sample. In addition to waist circumference and 
weight, vitals sign parameters at each visit, and change from baseline at the post-baseline 
visits will be summarized for the safety sample.  Body weight changes will be evaluated 
for the safety sample by calculating mean change from baseline and by tabulating the 
incidence of >=7% weight gain or loss by visit.  
If vital sign assessments are repeated for the same visit, the last repeat values are used for 
production of summary tables.  This is accomplished by sorting patient data by visit date 
and visit time (if applicable) within the same visit identification.  
5.5.4
Electrocardiograms (ECG) Data
All ECG analyses are made using observed data. Baseline is defined as average of ECG 
measurements at baseline visit as specified in Section 5.1.2.  Last visit is defined as 
defined as average of ECG measurements at last visit as specified in Section 5.1.2.  
Missing ECG data are not imputed.  For the calculation of QT correction by heart rate, 
QTc is missing only if all 3 consecutive beats are unreadable.  As long as there is at least
1 beat available in the lead, the data are included in the analysis. For each ECG, QT and 
RR intervals from three consecutive complexes (representing three consecutive heart 
beats) are measured manually.  The QT correction is performed on beat-to-beat basis.  
The mean of ratios (beat-to-beat) is calculated by (QTc1 + QTc2 + QTc3)/3 using each 


Protocol 31-10-270 Statistical Analysis Plan                                                        
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QT-RR pair: (QT1, RR1), (QT2, RR2) and (QT3, RR3).  The corrected QT intervals for 
QTcB, QTcF, and QTcN are defined as follows:

QTcB is the length of the QT interval corrected for heart rate by Bazett’s formula: 
QTcB = QT / (RR) 1/2.  

QTcF is the length of the QT interval corrected for heart rate by Fredericia’s 
formula: QTcF = QT / (RR) 1/3.

QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula: QTcN = QT/(RR) 0.37.  
Potentially clinically relevant ECG abnormalities will be listed by subject.  Criteria for 
potentially clinically relevant ECG abnormalities are provided in Appendix 3.  The 
incidences of abnormal ECGs of potentially clinical relevance based on the observation at 
the scheduled and the unscheduled post-baseline visits will be tabulated for the safety 
sample.  Descriptive statistics of change from baseline in heart rate and ECG intervals of 
PR, QRS, RR, QT, QTcB, QTcF, and QTcN will be presented for each scheduled visit and 
last visit for the safety sample, respectively.  
In summarizing the incidence of abnormalities, a subject must have had an evaluation 
that meets abnormality criteria by the end of trial.  Incidence rate will be calculated as the 
number of subjects having at least one abnormality within the trial divided by the number 
of subjects who are both exposed to trial medication and have an on-treatment evaluation. 
In addition, incidences of categorical change in ECG - QTc will be provided for change 
from baseline >30 millisecond, change from baseline >60 millisecond, new onset >450
millisecond, new onset >480 millisecond and new onset >500 millisecond for the safety 
sample. Change from baseline in ECG parameters will be calculated at scheduled visit 
and last visit for the safety sample.  
If ECG assessments are repeated for the same visit, the last repeat values are used for 
production of mean change from baseline. This is accomplished by sorting subject data 
by visit date and visit time (if applicable) within the same visit identification.  
5.5.5
Physical Examination
Physical examination findings will be listed by subject.
5.5.6
Other Safety Data Analysis
5.5.6.1
Special Interested Adverse Events
Incidence of treatment emergent adverse events of special interest, including EPS-related 
AEs, weight-related AEs, glucose-related AEs, lipid-related AEs, white blood cell 
abnormalities, orthostasis, prolactin-related AEs, QT-interval AEs, suicidality-related 


Protocol 31-10-270 Statistical Analysis Plan                                                        
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AEs, and injection-site-related AEs, will be tabulated for safety sample. In addition, 
proportion of subjects received anticholinergic medication for treatment-emergent EPS-
related events will be assessed for safety sample. 
5.5.6.2
Extrapyramidal Symptoms Rating Scales
Extrapyramidal symptoms rating scales included the SAS, AIMS, and the BARS. The 
SAS total score (range 10 to 50) is the sum of the rating scores for 10 items from the SAS 
panel in the CRF. The AIMS movement rating score (range 0 to 28) is the sum of the 
rating scores for facial and oral movements (items 1 to 4), extremity movements (items 5 
and 6), and trunk movements (item 7). A missing value of any item for the SAS or the 
AIMS movement scale could result in a missing SAS total score or AIMS movement 
rating score. The BARS global score (range 0 to5) is derived from the global clinical 
assessment of akathisia from the BARS panel in the CRF. Mean changes from baseline 
on the SAS total score, AIMS movement score, and the BARS global score will be
summarized by visit in descriptive statistics.  
5.5.6.3
Suicidality
Upon administration of the Columbia-Suicide Severity Rating Scale (C-SSRS) 
assessments, each subject is evaluated for active suicidal ideation with specific plan and 
intent. Data collected from the C-SSRS assessments will be summarized by the scheduled 
visit for the safety sample reporting suicidality; suicidal behavior only, emergence of 
suicidal behavior; suicidal ideation only, emergence of suicidal ideation, emergence of 
serious suicidal ideation, and worsening of suicidal ideation.  
Suicidality is defined as reporting any suicidal ideation or behavior. Suicidal behavior 
only is defined as reporting any type of suicidal behaviors (actual attempt, interrupted 
attempt, aborted attempt and preparatory acts or behavior) throughout assessment period. 
Emergence of suicidal behavior is defined as having no suicidal behavior at baseline and 
reporting any type of behavior at post-baseline.  Suicidal ideation only is defined as 
reporting any type of suicidal ideation.  Emergence of suicidal ideation is defined as 
having no suicidal ideation at baseline and reporting any type of ideation during 
treatment.  Emergence of serious suicidal ideation is defined as having no suicidal 
ideation at baseline and reporting serious suicidal ideation with score of 4 or 5 on suicidal 
ideation severity rating during the treatment.  At suicidal ideation severity rating
assessment, each person is giving a score of 0 (no ideation present) to 5 (active ideation 
with plan and intent).  Worsening of suicidal ideation is defined as having more severe in 
most severe suicidal ideation rating at post baseline than at baseline. Numbers of 
subjects reporting suicidal behavior will be reported by type of suicidal behavior.  


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Mean and mean change from baseline in suicidal ideation intensity total score for most 
sever ideation will be summarized by scheduled visit for the safety sample. The suicidal 
ideation intensity total score is sum of suicidal ideation severity rating scores for 
frequency, duration, controllability, deterrents and reasons for ideation.  For each item, 
each subject gets the intensity score from 0 (none) to 5 (worst).  Therefore, suicidal 
ideation intensity total score is range from 0 to 25.  If the subject did not endorse any 
suicidal ideation, a score of 0 is given for the intensity scale.  
5.5.6.4
Injection Site Reaction and Pain
Injection site reaction and pain are assessed every 6 months in the visual analogue scale 
(VAS) score (range 0-100mm) before and after IM depot injection at the scheduled visit.  
Descriptive statistics for VAS score will be tabulated by visit for the safety sample.  
Assessment pre 1st IM depot injection is used as baseline.  Proportions of subjects rated 
as absent, mild, moderate and severe level by the investigator for localized pain, redness, 
swelling, and induration will be tabulated by visit for safety sample.  In an addition, 
descriptive statistics for injection site reaction and pain are provided by order of injection.  
5.5.7
Other Data Analysis
5.5.7.1
Concomitant Medication
Proportions of subjects from the enrolled sample taking concomitant medications will be
tabulated by drug classification using the WHO drug prior to taking trial medication, in 
the trial period and in the follow-up period, respectively.  
Proportions of subjects taking concomitant medications such as benzodiazepine and 
anticholinergic will be provided. Concomitant medications for benzodiazepine and 
anticholinergic will be converted into lorazepam equivalent and benztropine equivalent, 
respectively, using the appropriate conversion factors. Daily dose of benzodiazepine 
(lorazepam or equivalent) and anticholinergic (benztropine or equivalent) concomitant 
medications will be summarized.  Daily dose for each subject is calculated in total dosage 
of the specific concomitant medications divided by the duration of subject in the trial
period.
5.5.7.2
Duration of Exposure to Trial Medication
Exposure to aripiprazole IM depot for the enrolled sample will be summarized in 
percentage of subjects receiving injections, average dose level per injection and average 
trial day of receiving each injection. In an addition, percentage of subjects will be
presented by dosing level per injection.  


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5.5.7.3
Compliance of Trial Medication
To maintain subjects on a schedule within acceptable time window is critical for subjects 
to achieving and maintaining stability of psychotic symptoms for the completion of this 
depot trial.  A missed dose of IM depot is defined as a lapse of > 38 days between 
injections. The minimum interval of 26 days and maximum interval of 38 days between 
injections is to ensure that therapeutic plasma concentrations of aripiprazole are 
maintained. Compliance of trial medication (aripiprazole IM Depot) will be summarized 
for the enrolled sample, in proportion of subjects having 100% compliance, along with 
the following key features of compliance:

the intervals between Aripiprazole IM depot injections <26 days;

missing at least 1 injection;

missing 2 consecutive injections at any time in the trial;

missing 3 injections within a 52-week time period.
5.5.7.4
Protocol Deviation
Protocol deviations will be listed, and tabulated by protocol deviation type, country and 
centers.  Protocol deviations are specified in the separate documentation: Programmable 
Deviation Specification for Protocol 31-10-270.   


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Appendix 1
Clinical Relevance Criteria for Laboratory Test Abnormalities
Laboratory Tests
Criterion Values
Chemistry a
AST(SGOT)
3x upper limit of normal (ULN)
ALT(SGPT)
3x ULN
Alkaline Phosphates
3x ULN
LDH
3x ULN
BUN
30 mg/dl
Creatinine
2.0 mg/dl
Uric Acid
Male
Female
10.5 mg/dl
8.5 mg/dl
Bilirubin (Total)
2.0mg/dl
CPK
3xULN
Prolactin
>ULN
Hematology a
Hematocrit
Male
Female
37% and 3% decrease from baseline
32% and 3% decrease from baseline
Hemoglobin
Male
Female
11.5 g/dl
9.5 g/dl
White Blood Count
2,800 /mm3 or 16,000 /mm3
Eosinophils
10%
Neutrophils
15%
Platelet Count
75,000 /mm3 or 700,000 /mm3
Urinalysis a
Protein
Increase of 2 units
Glucose
Increase of 2 units
Casts
Increase of 2 units
Additional Criteria
Chloride
90 mEq/L or 118 mEq/L
Potassium
2.5 mEq/L or 6.5 mEq/L
Sodium
126 mEq/L or 156 mEq/L
Calcium
8.2 mg/dL or 12 mg/dL
Glucose
Fasting
              Non-Fasting
115 mg/dL
200 mg/dL
Total cholesterol, Fasting
240 mg/dL
LDL cholesterol, Fasting
160mg/dL
HDL cholesterol, Fasting
30 mg/dL
Triglycerides, Fasting
Male
              Female
160 mg/dL
120 mg/dL
a As defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety 
Information in an Original NDA Submission and for Organizing Information in Periodic Safety 
Updates,” FDA Division of Neuropharmacological Drug Products draft (2/27/87).


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Appendix 2
Clinical Relevance Criteria for Vital Sign Abnormalities
VARIABLE
CRITERION VALUE a
CHANGE RELATIVE TO 
BASELINE a
HEART RATE b
>120 BPM
<50 BPM
INCREASE OF 15
DECREASE OF 15
SYSTOLIC BLOOD PRESSURE b
>180 MMHG
<90 MMHG
INCREASE OF 20
DECREASE OF 20
DIASTOLIC BLOOD PRESSURE b
>105 MMHG
<50 MMHG
INCREASE OF 15
DECREASE OF I5
ORTHOSTATIC HYPOTENSION
≥ 20 MMHG DECREASE 
IN SYSTOLIC BLOOD
PRESSURE AND ≥ 25 
BPM INCREASE IN 
HEART RATE FROM 
SUPINE TO 
SITTING/STANDING
WEIGHT
-
INCREASE 7%
DECEASE 7%
TEMPRATURE
37.8°C
INCREASE 1.1°C
a In order to be identified as “clinically relevantly abnormal,” an on-drug value must meet the “Criterion 
Value” and also represent a change from the patient’s pretreatment value of at least the magnitude 
shown in the “Change Relative to Baseline column. 
b As defined in “supplementary suggestions for Preparing an integrated Summary of Safety Information 
in an Original NDA Submission and for Organizing Information in period safety Updates,” FDA 
Division of Neuropharmacological Drug Products draft (2/27/87)


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Appendix 3
Clinical Relevance Criteria for ECG Abnormalities
Variable
Criteria/Change relative to Baseline
Rate
Tachycardia
120 bpm and increase of  15 bpm
Bradycardia
50 bpm and decrease of  15 bpm
Rhythm
Sinus tachycardia
120 bpm and increase of  15 bpm
Sinus bradycardia
50 bpm and decrease of  15 bpm
Supraventricular premature beat
Not present present
Ventricular premature beat
Not present present
Supraventricular tachycardia
Not present present
Ventricular tachycardia
Not present present
Atrial fibrulation
Not present present
Atrial flutter
Not present present
Conduction
10 A-V Block
PR   0.20 sec and increase of  0.05 sec
20 A-V Block
Not present present
30 A-V Block
Not present present
Left bundle-branch block 
Not present present
Right bundle-branch block 
Not present present 
Pre-excitation syndrome
Not present present
Other intraventricular conduction block
QRS 0.12 sec and increase of    0.02 sec
Infarction
Acute or Subacute
Not present present
Old
Not present - present at 12 weeks post entry into 
the trial
ST/T Morphology
Myocardial Ischemia
Not present present
Symmetrical T-wave inversion
Not present present
QTc
450 msec and 10% increase from baseline


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Appendix 4
Table of Contents for Tables and Listings
Clinical Summary Tables
CT-1.1
SUBJECT DISPOSITION
CT-1.2
SUBJECT DISPOSITION BY REGION, COUNTRY AND CENTER
CT-1.3
SUBJECT DURATION BY MONTH
CT-1.4
ENROLLMENT BY COUNTRY
CT-1.5
ENROLLMENT BY COUNTRY BY AGE GROUP
CT-2
REASONS FOR DISCONTINUATION
CT-3
DEMOGRAPHIC CHARACTERISTICS BY SEX
CT-4.1
CONCOMITANT MEDICATIONS TAKEN PRIOR TO STUDY PERIOD
CT-4.2
CONCOMITANT MEDICATIONS TAKEN DURING STUDY PERIOD
CT-4.3 
CONCOMITANT MEDICATIONS TAKEN POST STUDY PERIOD
CT-4.4
CONCOMITANT BENZODIAZEPINES AND ANTICHOLINERGICS USE 
CT-5 
CGI SEVERITY SCORE - MEAN CHANGE FROM BASELINE BY MONTH - OC   
CT-6.1.1
SIMPSON-ANGUS SCALE TOTAL SCORE - MEAN CHANGE FROM BASELINE BY MONTH - OC   
CT-6.1.2 
BARNES AKATHISIA GLOBAL SCORE - MEAN CHANGE FROM BASELINE BY MONTH - OC   
CT-6.1.3 
AIMS MOVEMENT RATING SCORE - MEAN CHANGE FROM BASELINE BY MONTH - OC   
CT-6.2.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) - INCIDENCE OF SUICIDALITY     
CT-6.2.2
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) - INCIDENCE OF SUICIDALITY BY TYPE    
CT-6.2.3
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) - MEAN CHANGE FROM BASELINE IN 
SUICIDAL IDEATION INTENSITY TOTAL SCORE    
CT-7.1
EXTENT OF EXPOSURE TO STUDY MEDICATION - ARIPIPRAZOLE IM DEPOT
CT-7.2
DESCRIPTIVE STATISTICS FOR STUDY DAYS OF ARIPIPRAZOLE IM DEPOT INJECTIONS
CT-7.3
EXTENT OF EXPOSURE TO STUDY MEDICATION BY INJECTION DOSE - ARIPIPRAZOLE IM DEPOT   
CT-8.1 
INCIDENCE OF ADVERSE EVENTS (ALL CAUSALITIES)   
CT-8.2.1 
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS 
CT-8.2.2
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND 
MEDDRA PREFERRED TERM 
CT-8.2.3
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS, MEDDRA 
PREFERRED TERM AND SEVERITY
CT-8.2.4.1
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS GREATER THAN 5% BY SYSTEM ORGAN 
CLASS AND MEDDRA PREFERRED TERM   
CT-8.2.4.2
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY MEDDRA PREFERRED TERM IN 
DESCENDING ORDER OF INCIDENCE RATE FOR TOTAL   
CT-8.2.4.3
INCIDENCE OF NON-SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS OCCURRING IN AT LEAST 
5% OF THE SUBJECTS  BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM
CT-8.2.4.4
OCCURRENCE (NUMBER OF EVENTS) OF NON-SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS 
BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM  
CT-8.2.5
INCIDENCE OF TREATMENT-EMERGENT EPS ADVERSE EVENTS
CT-8.2.6
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RELATED TO SUICIDAL 
IDEATION/SUICIDE   BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM 
CT-8.2.7
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RELATED TO INJECTION SITE BY 
SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM   
CT-8.2.8
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RELATED TO GLUCOSE METABOLISM 
BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM   
CT-8.2.9
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RELATED TO QT INTERVAL 
ABNORMALITIES BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM   
CT-8.2.10
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RELATED TO EFFECTS ON PROLACTIN 
BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM   
CT-8.2.11
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RELATED TO WBC ABNORMALITIES BY 
SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM   
CT-8.2.12
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RELATED TO ORTHOSTASIS   BY 
SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM 
CT-8.2.13
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RELATED TO LIPID PARAMETERS   BY 
SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM 
CT-8.2.14
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RELATED TO WEIGHT   BY SYSTEM 
ORGAN CLASS AND MEDDRA PREFERRED TERM 
CT-8.3.1
INCIDENCE OF POTENTIALLY DRUG-RELATED TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM ORGAN CLASS
CT-8.3.2 
INCIDENCE OF POTENTIALLY DRUG-RELATED TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM
CT-8.3.3 
INCIDENCE OF POTENTIALLY DRUG-RELATED TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM ORGAN CLASS, MEDDRA PREFERRED TERM AND SEVERITY
CT-8.4.1
INCIDENCE OF DEATHS DUE TO TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN 
CLASS AND MEDDRA PREFERRED TERM
CT-8.5.1 
INCIDENCE OF SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS


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CT-8.5.2 
INCIDENCE OF SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS 
AND MEDDRA PREFERRED TERM
CT-8.5.3 
INCIDENCE OF SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS
AND MEDDRA PREFERRED TERM AND SEVERITY
CT-8.5.4
OCCURRENCES (NUMBER OF EVENTS) OF SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS BY 
SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM
CT-8.5.5
OCCURRENCES (NUMBER OF EVENTS) OF POTENTIALLY DRUG-RELATED SERIOUS TREATMENT-
EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM
CT-8.6.1
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RESULTING IN DISCONTINUATIONS OF 
STUDY MEDICATION BY SYSTEM ORGAN CLASS
CT-8.6.2 
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RESULTING IN DISCONTINUATIONS OF 
STUDY MEDICATION BY SYSTEM ORGAN CLASS AND MEDDRA PREFERRED TERM
CT-8.6.3
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS RESULTING IN DISCONTINUATIONS OF 
STUDY MEDICATION   BY SYSTEM ORGAN CLASS, MEDDRA PREFERRED TERM AND SEVERITY
CT-9.1 
LISTING OF DEATHS
CT-9.2 
LISTING OF SERIOUS ADVERSE EVENTS
CT-9.3 
LISTING OF DISCONTINUATIONS DUE TO ADVERSE EVENTS
CT-9.4 
LISTING OF ADVERSE EVENTS RELATED TO SUICIDAL IDEATION/SUICIDE   
CT-9.5
LISTING OF POTENTIAL HY'S LAW CASES 
CT-10.1
LISTING OF LABORATORY VALUES OF POTENTIAL CLINICAL RELEVANCE BY SUBJECT   
CT-10.2
LISTING OF LABORATORY VALUES OF POTENTIAL CLINICAL RELEVANCE BY TEST   
CT-10.3
CRITERIA FOR LABORATORY VALUES OF POTENTIAL CLINICAL RELEVANCE
CT-10.4
CRITERIA FOR LABORATORY VALUES OF POTENTIAL CLINICAL RELEVANCE REVISED
CT-11.1
LISTING OF VITAL SIGNS OF POTENTIAL CLINICAL RELEVANCE BY SUBJECT   
CT-11.2
CRITERIA FOR POTENTIALLY CLINICALLY RELEVANT VITAL SIGN ABNORMALITIES   
CT-12.1
LISTING OF ECG MEASUREMENTS OF POTENTIAL CLINICAL RELEVANCE   
CT-12.2
CRITERIA FOR ECG MEASUREMENTS OF POTENTIAL CLINICAL RELEVANCE   
CT-12.3
ECG DIAGNOSIS MAPPING FOR ECG MEASUREMENTS OF POTENTIAL CLINICAL RELEVANCE   
CT-13.1.1
INCIDENCE OF LABORATORY VALUES OF POTENTIAL CLINICAL RELEVANCE   
CT-13.1.2
INCIDENCE OF POTENTIALLY CLINICALLY RELEVANT SHIFTS IN LIPIDS   
CT-13.1.3
INCIDENCE OF POTENTIALLY CLINICALLY RELEVANT SHIFTS IN GLUCOSE   
CT-13.1.4
INCIDENCE OF LABORATORY VALUES OF POTENTIAL CLINICAL RELEVANCE REVISED   
CT-13.2.1
LABORATORY TEST RESULTS FOR SERUM CHEMISTRY - MEAN CHANGE FROM BASELINE   
CT-13.2.2
LABORATORY TEST RESULTS FOR HEMATOLOGY - MEAN CHANGE FROM BASELINE   
CT-13.2.3
LABORATORY TEST RESULTS FOR URINALYSIS - MEAN CHANGE FROM BASELINE   
CT-13.2.4
LABORATORY TEST RESULTS FOR OTHER LABORATORY TESTS - MEAN CHANGE FROM BASELINE   
CT-13.2.5.1
INCIDENCE OF PROLACTIN LEVEL ABOVE UPPER LIMIT OF NORMAL RANGE BY SEX   
CT-13.2.5.2
LABORATORY TEST RESULTS FOR PROLACTIN - MEAN CHANGE FROM BASELINE BY SEX   
CT-14.1
INCIDENCE OF VITAL SIGNS OF POTENTIAL CLINICAL RELEVANCE   
CT-14.2
INCIDENCE OF POTENTIALLY CLINICALLY RELEVANT WEIGHT GAIN OR LOSS   
CT-14.3
MEAN CHANGE FROM BASELINE IN VITAL SIGNS PARAMETERS   
CT-15.1
INCIDENCE OF ECG MEASUREMENTS OF POTENTIAL CLINICAL RELEVANCE   
CT-15.2
ECG PARAMETERS - MEAN CHANGE FROM BASELINE   
CT-15.3
         INCIDENCE OF CATEGORICAL INCREASES IN ECG - QTC   
CT-16.1
VISUAL ANALOG SCALE SCORE FOR SUBJECT-REPORTED RATING OF PAIN AT MOST RECENT 
INJECTION SITE - MEAN SCORE
CT-16.2.1
PROPORTION OF SUBJECTS AT EACH LEVEL OF INVESTIGATOR’S ASSESSMENT OF MOST RECENT 
INJECTION SITE - PAIN
CT-16.2.2
PROPORTION OF SUBJECTS AT EACH LEVEL OF INVESTIGATOR’S ASSESSMENT OF MOST RECENT 
INJECTION SITE - SWELLING
CT-16.2.3
PROPORTION OF SUBJECTS AT EACH LEVEL OF INVESTIGATOR’S ASSESSMENT OF MOST RECENT 
INJECTION SITE - REDNESS
CT-16.2.4
PROPORTION OF SUBJECTS AT EACH LEVEL OF INVESTIGATOR’S ASSESSMENT OF MOST RECENT 
INJECTION SITE - INDURATION
CT-17.1
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND 
MEDDRA PREFERRED TERM BY REGION (US VS NON-US)   
CT-17.2
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND 
MEDDRA PREFERRED TERM BY SEX
CT-17.3
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND 
MEDDRA PREFERRED TERM BY RACE
CT-17.4
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND 
MEDDRA PREFERRED TERM BY AGE GROUP
CT-17.5
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND 
MEDDRA PREFERRED TERM BY ETHNICITY
CT-17.6
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND 
MEDDRA PREFERRED TERM BY BMI
CT-18.1
VISUAL ANALOG SCALE SCORE FOR SUBJECT-REPORTED RATING OF PAIN AT MOST RECENT 
INJECTION SITE - MEAN SCORE BY INJECTION


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CT-18.2.1
PROPORTION OF SUBJECTS AT EACH LEVEL OF INVESTIGATOR’S ASSESSMENT OF MOST RECENT 
INJECTION SITE BY INJECTION - PAIN
CT-18.2.2
PROPORTION OF SUBJECTS AT EACH LEVEL OF INVESTIGATOR’S ASSESSMENT OF MOST RECENT 
INJECTION SITE BY INJECTION - SWELLING
CT-18.2.3
PROPORTION OF SUBJECTS AT EACH LEVEL OF INVESTIGATOR’S ASSESSMENT OF MOST RECENT 
INJECTION SITE BY INJECTION - REDNESS
CT-18.2.4
PROPORTION OF SUBJECTS AT EACH LEVEL OF INVESTIGATOR’S ASSESSMENT OF MOST RECENT 
INJECTION SITE BY INJECTION - INDURATION
Clinical Data Listings 
DREAS-1
DISCONTINUED SUBJECTS AND REASONS FOR DISCONTINUATION
DREAS-2
ADVERSE EVENTS FOR SUBJECTS WHO WITHDREW CONSENT
PDEV-1
SUMMARY OF PROTOCOL DEVIATIONS BY REGION, CENTER AND TYPE OF DEVIATION
PDEV-2
PROTOCOL DEVIATIONS BY SUBJECT
PDEV-3
PROTOCOL DEVIATION CRITERIA
SUBEX-1
INCLUSIONS/EXCLUSIONS FROM THE EFFICACY ANALYSES 
DEMOG-1
DEMOGRAPHIC CHARACTERISTICS: AGE, SEX, RACE, HEIGHT, WEIGHT, AND BODY MASS INDEX
SMED-1.1
TRIAL MEDICATION (ARIPIPRAZOLE IM DEPOT) COMPLIANCE 
SMED-1.2
SUMMARY OF TRIAL MEDICATION (ARIPIPRAZOLE IM DEPOT) COMPLIANCE 
EFF-1
CHANGE FROM BASELINE IN CGI SEVERITY SCORE 
AE-1
ADVERSE EVENTS 
LAB-1
LABORATORY TEST RESULTS: SERUM CHEMISTRY
LAB-2
LABORATORY TEST RESULTS: HEMATOLOGY
LAB-3
LABORATORY TEST RESULTS: URINALYSIS
LAB-4
LABORATORY TEST RESULTS: OTHER LABORATORY TESTS
LAB-5
LABORATORY TEST RESULTS: URINE DRUG SCREEN
LAB-6
LABORATORY TEST RESULTS: URINE PREGNANCY TEST
PDATA-1.1
CONSTENTS AND ELIGIBILITY 
PDATA-1.2
INCLUSION AND EXCLUSION CRITERIA 
PDATA-2
SUBJECT DISPOSITION
PDATA-3
TRIAL COMPLETION STATUS AND REASONS FOR DISCONTINUATION
PDATA-4
DEMOGRAPHIC CHARACTERISTICS: AGE, SEX, RACE, HEIGHT, WEIGHT, AND BODY MASS INDEX 
PDATA-5
PSYCHIATRIC HISTORY
PDATA-6.1
CONCOMITANT MEDICATIONS: MEDICATIONS TAKEN PRIOR TO START OF TRIAL THERAPY
PDATA-6.2
CONCOMITANT MEDICATIONS: MEDICATIONS TAKEN DURING TRIAL PERIOD
PDATA-6.3
CONCOMITANT MEDICATIONS: MEDICATIONS TAKEN POST TRIAL THERAPY DURING FOLLOW-UP 
PERIOD
PDATA-7
TRIAL MEDICATION - ARIPIPRAZOLE IM DEPOT 
PDATA-8
MEDICAL HISTORY
PDATA-9
PHYSICAL EXAMINATION
PDATA-10
ADVERSE EVENTS
PDATA-11
VITAL SIGNS
PDATA-12.1
ELECTROCARDIOGRAM RESULTS
PDATA-12.2
ELECTROCARDIOGRAM RESULTS - RAW 3 BEAT DATA
PDATA-13
CLINICAL GLOBAL IMPRESSION (CGI) SCALE
PDATA-14
VISUAL ANALOG SCALE (VAS) FOR SUBJECT-REPORTED RATING OF INJECTION SITE PAIN 
PDATA-15
INVISTIGATOR’S ASSESSMENT OF MOST RECENT INJECTION SITE 
PDATA-16.1
SIMPSON-ANGUS SCALE (SAS)
PDATA-16.2
BARNES AKATHISIA RATING SCALE (BARS)
PDATA-16.3
ABNORMAL INVOLUNTARY MOVEMENT SCALE (AIMS)
PDATA-17
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)
PDATA-18
SCREENING FAILURES
PDATA-19
FOLLOW-UP
PDATA-20
PROTOCOL DEVIATIONS - CRF


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SIGNATURE PAGE
Document Name: P3110270_Statistical Analysis Plan_Final
Document Number: 1000025667
Document Version: 2.0
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Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Approval
02-Jan-2019
23:08:48
Biostatistics Approval
02-Jan-2019
21:53:50
PPD