A Cluster Randomized, Multi-center, Parallel-group, Rater-blind Study Comparing Treatment With Aripiprazole Once Monthly and Treatment as Usual on Effectiveness in First Episode and Early Phase Illness in Schizophrenia
Phase: PHASE4
Conditions: Schizophrenia
Sponsor: Vanguard Research Group

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1 
TITLE PAGE 
ARIPIPRAZOLE, ABILIFY MAINTENA® 
COLLABORATIVE CLINICAL PROTOCOL 
A Cluster Randomized, Multi-center, Parallel-group, Rater-blind Study Comparing Treatment 
with Aripiprazole Once Monthly and Treatment as Usual on Effectiveness in First-Episode and 
Early Phase Illness in Schizophrenia  
 
 
Collaborative Protocol No.  COL.AOM.2013.005 
 
 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Principal Investigator: 
John M Kane, MD 
Chair, Department of Psychiatry at Hofstra North 
Shore-Long Island Jewish School of Medicine 
The Feinstein Institute for Medical Research  
The Zucker Hillside Hospital-North Shore Long 
Island Jewish Health System  
75-59 263rd Street 
Glen Oaks, NY  11004 
Tel:  718-343-7739  
psychiatry@lij.edu  
 
 
 
 
 
 
Immediately Reportable Event: 
Vanguard Research Group 
Fax:  212-913-9850 
e-mail:  cgomes@hnhs.edu 
Tel:  347-804-3605 
 
 
Issue Date: 
29 July 2014, Original Protocol 
19 August 2015, Amendment 1.0 
29 October 2015, Amendment 2.0 
 
 
 
 
 
G-Port No.   

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REVISION HISTORY 
29 July 2014 
Original Protocol 
20 July 2015 
Amendment 0.1 
 
• 
Title Page:  Added amendment version number and date for revisions to the protocol. 
• 
Section 2:  Changes in baseline visit assessments and procedures, including timing, 
and the criteria that needs to be met before scheduling the once monthly visits; 
Canadian sites were removed from the study; randomization procedures were clarified; 
the criteria for calculation for the inpatient psychiatric hospitalization secondary 
endpoint was clarified; change from baseline in quality of life using the QLS was 
missing as a secondary endpoint; and additional inclusion and exclusion criteria were 
added. 
• 
Section 6:  Additional site information will be provided in the PI’s trial master file 
only (removed FDA form requirement). 
• 
Table 1:  Key Study Personnel and Contributors was updated to include the 
appropriate names for Other PI Study Staff and DSMB. 
• 
Section 9.1:  Changes in baseline visit assessments and procedures, the criteria that 
needs to be met before scheduling the once monthly visits, and additional information 
regarding recruitment methods for each cohort was added. 
• 
Figure 1:  Procedures during the Screening, Baseline 1, Baseline 2, and Treatment 
Visits were changed or updated.  
• 
Section 9.1.1:  Changes in baseline visit assessments and procedures and added text 
regarding timing of initial aripiprazole injection. 
• 
Section 9.1.2:  Section updated to reflect that the Canadian sites were removed from 
the study; further clarification of the randomization procedure; and the inclusion of the 
SCID-5, QLS, and Premorbid Adjustment Scale as assessments being remotely 
conducted. 
• 
Section 9.1.3.1:  Treatment and analysis procedures for subjects at LAI sites was 
clarified. 
• 
Section: 9.1.3.1.1:  Clarification of timing for the remote assessments of BPRS, CGI S, 
RBANS, QLS, and C SSRS to be conducted. 
• 
Section 9.1.4:  Addition of the QLS to the list of assessments conducted during Month 
24 Visit/Early Termination. 
• 
Section 9.2:  Removed training information for sites randomized to aripiprazole once 
monthly because it was already included in Section 9.1.3.1. 
• 
Section 9.3.1:  Additional inclusion criteria was added. 
• 
Section 9.3.2:  Additional exclusion criteria was added. 
• 
Section 9.4:  Source of study drug was clarified. 
• 
Section 9.4.2:  Storage procedures for study drug was updated. 
• 
Section 9.4.3:  Section updated to reflect that the Canadian sites were removed from 
the study. 
• 
Section 9.5.1:  Text regarding timing of the study assessments at Screening and 
Baseline Visits were added; the exact version of the SCID was added. 
• 
Section 9.5.1.5:  Hospitalization for administration of study drug or insertion of access 
for administration of study drug was removed from list of hospitalizations that are not 
considered SAEs. 
• 
Section 9.5.1.6.3:  Removed description of C SSRS scale and updated timing of the 
C-SSRS assessment. 

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• 
Section 9.5.1.8:  Added the Premorbid Adjustment Scale to the assessments for 
neuropsychiatric function. 
• 
Section 9.5.2.1:  Procedures for structural and diffusion tensor imaging was updated. 
• 
Section 9.5.2.2 and 9.5.2.3:  Section removed; task-based fMRI acquisition is not 
being used in this study. 
• 
Section 9.5.2.4:  Procedures for fMRI acquisition were changed; section was 
renumbered due to removal of previous sections; new section added for MRI 
assessments (replaced previous Sections 9.5.2.2 and 9.5.2.3). 
• 
Table 3 and Table 4:  The Schedule of Assessments for Year 1 and Year 2 were 
updated, including new assessments, timing of assessments, and footnote changes; 
footnotes were then reordered for clarity.’ 
• 
Section 9.6.3:  Data collection dates were updated. 
• 
Section 9.7.1.2:  Text was added to clarify the definition of “total times” and “gap 
times” and that only inpatient psychiatric hospitalization will be calculated for each 
subject as part of the secondary endpoints. 
• 
Section 9.7.1.3:  Definition of the Full Analysis Set was updated; text was added to 
describe the procedures for subgroup analyses of subjects at LAI sites. 
• 
Section 9.7.1.5:  Removal of the presentation of demographics of the Safety Analysis 
Set if there is more than a 5% difference from the Full Analysis Set. 
• 
Section 9.7.1.8.2:  Text was added to clarify that only inpatient psychiatric 
hospitalization will be calculated for each subject as part of the secondary endpoints. 
• 
Section 9.7.1.8.4:  Updated the criteria for the a priori sensitivity analyses. 
• 
Section 9.7.5:  Addition of requirement to send any changes to the SAP to the DSMB 
for review. 
• 
Section 10:  Any changes in the protocol that affect the safety of subjects, the scope of 
the investigation, or the scientific quality of the study must also be approved by the 
DSMB in addition to the applicable IRBs. 
• 
Various sections:  Random typographical errors corrected for reader clarity; no effect 
on safety or study conduct. 
29 October 2015 
• 
Amendment 2.0 
 
• 
Synopsis page 8: added “or deltoid” 
• 
Section 9.3.3.1 (Overall treatment): added “or deltoid” 
• 
Section 9.4.1 (Treatments Administered): added “or deltoid IM”  
 

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CLINICAL PROTOCOL SYNOPSIS 
Name of Sponsor:  Vanguard Research Group 
Name of Product:  Abilify Maintena®, aripiprazole 
Collaborative Protocol 
Title: 
A Cluster Randomized, Multi-center, Parallel-group, Rater-blind Study Comparing 
Treatment with Aripiprazole Once Monthly and Treatment as Usual on Effectiveness in 
First-Episode and Early Phase Illness in Schizophrenia 
Treatment Indication: 
Schizophrenia 
Objective(s): 
The primary objective of the study is: 
• 
To determine the effectiveness of treatment with aripiprazole once monthly 
compared with treatment as usual (TAU) as defined by time to first 
hospitalizations. 
The secondary objectives of the study are to: 
• 
Determine the effect of treatment with aripiprazole once monthly compared with 
TAU on brain structure volumes and white matter integrity over the 2-year study 
duration 
• 
Determine the effectiveness of treatment with aripiprazole once monthly 
compared with TAU on clinical outcomes beyond time to first hospitalization.  
The outcomes are: 
o 
Reducing the number of days in the hospital during the 2 years of follow-up 
o 
Reducing the time to all episodes of psychiatric hospitalization 
o 
Reducing psychopathology 
o 
Lowering cost of care 
o 
Improving neuropsychological functioning 
Study Design: 
This is a cluster randomized, two-arm, rater-blind, multi-center, parallel-group study 
designed to compare the effectiveness and changes in brain structure volumes of 
aripiprazole once monthly compared with TAU in subjects with first-episode and early 
phase (EP) schizophrenia. 
Approximately 40 sites will participate in the study in order to enroll approximately 
500 subjects during 1 year of recruiting.  Subjects will be recruited into two cohorts:  the 
first-episode cohort and the EP cohort, with approximately 250 subjects in each cohort.  
Ongoing evaluation of the numbers of subjects for each cohort will continue until target 
enrollment is reached.  Enrollment of subjects into the first-episode and EP cohort will be 
discontinued when the appropriate number for the target is reached. 
Sites, as a cluster, will be randomized, with half of the sites assigned to the long-acting 
injectable (LAI) aripiprazole once monthly and half of the sites assigned to TAU 
medications. 
One screening visit will occur over approximately 1 week.  After providing written 
informed consent, subjects will be screened for general eligibility by the clinical team at 
the site.  Basic demographic data will be collected to determine suitability for inclusion 
into the study and to account for subjects screened, but not included in the study.  The site 
will complete an information interview comprising of data regarding symptomology and 
history to enable the remote centralized assessment team to conduct their assessments.  
After screening, two baseline visits will occur, which will be no more than 4 weeks apart. 

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Name of Sponsor:  Vanguard Research Group 
Name of Product:  Abilify Maintena®, aripiprazole 
Study Design continued: 
Baseline Visit 1 will include: 
• 
Establish diagnostic eligibility with the Structured Clinical Interview for 
Diagnostic and Statistical Manual, Fifth Edition (DSM-5) Disorders (SCID-5) by 
the remote centralized assessment team 
• 
Evaluate psychopathology using the Brief Psychiatric Rating Scale (BPRS) and 
the Clinical Global Impression-Severity (CGI-S) scale by the remote centralized 
assessment team 
• 
Completion of the Heinrichs-Carpenter Quality of Life Scale (QLS) by the remote 
centralized assessment team 
• 
Completion of the Columbia Suicide Severity Rating Scale (C-SSRS) assessment 
by the remote centralized assessment team 
• 
Completion of the Premorbid Adjustment Scale by the remote centralized 
assessment team 
• 
Begin oral aripiprazole (LAI sites only)  
• 
Urine pregnancy test will be performed 
• 
If eligible per the SCID-5, LAI sites will start to assess tolerability to oral 
aripiprazole.  Visits will occur weekly until the clinician determines tolerability. 
Baseline Visit 2 is the final baseline visit and will include: 
• 
Magnetic resonance imaging (MRI) will be completed for subjects in the MRI 
substudy 
• 
Completion of the Repeatable Battery for the Assessment of Neuropsychological 
Status (RBANS) 
• 
Collection of study-specific demographic information 
• 
Recording of medical and psychiatric histories 
• 
Collection of information on use of services, insurance status, work, school 
attendance, and other service use outcomes will be assessed using the Service 
Utilization and Resources Form (SURF) 
• 
Height, body weight, waist circumference, temperature, pulse and blood pressure 
will be measured 
• 
Body mass index (BMI) will be calculated 
• 
Fasting blood samples for clinical laboratory testing will be collected, including a 
lipid panel (i.e., cholesterol:  total, high-density lipoprotein [HDL] low-density 
lipoprotein, [LDL], and triglycerides), a metabolic profile, prolactin and insulin 
concentrations, and a complete blood count (CBC) with differential, glycosylated 
hemoglobin (HbA1c) 
• 
Urinalysis with microscopic analysis 
• 
Completion of the Medication Visit Record 
• 
Record current medications 
• 
Completion of the Hospitalization and Emergency Room Visit (HEC) form 
All Baseline Visit 2 assessments must occur within 4 weeks of Baseline Visit 1.  Baseline Visit 2 will 
be considered completed when all assessments have been performed. 
The initial aripiprazole injection will be given at some point after the Baseline Visit 1 once 
tolerability to oral aripiprazole is established.  Future injections of aripiprazole will still be 
administered monthly; however, the injections may not coincide with the scheduled 
monthly visits. 

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Name of Sponsor:  Vanguard Research Group 
Name of Product:  Abilify Maintena®, aripiprazole 
Study Design continued: 
 
Aripiprazole once monthly will be prescribed and administered according to 
recommendations contained in the product labeling. 
Following the baseline visits and once tolerability has been established, subjects at the LAI 
sites will be scheduled for once monthly medication visits for aripiprazole once monthly 
injections, and subjects at the TAU sites will be scheduled for medication visits as required 
based on their TAU medications (i.e., at a minimum of every 3 months).  All subjects will 
receive bimonthly phone calls inquiring about any visits to emergency rooms and 
hospitalizations.  All subjects will receive phone calls every 4 months to complete the 
SURF.  The calls will be conducted by the local site research assistant or study coordinator 
and are not linked to participation in treatment.  All subjects are required to attend an 
in-person visit every 6 months (i.e., 6, 12, 18, and 24 months) during the 2-year study 
duration.  Subjects who prefer in-person visits at any time when a telephone visit is 
scheduled may request them at any time.  At the 6-, 12-, 18-, and 24-month visits, the 
following assessments will be performed: 
• 
Information on use of services, insurance status, work, school attendance, and 
other service use outcomes will be assessed using the SURF (i.e., 12- and 
24-month visits only) 
• 
Height, body weight, waist circumference, temperature, pulse and blood pressure 
will be measured 
• 
Fasting blood samples for clinical laboratory testing will be collected including a 
lipid panel (i.e., cholesterol:  total, HDL, LDL, and triglycerides), a metabolic 
profile, prolactin and fasting insulin concentrations, and a CBC with differential 
• 
Urine pregnancy test 
• 
Assessments for psychopathology using BPRS and CGI-S (i.e., 12- and 24- month 
visits only) 
• 
Completion of C-SSRS (i.e., 12- and 24-month visits only) 
• 
Administration of LAI medications including aripiprazole once monthly or 
prescription dispensation 
• 
Completion of the Medication Visit Record, including details of dispensing, 
prescribing, and administration information where appropriate 
• 
Reporting and recording of adverse events 
• 
Completion of the RBANS to measure neuropsychological function (i.e., 12- and 
24-month visits only) 
• 
Completion of QLS (i.e., 12- and 24-month visits only) 
Because subjects with schizophrenia have an estimated 8.5-fold greater risk of suicide than 
the general population, with young patients particularly at risk, subjects in this study will 
be monitored closely for suicidality at each study visit.  Instances of suicidality will be 
captured using an expanded serious adverse event form, and potential for suicidality will be 
monitored using the C-SSRS at the 12- and 24-month visits and at any other appropriate 
time, per the investigator’s judgment. 
In addition, a subset of an expected 114 first-episode and EP subjects at approximately 
10 clinical sites will undergo MRI at the baseline, 12- and 24-month visits to measure brain 
structure volumes and white matter integrity. 
The MRI sites (i.e., Five  TAU and Five  LAI) will be selected based on close proximity to 
centers with research MRI capabilities.  The first 57 subjects at both the TAU and LAI sites 
consenting to MRI will be enrolled into the MRI portion of the study. 

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Name of Sponsor:  Vanguard Research Group 
Name of Product:  Abilify Maintena®, aripiprazole 
Subject Population: 
An estimated 500 subjects with schizophrenia will be enrolled over a 1-year recruitment 
period to recruit an expected 0.5 to 1 subject with first-episode schizophrenia and 0.5 to 
1 subject with EP schizophrenia per month, allowing for an anticipated 250 subjects in the 
first-episode cohort and 250 subjects in the EP cohort.  Randomization at the 40 sites will 
be stratified by 1) urban versus non-urban treatment setting and 2) ethnic composition of 
the population served by the site.  All sites will provide detailed information about the 
ethnic composition of their patient population prior to randomization.  Half of the sites 
(i.e., 20/40) will be randomly assigned to administer aripiprazole once monthly and the 
remaining 50% of the sites will be randomly assigned to administer TAU antipsychotic 
medications. 
In addition, a subset of 114 first-episode and EP subjects at approximately 10 of the clinical 
sites will undergo MRI to measure brain structure volumes and white matter integrity.  The 
MRI sites (i.e., five TAU and five LAI) will be selected based on close proximity to centers 
with research MRI capabilities.  The first 57 subjects at both the TAU and LAI sites 
consenting to MRI will be enrolled into the MRI portion of the study. 
All subjects will have a current diagnosis of schizophrenia as defined by the DSM-5 
criteria.  The first-episode subjects are defined as those subjects with < 1 year of 
antipsychotic treatment and the EP subjects are defined as subjects with a 1- to 5-year 
history of antipsychotic treatment. 
Subjects will be selected by approaching all eligible patients at the participating clinics.  
The inclusion criteria are as broad as possible within an EP population.  Subjects must meet 
the following inclusion criteria to be eligible for the study: 
1. Are able to provide written informed consent 
2. Have a confirmed diagnosis of schizophrenia as defined by DSM-5 criteria using 
the SCID-5 
3. Are between the ages of 18 and 35, inclusive 
4. Have the following history with antipsychotic medications 
a. 
First episode subjects:  < 1 year of lifetime exposure to antipsychotic 
medication and only one episode of psychosis 
b. EP subjects:  between 1 year and 5 years of lifetime exposure to 
antipsychotic medication or subjects with < 1 year of lifetime 
antipsychotic medication and more than one episode of psychosis 
5. Subjects at LAI sites must be willing to accept an injectable form of treatment. 
Subjects must not have any of the following criteria to be eligible for the study: 
1. Have a current primary DSM-5 diagnosis other than schizophrenia, including 
schizophreniform disorder, schizoaffective disorder, major depressive disorder, 
bipolar disorder, delirium, dementia, and amnestic or other cognitive disorders. 
2. Subjects at LAI sites:  have a known allergy or intolerance to aripiprazole, or a 
past negative response to aripiprazole that is not explained by nonadherence 
3. Be pregnant or lactating 
4. Have any unstable medical condition that, in the opinion of the investigator, 
would be detrimental to the subject or would confound the results of the study 
5. Past or current treatment with clozapine  
6. Subjects in the MRI subset only who have: 
a. 
Received an LAI antipsychotic in the last 6 months 
b. Any metal implants, pacemakers, irremovable prosthetic device, or other 
device or situation that may preclude imaging 

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Name of Sponsor:  Vanguard Research Group 
Name of Product:  Abilify Maintena®, aripiprazole 
Study Drug, Dose, 
Formulation, Mode of 
Administration: 
 
 
 
 
All aripiprazole study drug will be purchased by the investigator.  Medication at the TAU 
sites will be prescribed based upon usual site practices.  In order not to influence or restrict 
which medications are prescribed at TAU sites, medications for TAU subjects will not be 
supplied by the study.  Reimbursement for medications at TAU sites will be by usual 
mechanisms (e.g., private or public insurance).  The following medications will be 
administered: 
• 
Aripiprazole administered once monthly via gluteal or deltoid intramuscular (IM) 
injection, as outlined in the product labeling. 
• 
Oral antipsychotics administered per oral including, but not limited to: 
o 
aripiprazole (Abilify®) 
o 
risperidone (Risperdal®) 
o 
lurasidone HCl (Latuda®) 
o 
quetiapine fumarate (Seroquel®) 
o 
olanzapine (Zyprexa®) 
o 
ziprasidone HCl (Geodon®) 
• 
Long-acting injectable medications administered intramuscular include but are not 
limited to:: 
o 
risperidone (Risperdal® Consta®) 
o 
haloperidal decanoate (Haldol® decanoate) 
o 
olanzapine (Zyprexa® Relprevv™) 
o 
paliperidone palmitate (Invega® Sustenna®) 
o 
fluphenazine decanoate (Prolixin® decanoate) 

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Name of Sponsor:  Vanguard Research Group 
Name of Product:  Abilify Maintena®, aripiprazole 
Criteria for Evaluation: 
Primary outcome variables: 
Efficacy: 
• 
Time to the first hospitalization 
Secondary outcome variables: 
Efficacy: 
• 
Change from baseline to the 1-year and 2-year time points in gray matter and 
white matter volume, and cortical thickness.  The 2-year time point is the primary 
time point 
• 
Time to all episodes of psychiatric hospitalization, including total times (e.g., time 
from randomization to first, second, or any subsequent hospitalizations) as well as 
gap times (e.g., time between first and second hospitalization, second and third 
hospitalization, etc.) 
• 
Total number of days of inpatient psychiatric hospitalization per quarter for each 
subject for the duration of the study 
• 
Change from baseline in BPRS and CGI-S 
• 
Cost of care from the SURF 
• 
Change from baseline in neuropsychological function (i.e., RBANS) 
• 
Change from baseline in quality of life (i.e., QLS) 
Safety: 
• 
Treatment-emergent adverse events 
• 
Blood pressure 
• 
Clinical laboratory testing including prolactin and lipid profiles 
• 
Body weight, height, and BMI 
• 
C-SSRS assessment for suicidality 
Pharmacodynamic: 
• 
Change from baseline to the 1-year and 2-year time points in gray matter and 
white matter volume, and cortical thickness with the 2-year time point as the 
primary time point 
Study Duration: 
The study is expected to be approximately 3 years in duration.  Subject recruitment is 
expected to occur over 1 year and the study conduct is approximately 2 years in duration 
for individual subjects. 
 

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3 
TABLE OF CONTENTS 
1 
TITLE PAGE ...................................................................................................................... 1 
2 
CLINICAL PROTOCOL SYNOPSIS ................................................................................ 4 
3 
TABLE OF CONTENTS .................................................................................................. 10 
LIST OF IN-TEXT TABLES ............................................................................................13 
LIST OF IN-TEXT FIGURES...........................................................................................13 
LIST OF APPENDICES ....................................................................................................13 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 14 
5 
ETHICS............................................................................................................................. 16 
5.1 
Informed Consent...................................................................................................16 
5.1.1 Magnetic Resonance Imaging Consent ......................................................16 
6 
INVESTIGATORS AND STUDY PERSONNEL ........................................................... 17 
7 
INTRODUCTION ............................................................................................................ 18 
7.1 
BRAIN CHANGES IN SCHIZOPHRENIA .........................................................18 
7.2 
ABILIFY (aripiprazole) .......................................................................................20 
7.3 
Relevant Nonclinical Studies .................................................................................20 
7.4 
Relevant Clinical Studies .......................................................................................20 
7.4.1 Schizophrenia Studies with Oral Aripiprazole ..........................................20 
7.4.2 Agitation Studies with Injectable Aripiprazole ..........................................22 
7.4.3 Clinical Studies in Schizophrenia with Aripiprazole Once Monthly.........22 
7.4.4 Known and Potential Risks and Benefits ...................................................23 
7.5 
Study Rationale ......................................................................................................25 
8 
STUDY OBJECTIVES ..................................................................................................... 27 
8.1 
Primary Objective ..................................................................................................27 
8.2 
Secondary Objectives.............................................................................................27 
9 
INVESTIGATIONAL PLAN ........................................................................................... 28 
9.1 
Overall Study Design and Plan ..............................................................................28 
9.1.1 Screening and Baseline Visits ....................................................................31 
9.1.2 Randomization ...........................................................................................32 
9.1.3 Treatment ...................................................................................................33 
9.1.3.1 
Overall......................................................................................33 
9.1.3.1.1 2-year Treatment Period ..............................................34 
9.1.4 Final Visit – Month 24 and Early Termination ..........................................34 
9.1.5 Follow-up Period .......................................................................................34 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................34 
9.3 
Selection of Study Population ................................................................................36 
9.3.1 Inclusion Criteria .......................................................................................36 
9.3.2 Exclusion Criteria ......................................................................................36 
9.3.3 Removal of Subjects from Therapy or Assessment ...................................37 
9.3.3.1 
Entire Study or Treatment Arms ..............................................37 
9.3.3.2 
Individual Center .....................................................................37 
9.3.3.3 
Individual Subject ....................................................................37 
9.4 
Treatments..............................................................................................................38 

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9.4.1 Treatments Administered ...........................................................................38 
9.4.1.1 
Dosage Adjustments for Missed Doses of Aripiprazole 
Once Monthly ..........................................................................39 
9.4.2 Identity and Storage of Investigational Product(s) ....................................39 
9.4.3 Method of Assigning Subjects to Treatment Groups .................................39 
9.4.4 Blinding......................................................................................................39 
9.4.5 Treatment Compliance ...............................................................................39 
9.4.6 Accountability ............................................................................................40 
9.5 
Study Assessments .................................................................................................40 
9.5.1 Assessments ...............................................................................................40 
9.5.1.1 
Demographics ..........................................................................40 
9.5.1.2 
Screening and Baseline Assessments.......................................40 
9.5.1.3 
Safety Assessments ..................................................................41 
9.5.1.3.1 Clinical Laboratory Tests .............................................41 
9.5.1.3.2 Blood Pressure .............................................................42 
9.5.1.4 
Adverse Events and Other Events of Interest ..........................42 
9.5.1.5 
Serious Adverse Events and Other Events of Interest .............44 
9.5.1.6 
Other Safety Assessments ........................................................45 
9.5.1.6.1 Body Weight, Body Mass Index, Height .....................45 
9.5.1.6.2 Prior and Concomitant Therapies ................................45 
9.5.1.6.3 Suicidality ....................................................................45 
9.5.1.6.4 Pregnancy Test .............................................................46 
9.5.1.7 
Efficacy Assessments...............................................................47 
9.5.1.7.1 Hospitalization and Emergency Room Visit 
Form .............................................................................47 
9.5.1.7.2 Clinical Global Impression–Severity ...........................47 
9.5.1.7.3 Brief Psychiatric Rating Scale .....................................47 
9.5.1.8 
Other Assessments – Neuropsychiatric Function ....................47 
9.5.1.9 
Other Assessments – Quality of Life .......................................49 
9.5.2 Pharmacodynamic Assessments ................................................................49 
9.5.2.1 
Structural and Diffusion Tensor Imaging ................................49 
9.5.2.2 
MRI Assessments.....................................................................49 
9.5.3 Schedules of Assessments..........................................................................50 
9.5.4 Appropriateness of Measurements .............................................................54 
9.5.5 Reporting of Serious Adverse Events, Pregnancy, and Other 
Events of Interest .......................................................................................54 
9.5.5.1 
Reporting of Serious Adverse Events ......................................54 
9.5.6 Completion/Discontinuation of Subjects ...................................................55 
9.5.7 Confirmation of Medical Care by Another Physician ...............................55 
9.6 
Data Quality Assurance .........................................................................................55 
9.6.1 Monitoring .................................................................................................55 
9.6.2 Auditing .....................................................................................................55 
9.6.3 Data Collection ..........................................................................................56 
9.6.3.1 
Cross-site Data Integration ......................................................56 
9.7 
Statistical Methods .................................................................................................56 
9.7.1 Statistical Considerations ...........................................................................56 

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9.7.1.1 
Primary Endpoint .....................................................................56 
9.7.1.2 
Secondary Endpoints ...............................................................56 
9.7.1.3 
Definitions of Analysis Sets.....................................................57 
9.7.1.4 
Subject Disposition ..................................................................58 
9.7.1.5 
Demographic and Other Baseline Characteristics ...................58 
9.7.1.6 
Prior and Concomitant Therapy ...............................................58 
9.7.1.7 
Safety Analyses ........................................................................58 
9.7.1.7.1 Extent of Exposure .......................................................58 
9.7.1.7.2 Adverse Events ............................................................58 
9.7.1.7.3 Laboratory Values ........................................................59 
9.7.1.7.4 Blood Pressure .............................................................60 
9.7.1.8 
Efficacy Analyses ....................................................................60 
9.7.1.8.1 Primary Efficacy Analysis ...........................................60 
9.7.1.8.2 Secondary Efficacy Analysis .......................................60 
9.7.1.8.3 Pharmacodynamic Analyses ........................................61 
9.7.1.8.4 a priori Analyses..........................................................61 
9.7.2 Determination of Sample Size ...................................................................61 
9.7.3 Interim Analysis .........................................................................................62 
9.7.4 Multiple Comparison Adjustment..............................................................62 
9.7.4.1 
Data Safety Monitoring Board .................................................63 
9.7.5 Procedure for Revising the Statistical Analysis Plan .................................63 
10 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS ...................................... 64 
10.1 
Changes to the Protocol .........................................................................................64 
10.2 
Adherence to the Protocol ......................................................................................64 
10.3 
Monitoring Procedures...........................................................................................64 
10.4 
Recording of Data ..................................................................................................65 
10.5 
Identification of Source Data .................................................................................65 
10.6 
Retention of Records..............................................................................................65 
10.7 
Reporting of Product Quality Complaints .............................................................66 
10.7.1 Information Required for Reporting Purposes ...........................................66 
10.7.2 Eliciting and Reporting Quality Complaints..............................................67 
10.7.3 Return Process ...........................................................................................67 
10.8 
Discontinuation of Study .......................................................................................67 
11 
REFERENCE LIST .......................................................................................................... 68 
12 
APPENDICES .................................................................................................................. 73 
 
 

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LIST OF IN-TEXT TABLES 
Table 1: 
Key Study Personnel and Contributors ..................................................................17 
Table 2: 
Safety Clinical Laboratory Tests ...........................................................................42 
Table 3: 
Schedule of Assessments Year 1 ...........................................................................51 
Table 4: 
Schedule of Assessments Year 2 ...........................................................................53 
Table 5: 
Number of Subjects per Site per Treatment Arm ..................................................62 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study Schematic.......................................................................................................1 
Figure 2: 
Functional Connectivity Correlations ....................................................................35 
 
LIST OF APPENDICES 
Appendix 1: 
SIGNATURE PAGE .............................................................................................73 
 

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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BPRS 
Brief Psychiatric Rating Scale 
CBC 
complete blood count 
CGI-S 
Clinical Global Impression-Severity 
CR 
competing risk 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DS 
dorsal striatum 
DSM-5 
Diagnostic and Statistical Manual, Fifth Edition 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
EP 
early phase 
EPI 
echo planar imaging 
EPS 
extrapyramidal side effects 
EQC 
Ethics, Quality, and Compliance 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
fMRI 
functional magnetic resonance imaging 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
HDL 
high-density lipoprotein 
HEC 
Hospitalization and Emergency Room Visit 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IM 
intramuscular 

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Abbreviation 
Term 
IRB 
institutional review board 
LAI 
long-acting injectable 
LDL 
low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
OAPI 
Otsuka America Pharmaceutical, Inc. 
OPC 
Otsuka Pharmaceutical Co., Ltd 
PANSS 
Positive and Negative Syndrome Scale 
PHREG 
proportional hazards regression 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PO 
per oral 
PQC 
product quality complaint 
PT 
preferred term 
QLS 
Heinrichs-Carpenter Quality of Life Scale 
QT 
interval from beginning of the QRS complex to end of the T wave in the 
frontal plane 
QTc 
corrected QT interval 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
RCT 
randomized clinical trial 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Safety Analysis Set 
SCID-5 
Structured Clinical Interview for DSM -5 Disorders 
SURF 
Service Utilization and Resources Form 
TAU 
treatment as usual 
TEAE 
treatment-emergent adverse event 
US 
United States 
VS 
ventral striatum 
 

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5 
ETHICS 
This study must be conducted in compliance with the protocol, Food and Drug Administration 
(FDA) regulations, the International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guideline, and all other applicable local laws and regulatory requirements.  Each study site 
will seek approval by an institutional review board (IRB) according to regional requirements.  The 
IRB will evaluate the ethical, scientific, and medical appropriateness of the study.  Further, in 
preparing and handling case report forms (CRFs), the investigator, sub-investigator, and their staff 
will take measures to ensure adequate care in protecting subject privacy.  To this end, a subject 
number and subject identification code will be used to identify each subject. 
5.1 
INFORMED CONSENT 
All subjects will have the purpose of the study, study interventions and evaluations, and the 
potential risks and benefits of participation explained to them and any questions will be answered.  
Subjects will also complete a written study review questionnaire that covers key aspects of the 
study (e.g., the ability to withdraw at any time).  If a subject consents to participation in this study, 
the subject will review and sign the informed consent form (ICF).  When ready, and after having 
satisfactorily answered all questions on the study review questionnaire indicating understanding 
of the study procedures, subjects will be asked to give written consent to participate in the study.  
After both the subject and the investigator sign the ICF, each subject will be given a copy of the 
signed ICF. 
Written informed consent will be obtained from all subjects or their guardian or legal 
representative, as applicable for local laws.  Consent will be documented on a written ICF.  The 
ICF will be approved by the same IRB that approves this protocol.  Each ICF will comply with the 
FDA regulations in Title 21 Code of Federal Regulations Part 50 ICH, GCP, and local regulatory 
requirements.  The investigator agrees to obtain approval from the sponsor of any written ICF used 
in the study, prior to submission to the IRB. 
Investigators may discuss study availability 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 determination of 
eligibility for this study, including withdrawal from current medication(s). 
Once the appropriate essential information has been provided and fully explained in layman’s 
language to the subject by the investigator, or a qualified designee, the IRB-approved written ICF 
will be signed and dated by both the subject and the person obtaining consent (i.e., investigator or 
designee), as well as by any other parties required by the IRB.  The subject will receive a copy of 
the signed ICF and the original shall be kept on file by the investigator. 
5.1.1 
Magnetic Resonance Imaging Consent 
Subjects enrolled for the magnetic resonance imaging (MRI) portion of the study must give 
separate informed consent before any MRI procedures can be performed. 

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6 
INVESTIGATORS AND STUDY PERSONNEL 
This is a collaboratively designed, investigator-sponsored study that will be conducted at 
approximately 40 sites across North America. 
The Principal Investigator (PI) and study staff at the PI site are listed below along with information 
for other key contributors to the study.  Information regarding the additional sites will be provided 
in the PI’s trial master file. 
Table 1: 
Key Study Personnel and Contributors 
Principal Investigator 
Other PI Study Staff 
John M Kane, MD 
Chair, Department of Psychiatry at Hofstra North 
Shore University Hospital and Long Island Jewish 
School of Medicine 
The Feinstein Institute for Medical Research  
The Zucker Hillside Hospital-North Shore Long Island 
Jewish Health System  
75-59 263rd Street 
Glen Oaks, NY  11004 
Tel:  718-343-7739  
psychiatry@lij.edu 
Co-Principal Investigators: 
Christoph Correll, MD 
Patricia Marcy, BSN 
Delbert Robinson, MD 
Nina Schooler, PhD 
Co-Investigator: 
Eric Achtyes, MD 
Director of Operations: 
Patricia Marcy, BSN 
IRB for PI site: 
Site Monitoring: 
North Shore–Long Island Jewish Health System 
Institutional Review Board 
FWA#00002505 
350 Community Drive, 4th Floor 
Manhasset, NY  11030 
Sites not using the above-referenced IRB will provide 
the appropriate IRB approval and documents to the PI 
prior to initiating any study-related procedures. 
Project Director:  Zucker Hillside Hospital  
Data Management 
Nathan Kline Institute for Psychiatric Research 
140 Old Orangeburg Road 
Orangeburg, NY  10962 
Remote Assessments 
DSMB: 
The Zucker Hillside Hospital 
Independent DSMB  
Scientific Administrator:  Joanne B. Severe, MS  
Chair:  Alexander Miller, MD 
DSMB = Data Safety Monitoring Board, IRB = Institutional Review Board, PI = Principal Investigator,  
Otsuka contact: 
Susan N. Legacy, MD 
Associate Director-CNS Medical Affairs 
Phone:  609-249-6597  
Fax:  609-249-0597 

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7 
INTRODUCTION 
Non-adherence remains an enormous challenge in schizophrenia.  Long-acting injectable (LAI) 
antipsychotics have been shown in some mirror image, naturalistic, and randomized clinical trials 
(RCTs) to significantly reduce rates of relapse and re-hospitalization in comparison with oral 
antipsychotics.  However, a recent meta-analysis1 of RCTs did not show an overall advantage.  
This change from a previous analysis published only 2 years ago2 is largely due to the findings of 
two recent studies funded by the Veteran’s Administration and National Institutes of Mental 
Health3,4, which were both unable to demonstrate superiority for LAIs, despite state-of-the-art 
methodology.  Given the apparent disconnect between some naturalistic data5,6 and recent RCTs, 
it is important to consider the possibility that the types of RCTs that have traditionally been 
conducted do not really succeed in recruiting representative patients or in fully achieving an 
effectiveness treatment trial model for LAIs.  A well-designed effectiveness trial that overcomes 
the limitations of prior studies is necessary to better address the question of the utility of LAIs in 
settings that approximate real world care.  Health policy makers, payers and providers, particularly 
those in the United States (US), will be less likely to actively facilitate the use of LAIs, unless 
there is compelling evidence to support their use, including cost effectiveness data. 
Given the increasing recognition that early and effective interventions hold the greatest promise 
for improving the overall trajectory and outcome of schizophrenia, including rates of recovery, it 
is particularly important to determine the impact of “guaranteed medication” in the earliest 
possible phases of illness.  This is underscored by the well-documented enormous challenge of 
medication acceptance and adherence among first-episode and early phase (EP) patients.  In 
addition, there are some suggestions that LAI medication administration may be particularly 
effective in the early phase of schizophrenia7-10. 
Aripiprazole once monthly is particularly well suited to a large simple trial because monthly 
administration more closely mirrors clinical practice.  In both recent LAI studies, risperidone 
microspheres were used, which require biweekly administration.  Moreover, the relatively lower 
side effect burden of aripiprazole once monthly when compared with most other first line agents, 
including paliperidone, the only other once-monthly second generation antipsychotic, increases its 
acceptability for and utility in EP patients. 
7.1 
BRAIN CHANGES IN SCHIZOPHRENIA 
Antipsychotic medications are widely prescribed for the treatment of schizophrenia and related 
psychotic disorders; thus, understanding their potential impact on the brain has significant health 
implications.  Moreover, better understanding of how brain changes relate to long-term 
antipsychotic treatment could improve our understanding of the mechanisms of antipsychotic 
efficacy (especially in the developing brain), inform neurobiological models of schizophrenia, and 
translate into improved clinical care by clarifying their impact on long-term cognitive and 
functional outcome.  The early phase of psychosis is likely the most critical period for treatment 
intervention, and the ideal time to study key mechanisms associated with brain plasticity. 
There is now considerable evidence that both typical and atypical antipsychotic medications may 
be associated with structural and functional changes in the brain.  Initial longitudinal studies 
conducted by our group and others suggested that basal ganglia volumes increase over time 

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following treatment with typical antipsychotics, and that this enlargement may be reversed or 
normalized following treatment with clozapine11-14.  Comprehensive literature reviews indicate 
that antipsychotics may contribute to the genesis of some of the structural abnormalities that are 
usually attributed to schizophrenia15.  Furthermore, several longitudinal neuroimaging studies 
reported white matter volume reductions in association with greater exposure to antipsychotic 
medications16 and reductions in white matter integrity in treatment-naïve patients following 
antipsychotic treatment17-19. 
A critical limitation of prior neuroimaging studies assessing the impact of antipsychotics on brain 
structure and function is the lack of information regarding medication compliance and the 
possibility that such purported neuroanatomic changes may reflect illness progression.  Few 
studies in the literature have addressed this critical issue.  Of particular relevance to this study is 
work by Bartzokis et al20, who examined the impact of antipsychotic formulations on white matter 
volume during a 6-month trial of LAI risperidone versus oral risperidone in first-episode 
schizophrenia patients.  White matter volume remained stable in the patients treated with LAI 
risperidone, but decreased significantly among patients treated with oral risperidone.  This work 
was subsequently extended by Bartzokis et al21 to indicate that frontal lobe intracortical myelin 
volume increased significantly among patients receiving LAI risperidone, but no significant 
longitudinal effects were evident among patients treated with oral risperidone.  Notably, patients 
receiving LAI risperidone had better medication adherence and greater intracortical myelin 
increases. 
Conclusions gleaned from prospective studies examining the relationship between antipsychotic 
treatment and brain integrity in schizophrenia must be interpreted in the context of research 
demonstrating a deleterious effect of psychosis on the brain independent of antipsychotic 
medication exposure.  For example, Ziermans et al22 reported that those individuals who were at 
ultra-high risk for psychosis and became psychotic demonstrated a greater reduction in total brain 
and white matter volume over time, compared with healthy controls and individuals who did not 
become psychotic.  Other studies suggest that a greater duration of untreated psychosis may be 
neurotoxic to the brain.  Filippi et al23 reported that 43 first-episode, drug-naïve patients with 
schizophrenia demonstrated gray and white matter structural alterations, which were associated 
with a longer duration of untreated psychosis and positive symptom severity compared with 
healthy volunteers.  In addition, Cahn et al24 found that a greater duration of psychosis was 
associated with gray matter volume reductions and ventricular volume increases among 
48 first-episode schizophrenia patients scanned at the onset of illness, and then again 5 years later.  
Similarly, Malla et al25 reported that individuals with a greater duration of untreated psychosis had 
significantly greater grey matter volume reductions in the bilateral medial frontal and rectal gyrus 
compared with patients with a short duration of untreated psychosis.  Taken together, these studies 
suggest that untreated psychosis is a contributing factor to brain volumetric abnormalities 
identified in patients with schizophrenia. 
The proposed study will test the hypothesis that better antipsychotic medication compliance using 
aripiprazole once monthly will be associated with less severe progression of neuroanatomic 
deficits over the course of illness in schizophrenia. 

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7.2 
ABILIFY (ARIPIPRAZOLE) 
Aripiprazole (ABILIFY®) is a dopamine partial agonist discovered by Otsuka Pharmaceutical Co., 
Ltd., (OPC) and co-developed by Bristol-Myers Squibb and OPC.  OPC and H. Lundbeck A/S are 
jointly developing the intramuscular (IM) injection formulation of aripiprazole.  Aripiprazole oral 
tablets are approved in the 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 major depressive disorder.  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 injection 
formulation is approved for agitation in schizophrenia and bipolar mania in the US and EU.  In 
addition, an oral solution formulation and orally disintegrating (i.e., dispersible) tablets have been 
approved and marketed for use in the US and EU.  The favorable side effect profile of oral 
aripiprazole, including its low incidence of extrapyramidal side effects (EPS), low risk of prolactin 
elevation, decreased adrenergic and anticholinergic side effects, and minimal weight gain, makes 
it an excellent candidate for an LAI formulation.  The aripiprazole once monthly formulation was 
recently approved for treatment of schizophrenia in the US. 
A brief summary of nonclinical and clinical data is included below. 
7.3 
RELEVANT NONCLINICAL STUDIES 
The mechanism of action of aripiprazole differs from that of currently marketed typical and 
atypical antipsychotics.  It has been proposed that the effectiveness of aripiprazole in schizophrenia 
is mediated through a combination of partial agonism 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 and serotonin 5-HT1A and 5-HT2A receptors, and moderate affinity for dopamine D4, 
serotonin 5-HT2C and 5-HT7, alpha1-adrenergic, and 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 subjects with schizophrenia.  It seems likely that the favorable safety and tolerability 
profile of aripiprazole, including its low incidence of EPS, lack of prolactin elevation, decreased 
adrenergic and anticholinergic side effects, and decreased weight gain, is also mediated by its 
unique profile of interaction with central neuroreceptors.  Please refer to the Investigator’s 
Brochure (IB)26 for information regarding nonclinical toxicity and pharmacokinetic (PK) studies 
conducted using aripiprazole in animals. 
7.4 
RELEVANT CLINICAL STUDIES 
7.4.1 Schizophrenia Studies with Oral Aripiprazole 
A comprehensive clinical program to evaluate the effectiveness of oral aripiprazole monotherapy 
was conducted.  These studies of subjects with an acute exacerbation of schizophrenia established 

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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. 
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 studies established the efficacy of aripiprazole in doses of 10, 
15, 20, and 30 mg for the treatment of acute relapse of schizophrenia or schizoaffective disorder.  
The two 4-week studies (i.e., 31-97-20127 and 31-97-20228) each included two fixed doses of 
aripiprazole (i.e., 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 studies 
indicated that all of the doses of aripiprazole were effective in the treatment of acute psychosis.  
All aripiprazole doses were statistically significant compared with 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 (i.e., CN138001)29 was 6 weeks in duration and included 
aripiprazole doses of 10, 15, and 20 mg.  All doses of aripiprazole demonstrated significant 
improvement compared with placebo for mean change from baseline to endpoint 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 CN13804730,31 was a 26-week study designed to document the long-term 
efficacy of aripiprazole 15 mg compared with placebo in stable schizophrenic subjects.  The 
primary efficacy variable was time to relapse from randomization, as measured by Clinical Global 
Impression-Improvement 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 (i.e., 31-98-217 and 
31-98-304-01)32,33 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 (i.e., 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 for negative symptoms, depressive symptoms, 
and discontinuation for any reason. 
The subject-rated and investigator-rated acceptability of aripiprazole treatment was examined in 
several open-label studies.  Subjects treated with open-label aripiprazole 10 to 30 mg for 8 weeks 
indicated a general preference for aripiprazole over the antipsychotic medication(s) taken prior to 
entering the studies (i.e., CN138087 and CN138100)34.  A separate open-label study (i.e., 
CN138152)35,36 compared aripiprazole 10 to 30 mg daily with standard of care treatment (i.e., 
clinician-prescribed olanzapine, risperidone, or 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, 
which provides an overall assessment of efficacy and tolerability37. 

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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 dose for aripiprazole in the treatment of 
schizophrenia is 10 mg or 15 mg/day administered on a once daily schedule without regard to 
meals.  Aripiprazole has been systematically evaluated and shown to be effective in a dose range 
of 10 to 30 mg/day; however, there is no evidence that doses higher than 15 mg/day are associated 
with increased efficacy.  Additional details of results of clinical studies with aripiprazole in other 
indications are provided in the IB26. 
7.4.2 Agitation Studies with Injectable Aripiprazole 
The efficacy of immediate-release IM aripiprazole for the treatment of agitation was established 
in three short-term (i.e., 24-hour) placebo-controlled studies38.  Two studies in agitated inpatients 
with schizophrenia, schizoaffective disorder, or schizophreniform disorder showed that 
aripiprazole at doses of 5.25, 9.75, and 15 mg/day was significantly more effective than placebo 
for controlling agitation, as measured by change from baseline in PANSS Excited Component at 
2 hours post-injection.  A similar result was observed in agitated inpatients with bipolar disorder 
who received aripiprazole 9.75 mg/day. 
7.4.3 Clinical Studies in Schizophrenia with Aripiprazole Once Monthly 
CN138020, a clinical study conducted by Bristol-Myers Squibb, assessed the safety, tolerability, 
and PK of single doses of the aripiprazole once monthly formulation.  This was an open-label, 
two-phase, nonrandomized, ascending dose, sequential panel study in subjects with a confirmed 
diagnosis of chronic schizophrenia or schizoaffective disorder.  Subjects received a single 5 mg 
dose of the standard IM formulation, followed by safety and PK monitoring.  After a minimum 
28-day washout, subjects who qualified (i.e., based on no significant adverse events [AEs] or 
clinical laboratory abnormalities) received a single dose of 15, 50, 100, 200, 300, or 400 mg of 
aripiprazole once monthly formulation, followed by safety and PK monitoring.  The IM 
formulation appeared to be well tolerated.  Peak plasma concentrations in most subjects were 
observed after approximately 100 hours.  Most AEs were mild (43%) to moderate (33%) in 
severity.  The most commonly reported treatment-emergent adverse events (TEAEs) were 
headache (4 subjects, 19%) and anxiety (3 subjects, 14.3%).  All other AEs occurred in ≤ 2 
subjects.  There were no discontinuations due to AEs and none of the AEs appeared to be 
dose-related.  There were two serious adverse events (SAEs) (i.e., attempted suicide and 
exacerbation of schizophrenia) that were considered to be unrelated to study drug. 
Otsuka Pharmaceutical Development & Commercialization, Inc. conducted a Phase 1B study (i.e., 
31-05-244) to assess the safety, tolerability, and PK of multiple doses of the aripiprazole once 
monthly formulation in subjects with schizophrenia.  The results showed that once monthly 
administration of the 400-mg and 300-mg IM injections resulted in mean aripiprazole trough and 
average plasma concentrations that were comparable to the therapeutic concentrations of 10 to 
30 mg oral aripiprazole administered daily to schizophrenic subjects.  All three doses of 
aripiprazole once monthly (i.e., 200, 300, and 400 mg) demonstrated acceptable safety, 
tolerability, and potential effectiveness39. 

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A Phase 3 study (i.e., 31-07-246) was conducted to evaluate the efficacy and safety of aripiprazole 
once monthly compared with placebo in schizophrenic subjects who had maintained stability on 
aripiprazole once monthly for at least 12 weeks.  Aripiprazole once monthly 400 mg or 300 mg 
administered as monthly gluteal injections was effective for the maintenance treatment of 
schizophrenia in adults as demonstrated by a statistically significant difference, when compared 
with placebo, in the primary efficacy endpoint of time to impending relapse.  The percentage of 
subjects who met the criteria for impending relapse was significantly lower in the aripiprazole 
once monthly group than in the placebo group.  The maintenance of stability was also demonstrated 
by statistically significant differences favoring aripiprazole once monthly in PANSS and CGI 
scores, which remained significant throughout the double-blind, placebo-controlled phase.  In 
addition, the Personal and Social Performance Scale total score, cognitive function assessments, 
and Investigator Assessment Questionnaire score were supportive of the efficacy of aripiprazole 
once monthly treatment.  Aripiprazole once monthly was well tolerated by adult subjects with 
schizophrenia, as demonstrated by an AE profile similar to placebo.  Most TEAEs were either mild 
or moderate in severity.  Tremor was the only TEAE with an incidence of at least twice that of 
placebo and reported by ≥ 5% of subjects receiving aripiprazole once monthly.  The increased rate 
of tremor over placebo treatment was consistent in studies with oral aripiprazole, as also reported 
in the aripiprazole product labeling.  Generally, AEs of tremor were mild in severity and occurred 
with a low frequency throughout the study.  No report of tremor was classified as a SAE or was 
associated with discontinuation of treatment.  There were no clinically relevant findings with 
regard to laboratory values, vital signs, weight, electrocardiogram (ECG) findings, EPS, 
suicidality, or injection site. 
7.4.4 Known and Potential Risks and Benefits 
As of 10 Jun 2010, 15,088 adult subjects were treated with aripiprazole oral tablet formulation in 
Phase 2, 3, and 4 studies, representing 8,577 subject-exposure years.  Of these, 3,901 (25.9%) 
subjects were treated with aripiprazole for 180 days or longer, 2,259 (15.0%) subjects received 
aripiprazole for at least 360 days, and 933 (6.2%) subjects continued aripiprazole treatment for at 
least 720 days. 
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 with an incidence of more than twice that of 
placebo (8% versus 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 group31. 
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%)33. 

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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 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 elevation40. 
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or 
death, has been reported in patients treated with atypical neuroleptics.  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 neuroleptic 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 neuroleptic 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 neuroleptics included in these 
studies.  Since 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 neuroleptics are not available. 
Elderly patients with dementia-related psychosis treated with atypical neuroleptic 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 (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in 
nature.  Overall, 1.3% of aripiprazole-treated subjects reported cerebrovascular AEs (e.g., stroke, 
transient ischemic attack) compared with 0.6% of placebo-treated subjects in these studies.  This 
difference was not statistically significant; however, in one fixed-dose study, there was a 
significant dose-response relationship for cerebrovascular AEs in patients treated with 
aripiprazole.  Aripiprazole is not approved for the treatment of dementia-related psychosis.  In 
clinical studies and post-marketing experience, accidental or intentional acute overdose of 
aripiprazole alone was reported in adult 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 (i.e., 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 changes in vital signs, 
laboratory assessments, or ECGs.  Additional information can be obtained from the ABILIFY US® 
package insert. 

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7.5 
STUDY RATIONALE 
Aripiprazole once monthly is particularly well suited to a large simple trial because monthly 
administration more closely mirrors clinical practice.  We hypothesize that treatment with 
aripiprazole once monthly will have significantly greater effectiveness than treatment as usual 
(TAU) based on time to hospitalization due to increased medication adherence and compliance. 
The proposed study will also test the hypothesis that better antipsychotic medication compliance 
using aripiprazole once monthly will be associated with less severe progression of neuroanatomic 
deficits over the course of illness in schizophrenia.  Ultimately, the identification of in vivo 
biomarkers, such as change in brain structure volumes or cortical thickness, that reflect these 
processes could help clarify mechanisms of action for effective treatment intervention. 
In addition, we believe that treatment with aripiprazole once monthly will have significantly 
greater effectiveness than TAU due to increased medication adherence and compliance in the 
following: 
• Reducing total number of days in hospital during the 2 years of follow-up 
• Reducing psychopathology than TAU 
• Significantly lower cost of care than TAU 
• Improve cognitive functioning and quality of life 
We believe that LAIs are grossly under used in much of the world and should be the TAU standard 
for patients receiving antipsychotics.  The current design directly addresses the question if a 
clinician has a patient on oral medication should they keep that patient on their ongoing oral regime 
or switch to an LAI?  The answer to this question could change current clinical practice. 
Regarding the risk of deterioration, in the 52-week, placebo-controlled trial of aripiprazole once 
monthly41, there was a 3% "lack of efficacy" discontinuation rate in the switch to oral aripiprazole 
and a 2% "lack of efficacy" discontinuation rate in the switch from oral to aripiprazole once 
monthly.  We believe that the 3% discontinuation rate is relevant to the present discussion, whereas 
the 2% discontinuation rate is an inevitable part of the process of switching to the LAI formulation 
of the same drug. 
In this study (i.e., COL.AOM.2013.005), we will employ training for all LAI sites on the proper 
process for switching from oral medications to LAIs using a two-stage model that 1) facilitates 
engagement and development of a therapeutic alliance, followed by 2) completion of enrollment 
in the study and administration of LAI aripiprazole.  This model has been used successfully in 
prior trials and is designed to provide information regarding the possibilities and potential value 
of LAI treatment7. 
In the Stroup et al. study42, patients with schizophrenia or schizoaffective disorder with a body 
mass index (BMI) ≥ 27 and non-high-density lipoprotein (HDL) cholesterol ≥ 130 mg/dl who were 
on a stable treatment dosage of olanzapine, quetiapine, or risperidone were randomly assigned to 
switch to aripiprazole (N = 109) for 24 weeks or stay on their current medication (N = 106).  

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Patients had a mean PANSS total score of 66.0 ± 16.3 and a mean CGI-S score of 4.0 ± 0.9.  
Twenty-two (20.6%) of the patients who switched and 18 (17.0%) of the patients who stayed on 
their medication experienced protocol-defined efficacy failure.  Although overall more patients in 
the switch versus stay arm discontinued the study prematurely (43.9% versus 24.5%), it is 
important to note that there was no significant difference in time to efficacy failure (i.e., hazard 
ratio for switching = 0.747; 95% confidence interval = 0.395 – 1.413, p = 0.3703).  There were 
also no differences between groups in psychopathology changes as measured by the PANSS total 
score, change in CGI-S score, or change in the Medical Outcomes Study 12-Item Short-Form 
Health Survey mental health scores. 
In a 16-week, double-blind study, 173 subjects with schizophrenia or schizoaffective disorder who 
were previously treated with olanzapine were randomly assigned to switch to aripiprazole (n = 88) 
or stay on olanzapine (n = 85)43.  Primary and secondary endpoints were mean weight change from 
baseline and percentage change from baseline in fasting triglyceride levels, respectively.  Patients 
must have been on olanzapine monotherapy for 1 to 24 months, have a BMI of at least 24 and a 
CGI-S score of ≤ 4 (i.e., moderately ill, mean = 3.0 ± 0.9) to be included in the study.  In this study, 
56 (63.6%) of the 88 patients who switched to oral aripiprazole and 63 (74.1%) of 85 patients who 
stayed on their previous olanzapine treatment completed the 16-week study.  This was a difference 
of 9.5% when switching from one of the most antihistaminergic and anticholinergic 
second-generation antipsychotics.  Specifically, discontinuations in the switch arm from 
olanzapine to aripiprazole and in the stay arm on olanzapine were 8% and 9% for intolerability 
and 8% versus 0% for inefficacy, respectively. 
Although there were some increased rates of discontinuation in the switch arm compared with the 
stay arm in both studies reviewed above, the differences were not large.  Moreover, in our opinion, 
this risk would be even lower in first-episode and EP patients, as they tend to be more responsive 
to medications in general and less likely to deteriorate when switched from one drug to another.  
This argument is further supported by the lack of a difference in efficacy between antipsychotics 
in first-episode schizophrenia, including even clozapine as a comparator44,45. 
In addition, for stable EP patients, there is no ethically acceptable rationale to require a change in 
medication from one oral formulation to another, unless there are side effects or clinical symptoms 
justifying such a change.  Parenthetically, a switch due to intolerability or inefficacy may very well 
be an outcome in the naturalistic oral antipsychotic comparison group during the duration of the 
trial, so that at the end the two groups will not be as polarized as 100% switch versus 0% switch. 
On the other hand, the change from oral to an LAI is ethically justifiable, as we are hypothesizing 
that for stable patients this will lead to a better long-term outcome.  If we required all patients to 
be appropriate for a medication change, based on lack of efficacy or intolerability, this would limit 
an already precious sample to a degree that would make the study impossible to do.  Moreover, as 
suggested above, the thrust of this study of using LAI formulations as a preemptive and preventive 
step in all patients who can be expected to relapse as time goes on would be undermined. 

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8 
STUDY OBJECTIVES 
8.1 
PRIMARY OBJECTIVE 
The primary objective of the study is: 
• To determine the effectiveness of treatment with aripiprazole once monthly compared 
with TAU as defined by time to first hospitalization. 
8.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to: 
• Determine the effect of treatment with aripiprazole once monthly compared with TAU 
on brain structure volumes and white matter integrity over the 2-year study duration 
• Determine the effectiveness of treatment with aripiprazole once monthly compared 
with TAU on clinical outcomes beyond time to first hospitalization.  The outcomes are: 
o Reducing the number of days in the hospital during 2 years of follow-up 
o Reducing the time to all episodes of psychiatric hospitalization in subjects with 
schizophrenia 
o Reducing psychopathology 
o Lowering cost of care 
o Improving neuropsychological functioning 

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9 
INVESTIGATIONAL PLAN 
9.1 
OVERALL STUDY DESIGN AND PLAN 
This is a cluster randomized, two-arm, rater-blind, multi-center, parallel-group study designed to 
compare the effectiveness and changes in brain structure volumes of aripiprazole once monthly 
compared with TAU in subjects with first-episode and EP schizophrenia. 
Approximately 40 sites will participate in the study in order to enroll an estimated 500 subjects 
with schizophrenia over a 1 year recruitment period to recruit an expected 0.5 to 1 subject with 
first-episode schizophrenia and 0.5 to 1 subject with EP schizophrenia per month, allowing for an 
anticipated 250 subjects in the first episode cohort and 250 subjects in the EP cohort.  Ongoing 
evaluation of the numbers of subjects for each cohort will continue until target enrollment is 
reached.  Enrollment of subjects into the first-episode and EP cohort will be discontinued when 
the appropriate number for the target is reached. 
Randomization will occur by site, with half of the sites assigned to the LAI aripiprazole once 
monthly and half of the sites assigned to TAU medications.  Prior to randomization, one screening 
visit will occur over approximately 1 week.  After providing written informed consent, subjects 
will be screened for general eligibility by the clinical team at the site.  Basic demographic data will 
be collected to determine suitability for inclusion into the study and to account for subjects 
screened, but not included in the study.  The site will complete an information interview 
comprising of data regarding symptomology and history to enable the remote centralized 
assessment team to conduct their assessments.  After screening, two baseline visits will occur at 
no more than 4 weeks apart to confirm the diagnosis of schizophrenia, evaluate psychopathology, 
collect demographic information, record baseline histories, take study measurements, collect blood 
samples for PK and clinical safety laboratory testing, and for the LAI sites only, determine 
tolerability to aripiprazole.  For the LAI sites, the first dose of oral aripiprazole will be given at the 
first baseline visit after the diagnosis of first-episode or EP schizophrenia is confirmed.  Once the 
clinical team determines tolerability to oral aripiprazole at the second baseline visit, the first dose 
of aripiprazole once monthly will be administered and the subjects will next be seen at the 
Month 1 Visit (i.e., medication visit) of the treatment phase.  Aripiprazole once monthly will be 
prescribed and administered according to recommendations contained in its respective product 
labeling.  Subjects at the TAU sites will attend both baseline visits while continuing on their TAU 
medications. 
Following the baseline visits and once tolerability has been established, subjects at the LAI sites 
will be scheduled for medication visits once monthly for aripiprazole once monthly injections and 
subjects at the TAU sites will be scheduled for medication visits as required based on their TAU 
medications at a minimum of every 3 months.  All subjects will receive bimonthly phone calls 
inquiring about any visits to emergency rooms and hospitalizations for completion of the 
Hospitalization and Emergency Room Visit Form (HEC).  All subjects will receive phone calls 
every 4 months to complete the Service Utilization and Resources Form (SURF).  The calls will 
be conducted by the local site research assistant or study coordinator and are not linked to 
participation in treatment.  All subjects are required to attend an in-person visit every 6 months 
(i.e., 6, 12, 18, and 24 months) during the 2-year study duration for the completion of the HEC and 
the SURF, to take study measurements, and collect blood samples for clinical safety laboratory 

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testing.  Measurements of psychopathology using the Brief Psychiatric Rating Scale (BPRS), 
CGI-S, and the Heinrichs-Carpenter Quality of Life Scale (QLS) will be completed at the 12- and 
24-month visits only.  Measurement of neuropsychological function using the Repeatable Battery 
for the Assessment of Neuropsychological Status (RBANS) will be completed at the 12- and 
24-month visits only.  Subjects who prefer in-person visits at a time when a telephone visit is 
scheduled may request them at any time. 
Because subjects with schizophrenia have an estimated 8.5-fold greater risk of suicide than the 
general population, with young patients particularly at risk, subjects in this study will be monitored 
closely for suicidality, at each study visit.  Instances of suicidality will be captured using an 
expanded SAE form, and potential for suicidality will be monitored using the Columbia Suicide 
Severity Rating Scale (C-SSRS) at every annual (i.e., 12 and 24 months) in-person visit and at any 
other appropriate time, per the investigator’s judgment. 
In addition, a subset of 114 first-episode and EP subjects at approximately 10 clinical sites will 
undergo MRI at the baseline, 12- and 24-month visits to measure brain structure volumes and 
white matter integrity.  The MRI sites (i.e., five TAU and five LAI) will be selected based on close 
proximity to centers with research MRI capabilities.  The first 57 subjects at both the TAU and 
LAI sites consenting to MRI will be enrolled into the MRI portion of the study. 
An overview of the study design is provided in Figure 1. 

Collaborative Protocol COL.AOM.2013.005 
 
Figure 1: 
Study Schematic 
 
Screening 
Visita 
Baseline Visits 
Treatment 
1 
2 
 
Informed consent 
Eligibility 
AE = adverse event, BPRS = Brief Psychiatric Rating Scale, CGI-S = Clinical Global Impression–Severity, DSM-5 = Diagnostic and Statistical Manual, Fifth Edition, 
LAI = long-acting injectable, MRI = magnetic resonance imaging, QLS = Heinrichs-Carpenter Quality of Life Scale, RBANS = Repeatable Battery for the Assessment of 
Neuropsychological Status, SCID-5 = Structured Clinical Interview for DSM-5 Disorders, TAU = treatment as usual 
a:  Sites are randomized to either LAI or TAU.  Subjects will not be randomized; study-drug allocation is determined by the site at which they enter the study 
b:  Adverse events will be elicited and recorded at the 6-, 12-, 18-, and 24-month visits.  Spontaneous reports will be recorded and assessed when the site is notified, per 
the AE reporting section.  Serious AEs will be reported as outlined in Section 9.5.5. 
If continuing 
eligibility is 
confirmed 
proceed to 
Baseline Visits 
1 and 2 and if 
applicable, 
schedule MRI 
40 sites 
(10 for MRI 
subjects) 
Eligibility 
remote 
assessments: 
SCID-5, 
BPRS, CGI-S, 
QLS 
LAI sites begin 
assessment of 
tolerability to 
oral 
aripiprazole 
TAU sites, 
continue TAU 
On-site and 
telephone visits: 
Once monthly for 
LAI sites 
As appropriate for 
TAU sites, but 
every 3 months at 
a minimum;  
Required at 
Months 6, 12, 
and 18 
MRI (for the MRI 
subset) and 
RBANS at 
12 months 
End of Study & 
Early Terminationb 
Month 24 Visit or at 
time of study 
termination 
Eligible 
subjects 
Screen failures and 
ineligible subjects will be 
dropped and documented 
Ineligible 
subjects 
Approximately 1 to 2 weeks, or up to 4 weeks 
2 years 
Baseline 2 
assessments: 
TAU sites, 
continue TAU 
LAI sites 
continue to 
assess 
tolerability or 
administer 
aripiprazole 
once monthly 
MRI for MRI 
subset 
subjects 
Baseline 1a 
Baseline 2b 
Screening and Enrollment 
Treatmentb 

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9.1.1 
Screening and Baseline Visits 
All recruitment methods will conform to the guidelines of the IRB at the clinical site.  The subjects 
participating in this study must be capable of understanding the nature of this study.  The ICF 
contains a full description of the procedures and their associated risks.  Subjects will be given both 
verbal and written descriptions of the procedures, discomforts, risks, and potential benefits by 
study personnel.  After a briefing on the reasons for the research, their rights as a subject, and the 
risks involved, the subjects will be given the opportunity to ask questions.  Subjects will be asked 
to paraphrase the ICF.  Subjects will also complete a written study review questionnaire that covers 
key aspects of the study (e.g., the ability to withdraw at any time).  When ready, and after having 
satisfactorily answered all questions on the study review questionnaire indicating understanding 
of the study procedures, subjects will be asked to give written consent to participate in the study.  
After both the subject and the investigator sign the ICF, each subject will be given a copy of the 
signed ICF.  The investigator will have full responsibility for addressing all issues pertaining to 
informed consent.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.1. 
Eligibility for the study will be determined over a series of screening and baseline visits.  During 
the Screening Visit, the following procedures will be completed according to Table 3: 
• Review of the inclusion and exclusion criteria 
• Preliminary demographic information 
• An information interview will be conducted comprising data regarding symptomology and 
history to enable the remote centralized assessment team to conduct their assessments 
During Baseline Visit 1, the following assessments will be performed remotely: 
• Structured Clinical Interview for Diagnostic and Statistical Manual, Fifth Edition (DSM-5) 
Disorders (SCID-5) 
• BPRS 
• CGI-S 
• C-SSRS 
• QLS 
• Premorbid Adjustment Scale 
A urine pregnancy test will be performed on all women of childbearing potential during Baseline 
Visit 1.  In addition, a subset of 114 first-episode and EP subjects at approximately 10 clinical sites 
(i.e., five LAI sites [n = 57 subjects] and five TAU sites [n = 57 subjects]) will be scheduled to 
undergo MRI at the baseline, 12-, and 24-month visits to measure brain structure volumes and 
white matter integrity.  The MRI sites will be selected based on close proximity to centers with 
research MRI capabilities.  The first 57 subjects at both the TAU and LAI sites consenting to MRI 

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will be enrolled into the MRI portion of the study.  The MRI can be completed at any time 
following completion of the Baseline Visit 1 assessments, but no later than at Baseline Visit 2. 
Once the diagnosis of first-episode or EP schizophrenia is confirmed at Baseline Visit 1, subjects 
at the LAI sites who are not already taking oral aripiprazole once monthly will be given oral 
aripiprazole and will be assessed for tolerability to oral aripiprazole.  Visits will occur weekly until 
the clinician determines tolerability.  Tolerability will be based upon the clinical judgment of the 
research prescriber.  Subjects who do not tolerate aripiprazole based upon clinical judgment will 
discontinue aripiprazole treatment and be given clinician choice treatment and continue study 
outcome assessments.  Subjects at the LAI sites who enter the study currently taking aripiprazole 
once monthly will be continued on their clinically appropriate aripiprazole once monthly schedule, 
if the subject is tolerating aripiprazole once monthly. 
The Baseline Visit 2 will be scheduled a maximum of 1 month following the Baseline Visit 1.  
During Baseline Visit 2, complete demographic data and medical and psychiatric histories will be 
recorded.  The SURF, HEC form, medication visit record, and the RBANS will be completed.  
Body weight, height, and blood pressure will be measured and BMI will be calculated. 
Current medications will be reviewed and recorded.  Previous medications taken within 7 days 
prior to starting study drug and all central nervous system-active compounds taken within 30 days 
preceding the first dose of study drug will be recorded.  Concomitant medications including details 
(e.g., drug name, dose, and frequency) of all current antipsychotic medication(s) and any 
antipsychotic medications taken within 30 days of screening will be recorded. 
Blood samples for clinical laboratory tests will be obtained.  All attempts should be made to obtain 
blood samples at the same time of day for each visit.  Subjects should come to the clinic after an 
overnight fast of ≥ 10 hours; however if they are not fasting, samples will be collected and the 
subject will be reminded to fast for the next visit.  Non-fasting samples will be recorded as such in 
the source documents and CRFs. 
All Baseline Visit 2 assessments must occur within 4 weeks of Baseline Visit 1.  Baseline Visit 2 
will be considered completed when all assessments have been performed. 
The initial aripiprazole injection will be given at some point after the Baseline Visit 1 once 
tolerability to oral aripiprazole is established.  Future injections of aripiprazole will still be 
administered monthly; however, the injections may not coincide with the scheduled monthly visits. 
9.1.2 
Randomization 
Randomization will be by site rather than by individual subject and will be stratified by relevant 
sociodemographic variables to assure appropriate representativeness.  Randomization at the 
40 sites will be stratified by 1) urban versus non-urban treatment setting and 2) ethnic composition 
of the population served by the site.  All sites will provide detailed information about the ethnic 
composition of their patient population prior to randomization.  Sites will be randomized in a 
1:1 ratio to either the LAI treatment (i.e., aripiprazole once monthly) or TAU.  Each subject 
enrolled at the site will receive the type of treatment (i.e., either aripiprazole once monthly or TAU) 
allocated for that site. 

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This will be a rater-blind study.  The investigator and the subjects will not be blinded to study 
treatment; however, the remote assessment team responsible for conducting the SCID-5, BPRS, 
QLS, Premorbid Adjustment Scale, and CGI-S will be blinded to study treatment. 
9.1.3 
Treatment 
9.1.3.1 
Overall 
• Aripiprazole once monthly, administered via gluteal or deltoid IM injection, at a starting 
dose based on the investigator’s judgment and in accordance with product labeling. 
• Oral antipsychotic medications taken per oral (PO) including, but not limited to: 
○ aripiprazole (Abilify®) 
○ risperidone (Risperdal®) 
○ lurasidone HCl (Latuda®) 
○ quetiapine fumarate (Seroquel®) 
○ olanzapine (Zyprexa®) 
○ ziprasidone HCl (Geodon®) 
• LAI antipsychotic medications including, but not limited to: 
○ risperidone (Risperdal® Consta®) 
○ haloperidal decanoate (Haldol® decanoate) 
○ olanzapine (Zyprexa® Relprevv™) 
○ paliperidone palmitate (Invega® Sustenna®) 
○ fluphenazine decanoate (Prolixin® decanoate) 
For LAI subjects who were not taking aripiprazole once monthly at study entry, the first dose of 
aripiprazole once monthly will be administered once tolerability to oral aripiprazole is established.  
In addition, these subjects allocated to aripiprazole once monthly will continue to receive oral 
aripiprazole for 14 days following the first injection.  Those subjects allocated to TAU will 
continue with their TAU medications. 
Subjects at LAI sites who do not agree to an injection of aripiprazole once monthly when 
tolerability is established will be continued in the study.  These subjects will be given continued 
education about aripiprazole once monthly and given the opportunity to start aripiprazole once 
monthly later in the study. 

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Sites that are randomly assigned to administer aripiprazole once monthly will receive training on 
proper switching to aripiprazole and LAI processes using a two-stage model that 1) facilitates 
engagement and development of a therapeutic alliance, followed by 2) completion of enrollment 
in the study and administration of LAI aripiprazole.  This model has been used successfully in 
prior trials and is designed to provide information regarding the possibilities and potential value 
of LAI treatment7.  Sites allocated to LAI will be instructed on appropriate methods for 
administering the injection, and standard follow-up for the site should be used to remind the 
subjects to return for their monthly injections. 
9.1.3.1.1 2-year Treatment Period 
During the 2-year Treatment Period, assessments will be performed according to Table 3 and 
Table 4 at regularly scheduled intervals.  For the LAI group, monthly visits are mandatory for 
aripiprazole once monthly injections.  For the TAU group, visits will be conducted in a 
combination of telephone and clinic visits, dependent on their particular treatment modality and if 
applicable, their preference, at any time for attending visits at the clinic versus a telephone visit. 
For all groups, attendance at the clinic is required at the 6-, 12-, and 18-month time points for 
clinical laboratory testing and measurements of body weight, waist circumference, temperature, 
pulse, and blood pressure.  Remote assessments of BPRS, CGI-S, RBANS, QLS, and C-SSRS will 
occur at the 12- and 24-month visit.  All subjects are required to attend the final visit, which occurs 
at the 24-Month Visit.  Adverse events will be elicited and recorded at the 6-, 12-, 18-, and 
24-month visits.  Spontaneous reports will be recorded and assessed when the site is notified, per 
the AE reporting section.  Serious AEs will be reported as outlined in Section 9.5.5. 
In addition, MRI will occur at the 12- and 24-month visits for those subjects in the subset who are 
participating in the imaging portion of the study. 
9.1.4 
Final Visit – Month 24 and Early Termination 
All subjects who complete the study are required to attend this final study visit.  In addition, any 
subject that is discontinued from the study for any reason should have the final visit (i.e., 
Month 24) procedures completed if possible.  Procedures to be completed will be performed 
according to Table 4 and include clinical laboratory testing; measurements of body weight, waist 
circumference, temperature, pulse , and blood pressure; and remote BPRS, CGI-S, QLS, and 
C-SSRS assessments. 
9.1.5 
Follow-up Period 
All subjects who receive at least one dose of study drug and who are discontinued from the study 
for any reason, including completion, will be followed for safety reasons for approximately 
30 days following the last dose of study drug.  At 30 (± 3) days, each subject will be contacted by 
telephone or will attend a visit at the clinic for safety follow-up. 
9.2 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL GROUPS 
Non-adherence remains an enormous challenge in schizophrenia.  Long-acting injectable 
antipsychotics have been shown in some mirror image, naturalistic, and RCTs to significantly 

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reduce rates of relapse and rehospitalization in comparison with oral antipsychotics.  However, the 
most recent meta-analysis1 of RCTs did not show an overall advantage.  The proposed large simple 
trial is designed to address the limitations of conventional RCTs that compare LAI and oral 
antipsychotics.  Cluster (i.e., site) randomization is utilized to eliminate bias in perceived subject 
preference; subjects either consent to the study treatment at that site or continue with their care as 
usual at the clinic and are not enrolled in the study.  Sites randomized to TAU will not see the 
study subjects at a frequency typical to a conventional RCT.  Assessments will be infrequent, 
occurring every 6 months.  Given that investigators will not be blinded to treatment, centralized 
ratings have been incorporated into the study to allow for blinded assessment of psychopathology 
outcomes.  In addition, the subjects eligible for the study are those who are early in the course of 
the illness, and for whom prior data suggest that early intervention provides potential for a higher 
likelihood of improved outcome6-10. 
Twenty-four patients with first-episode psychosis underwent resting state functional MRI (fMRI) 
scanning and symptom ratings while acutely psychotic and after 12 weeks of treatment with either 
risperidone or aripiprazole.  In addition, baseline and follow-up resting state fMRI exams were 
obtained in 24 age-, sex-, and handedness-matched controls.  Antipsychotic treatment resulted in 
a significant reduction in positive symptoms, as measured by the Thought Disturbance factor of 
the BPRS.  We present data on resting-state connectivity based on seeds, defined by the 
Harvard-Oxford Structural Atlas, placed in the caudate (i.e., dorsal striatum [DS]) and nucleus 
accumbens (i.e., ventral striatum [VS]).  Consistent with prior literature41, our healthy volunteers 
demonstrated strong correlations between DS and dorsal prefrontal cortex, including both lateral 
and medial aspects, and between VS and ventral prefrontal cortex (i.e., primarily medial).  
Importantly, upon re-scanning after 12 weeks, healthy subjects showed no significant longitudinal 
changes in functional interactions of DS or VS.  As symptoms improved in patients, both of the 
striatal structures showed an increase in correlative activity within the prefrontal cortex in the 
“normal” dorso-ventral pattern (Figure 2).  Specifically, DS showed an increase in functional 
connectivity in a region within the dorsolateral prefrontal cortex as positive symptoms improved.  
Similarly, as positive symptoms improved, functional connectivity of VS was increased to a region 
within the ventral prefrontal cortex.  Overall, these results suggest that “frontalization” and 
normalization of frontostriatal connections may underlie the successful treatment of psychosis. 
 
Figure 2: 
Functional Connectivity Correlations 
Note:  all activations are thresholded at p < 0.005) in the imaging photo; in the scatter plot r2 = 0.41 

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Based on these data, fMRI scanning is an appropriate measure to evaluate progression of 
neuroanatomic deficits and evaluate the utility of biomarkers, such as brain structure volumes and 
cortical thickness, as mechanisms of action for effective treatment intervention. 
Randomization will be used in this study to avoid bias in the assignment of subjects to treatment. 
9.3 
SELECTION OF STUDY POPULATION 
Approximately 500 subjects will be enrolled at approximately 40 sites.  Subjects who do not meet 
all of the inclusion criteria or who meet any of the exclusion criteria will not be eligible to receive 
study drug.  Subjects will be selected by approaching all eligible patients at the participating 
clinics.  The inclusion criteria are as broad as possible within an EP population. 
9.3.1 
Inclusion Criteria 
Subjects must meet the following inclusion criteria to be eligible for the study: 
1. Are able to provide written informed consent 
2. Have a confirmed diagnosis of schizophrenia as defined by DSM-5 criteria using the 
SCID-5 
3. Are between the ages of 18 and 35, inclusive 
4. Have the following history with antipsychotic medications 
a. First-episode subjects:  < 1 year of lifetime exposure to antipsychotic medication and 
only one episode of psychosis 
b. EP subjects:  between 1 year and 5 years of lifetime exposure to antipsychotic 
medication or subjects with < 1 year of lifetime antipsychotic medication and more 
than one episode of psychosis 
5. Subjects at LAI sites must be willing to accept an injectable form of treatment 
9.3.2 
Exclusion Criteria 
Subjects must not have any of the following criteria to be eligible for the study: 
1. Have a current primary DSM-5 diagnosis other than schizophrenia, including 
schizophreniform disorder, schizoaffective disorder, major depressive disorder, bipolar 
disorder, delirium, dementia, and amnestic or other cognitive disorders 
2. Subjects at LAI sites:  have a known allergy or intolerance to aripiprazole, or a past 
negative response to aripiprazole that is not explained by nonadherence 
3. Be pregnant or lactating 

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4. Have any unstable medical condition that, in the opinion of the investigator, would be 
detrimental to the subject or would confound the results of the study 
5. Past or current treatment with clozapine 
6. Subjects in the MRI subset only who have: 
a. Received an LAI antipsychotic in the last 6 months 
b. Any metal implants, pacemakers, irremovable prosthetic devices, or other devices or 
situations that may preclude imaging 
9.3.3 
Removal of Subjects from Therapy or Assessment 
9.3.3.1 
Entire Study or Treatment Arms 
If the investigator terminates or suspends the study for safety or unanticipated other reasons, 
prompt notification will be given to Otsuka America Pharmaceutical, Inc. (OAPI), IRBs, and 
regulatory authorities in accordance with regulatory requirements. 
9.3.3.2 
Individual Center 
The investigator will notify OAPI promptly if the investigator or the IRB at the site terminates the 
study. 
9.3.3.3 
Individual Subject 
If a subject discontinues from the study prematurely, the reason must be fully evaluated and 
recorded appropriately in source documents and the CRF.  If the subject is being withdrawn 
because of an AE, that AE should be indicated as the reason for withdrawal. 
An increase in suicidal ideation or homicidal ideation will result in withdrawal from the study, 
based on the investigator’s discretion. 
All subjects have the right to withdraw at any point during treatment without prejudice.  The 
investigator can discontinue a subject’s participation in the study at any time if medically 
necessary.  In addition, subjects meeting any of the following criteria must be withdrawn from the 
study: 
1. Occurrence of any AE, intercurrent illness or abnormality in a laboratory assessment that, 
in the opinion of the investigator, warrants the subject’s permanent withdrawal from the 
study 
2. Subject noncompliance, defined as refusal or inability to adhere to the study schedule or 
procedures per the investigator’s discretion 
3. At the request of the subject, investigator, OAPI or designee, or regulatory authority 
4. Subject becomes pregnant 

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5. Subject is lost to follow-up 
The investigator will notify OAPI promptly when a subject is withdrawn. 
9.4 
TREATMENTS 
The investigator will purchase or be supplied with the aripiprazole study drugs.  Medication at the 
TAU sites will be prescribed based upon usual site practices.  In order not to influence or restrict 
which medications are prescribed at TAU sites, medications for TAU subjects will not be supplied 
by the study.  Reimbursement for medications at TAU sites will be by usual mechanisms (e.g., 
private or public insurance). 
9.4.1 
Treatments Administered 
Aripiprazole once monthly will be prescribed and administered according to recommendations 
contained in their respective product labeling.  
The following treatments will be administered to subjects in this study: 
• Aripiprazole once monthly administered via gluteal or deltoid IM injection. 
• TAU oral antipsychotic medications administered PO including, but not limited to: 
o aripiprazole (Abilify®) 
o risperidone (Risperdal®) 
o lurasidone HCl (Latuda®) 
o quietapine fumarate (Seroquel®) 
o olanzapine (Zyprexa®) 
o ziprasidone HCl (Geodon®) 
• LAI antipsychotic medications administered IM including, but not limited to: 
o risperidone (Risperdal® Consta®) 
o haloperidal decanoate (Haldol® decanoate) 
o olanzapine (Zyprexa® Relprevv™) 
o paliperidone palmitate (Invega® Sustenna®) 
o fluphenazine decanoate (Proloxin® decanoate) 

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9.4.1.1 
Dosage Adjustments for Missed Doses of Aripiprazole Once Monthly 
If the second or third doses are missed: 
• If > 4 weeks and < 5 weeks have elapsed since the last injection, administer the injection 
as soon as possible 
• If > 5 weeks have elapsed since the last injection, restart concomitant oral aripiprazole for 
14 days with the next administered injection 
If the fourth or subsequent doses are missed: 
• If > 4 weeks and < 6 weeks have elapsed since the last injection, administer the injection 
as soon as possible 
• If > 6 weeks have elapsed since the last injection, restart concomitant oral aripiprazole for 
14 days with the next administered injection 
9.4.2 
Identity and Storage of Investigational Product(s) 
Study drugs can be stored at the clinical site as long as the medication is kept in a securely locked 
cabinet in an area with a minimum/maximum thermometer that constantly monitors temperature.  
All study drug will be kept according to the storage instructions on the product labeling.  Access 
will be limited to the investigators and their designees.  Neither investigators nor any designees 
may provide study drugs to any subject not participating in this protocol. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
A total of 500 subjects are planned to be enrolled in the study at approximately 40 sites.  
Randomization within the group of 40 US sites will be balanced by 1) urban versus non-urban 
treatment setting and 2) ethnic composition of the population served by the site.  Sites will be 
randomized in a 1:1 ratio to either the LAI treatment (i.e., aripiprazole once monthly) or TAU.  
Each subject enrolled at the site will receive the type of treatment (i.e., either aripiprazole once 
monthly or TAU) allocated for that site. 
9.4.4 
Blinding 
This is a rater-blind study.  The investigator and the subjects will not be blinded to study treatment; 
however, the remote assessment team responsible for conducting the SCID-5, BPRS, CGI-S, and 
QLS will be blinded to study treatment. 
9.4.5 
Treatment Compliance 
No formal measures of compliance will be performed. 

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9.4.6 
Accountability 
Study drug will not be prescribed or administered until the investigator has provided the following 
documentation to OAPI: 
• A copy of the final signed and dated protocol signature page 
• Written proof of approval of the protocol, the ICFs, and any other information provided to 
the subjects by the IRB for the institution where the study is to be conducted 
• A copy of the IRB-approved ICF and any other documentation provided to the subjects to 
be used in this study 
• A signed and dated clinical studies agreement 
The investigator and the study staff will be responsible for the accountability of all study drugs 
(i.e., dispensing, inventory, and record keeping), and following and adhering to GCP guidelines as 
well as local or regional requirements. 
Under no circumstances will the investigator allow the study drugs to be used other than as directed 
by this protocol.  Study drugs will not be dispensed to any individual who is not enrolled in the 
study. 
The investigator, or designee, must maintain an inventory record of all study drugs (including 
study drug, active control, or placebo) received, dispensed, administered, and returned. 
The study drugs and inventory records must be made available, upon request, for inspection by a 
designated representative of OAPI or a representative of a health authority (e.g., FDA).  As 
applicable, all unused study drugs are to be returned to the investigator by the subject. 
9.5 
STUDY ASSESSMENTS 
9.5.1 
Assessments 
9.5.1.1 
Demographics 
Subject demographic information will be collected at the Screening Visit.  Demographic 
information includes date of birth, age, sex, and race or ethnicity.  Study-specific demographic 
information will be collected at the Baseline 2 Visit. 
9.5.1.2 
Screening and Baseline Assessments 
MEDICAL HISTORY 
Medical history, surgical history, and current medical conditions will be recorded at the 
Baseline 2 Visit.  All relevant medical and surgical history within 10 years must be noted in the 
CRF. 

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PSYCHIATRIC HISTORY 
A review of the subject’s psychiatric history will be performed, including lifetime use of 
antipsychotic medications, at the Baseline 2 Visit. 
STRUCTURED CLINICAL INTERVIEW FOR DSM DISORDERS 
Study diagnoses will be established using the SCID-5 interview.  The SCID-5 is a semi-structured 
interview for making the major DSM-5 Axis I diagnoses.  The instrument is designed to be 
administered by a clinician or trained mental health professional.  The SCID-5 is broken down into 
separate modules corresponding to categories of diagnoses.  Most sections begin with an entry 
question that would allow the interviewer to "skip" the associated questions if not met.  For all 
diagnoses symptoms are coded as present, subthreshold, or absent. 
The SCID-5 will be administered remotely at the Baseline 1 Visit only. 
INFORMATION INTERVIEW 
An information interview will be conducted for each subject at each site to record symptomology 
and history to enable the remote team to conduct their assessments.  This interview will be 
conducted during screening. 
9.5.1.3 
Safety Assessments 
Safety will be assessed by AE reporting, clinical laboratory tests (i.e., hematology and fasting 
clinical chemistry), and vital signs.  In addition, body weight, BMI, and serum prolactin 
concentrations will be monitored. 
9.5.1.3.1 Clinical Laboratory Tests 
The local laboratory will be used for all laboratory testing required during the study.  Reports from 
the laboratory should be filed with the source documents for each subject.  Samples will be 
obtained at the visits designated in Table 3 and Table 4, and as far as possible, samples should be 
drawn at the same time of day at each visit. 
Additional samples may be collected for further evaluation of safety as warranted by the 
investigator’s discretion.  Subjects should be fasting for a minimum of 10 hours prior to blood 
draws for assessment of safety, including screening.  Fasting samples should be collected 
whenever possible; however, if they are not fasting, samples will be collected and the subject will 
be reminded to fast for the next visit.  Non-fasting samples will be recorded as such in the source 
documents and CRFs. 
Standard clinical laboratory tests will be performed if clinically indicated.  Clinical laboratory tests 
that may be performed during the study are provided in Table 2. 

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Table 2: 
Safety Clinical Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count with differential 
Fasting Serum Chemistry: 
Alanine transaminase 
Alkaline phosphatase 
Aspartate transaminase 
Bilirubin, total 
Blood urea nitrogen 
Calcium 
Cholesterol (total, LDL, and HDL), triglycerides 
Creatinine 
Fasting lipid profile 
Gamma glutamyl transferase 
Glucose 
Glycosylated hemoglobin (HbA1c) 
Lactate dehydrogenase 
Potassium 
Protein, total 
Sodium 
Additional Tests: 
Fasting insulin 
Serum prolactin 
Urinalysis with microscopic analysisa 
Urine β-hCGb for women of child-bearing potential 
β-hCG = beta-human chorionic gonadotropin, HDL = high-density lipoprotein, LDL = low-density lipoprotein 
a:  Sample for urinalysis will be collected and analyzed when clinically indicated. 
b:  Serum β-hCG will be performed if the urine pregnancy test is positive or if the subject or investigator suspects that 
the subject may be pregnant. 
9.5.1.3.2 Blood Pressure 
Blood pressure measurements (i.e., systolic and diastolic blood pressure [mmHg]) will be obtained 
at the visits designated on the Schedules of Assessments (Table 3 and Table 4) by a validated 
method.  Blood pressure will be measured after the subject has been sitting for 5 minutes and then 
standing after 3 minutes, but no longer than 5 minutes.  All blood pressure measurements should 
be performed on the same arm, preferably by the same person. 
9.5.1.4 
Adverse Events and Other Events of Interest 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal relationship 
with the study drug.  For this study, the study drugs are aripiprazole once monthly and any other 
antipsychotic treatment. 
The criteria for identifying AEs are: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product 
• Any new disease or exacerbation of an existing disease 
• Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (e.g., ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug 

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• Recurrence of an intermittent medical condition (e.g., headache) not present pretreatment 
(i.e., baseline) 
• An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or not 
A laboratory result should be considered by the investigator to be an AE if it: 
• Results in the withdrawal of study drug 
• Results in withholding of study drug pending some investigational outcome 
• Results in an intervention, based on medical evaluation (e.g., potassium supplement for 
hypokalemia) 
• Results in any out of range laboratory value that in the investigator’s judgment fulfills the 
definitions of an AE with regard to the subject’s medical profile 
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of relationship 
to study drug or procedure, should be collected beginning from the time the subject signs the study 
ICF through the last visit.  Serious AEs will be collected for 30 days after the last dose or at the 
Follow-up Visit, whichever comes later. 
Abnormal laboratory values should not be listed as separate AEs if they are considered part of the 
clinical syndrome that is being reported as an AE.  Any laboratory abnormality considered to 
constitute an AE should be reported as an AE on the CRF. 
It is the responsibility of the investigator to review all laboratory findings in all subjects and 
determine if they constitute an AE.  Medical and scientific judgment should be exercised in 
deciding whether an isolated laboratory abnormality should be classified as an AE. 
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects and 
determine if any result constitutes an AE.  Medical and scientific judgment should be exercised in 
deciding whether an isolated suicidality rating scale response should be classified as an AE (see 
Other Safety Assessments [Section 9.5.1.6] for a description of the C-SSRS). 
Every effort must be made by the investigator to categorize each AE according to its severity and 
its relationship to the study treatment. 
ASSESSING SEVERITY OF ADVERSE EVENTS 
AEs will be graded on a 3-point scale (i.e., mild, moderate, and severe) and reported in detail as 
indicated on the CRF.  The definitions are as follows: 
Mild: 
Discomfort noticed, but no disruption of normal daily activity 
Moderate: 
Discomfort sufficient to reduce or affect normal daily activity 

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Severe: 
Incapacitating, with inability to work or to perform normal daily activity 
The criteria for assessing severity are different than those used for seriousness (see Serious 
Adverse Events and Other Events of Interest [Section 9.5.1.5] for the definition of an SAE). 
The causal relationship of the study drug to an AE will be assessed as related or unrelated, as 
follows: 
Related: 
Definite: 
There is a reasonable causal relationship between the study drug and the AE, 
when the event responds to withdrawal of the study drug (i.e., dechallenge), 
and recurs with rechallenge by administration of the study drug. 
Probable: 
There is a reasonable causal relationship between the study drug and the AE.  
The event responds to dechallenge.  Rechallenge is not required. 
Possible: 
There is a reasonable causal relationship between the study drug and the AE.  
Dechallenge is lacking or unclear. 
Unrelated: 
Not Likely: 
There is a temporal relationship to study drug administration, but not a 
reasonable causal relationship between the study drug and the event. 
Not Related: 
There is not a temporal or causal relationship to the study drug 
administration. 
9.5.1.5 
Serious Adverse Events and Other Events of Interest 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (i.e., the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or was 
allowed to continue, might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect in the child of a subject who was exposed to the 
study drug 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization but, when based on appropriate medical judgment, may jeopardize the subject or 
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should also be considered SAEs.  Medical and scientific judgment should be exercised in deciding 
whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest include pregnancy or exposure to study drug 
through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or medication 
error; and any treatment-emergent significant laboratory abnormality.  These events of interest are 
to be captured using the SAE procedures but are to be considered SAEs only if they meet one of 
the above criteria.  All AEs associated with events of interest are to be reported on the CRF whether 
or not they meet the criteria for SAEs. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
• Hospitalizations for respite care 
• Hospitalization planned before informed consent where the condition requiring the 
hospitalization has not changed post-study drug administration 
• Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
9.5.1.6 
Other Safety Assessments 
9.5.1.6.1 Body Weight, Body Mass Index, Height 
An assessment for potential of prolactin-related effects will be performed via measurement of body 
weight (kg), height (m, for determination of BMI), and determination of BMI. 
The calculation for BMI is: 
weight (kg) 
[height (m)]2 
 
9.5.1.6.2  
Prior and Concomitant Therapies 
Prior and concomitant therapies will be collected via self-report using the SURF.  The SURF 
Medication Visit Record is a standardized form on which the medication name, dose, and regimen 
are recorded for prescribed medications. 
9.5.1.6.3 Suicidality 
All subjects will be treated as usual in the clinic for any suspected suicidality or suicidal ideation, 
irrespective of study involvement.  For the purposes of the study, in these cases, suicidality 
information will be collected on the SAE form, and a clinical intervention assessment of risk will 
be performed per the PI’s judgment. 
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COLUMBIA SUICIDE SEVERITY RATING SCALE 
The C-SSRS was designed to distinguish the domains of suicidal ideation and suicidal behavior.  
The baseline C-SSRS form will be completed at baseline of Phase 1.  Later C-SSRS assessments 
will be completed at 1 year and 2 years. 
Four constructs are measured: 
1. The severity of ideation (i.e., the “severity subscale”) is rated on a 5-point ordinal scale 
with 1 = wish to be dead, 2 = nonspecific active suicidal thoughts, 3 = suicidal thoughts 
with methods, 4 = suicidal intent, and 5 = suicidal intent with plan. 
2. The intensity of ideation subscale (i.e., the “intensity subscale”) rates frequency, duration, 
controllability, deterrents, and reason for ideation on a 5-point ordinal scale. 
3. The behavior subscale rates actual, aborted, and interrupted attempts; preparatory behavior; 
and non-suicidal self-injurious behavior on a nominal scale. 
4. The lethality subscale assesses actual attempts; actual lethality is rated on a 6-point ordinal 
scale, and if actual lethality is 0, potential lethality of attempts is rated on a 3-point ordinal 
scale. 
9.5.1.6.4 Pregnancy Test 
Before enrolling women of childbearing potential in this clinical study, investigators must review 
guidelines about study participation for women of childbearing potential.  The topics should 
generally include: 
• General information 
• ICF 
• Pregnancy prevention information 
• Drug interactions with hormonal contraceptives 
• Contraceptives in current use 
• Guidelines for the follow-up of a reported pregnancy 
Prior to study enrollment, women of childbearing potential must be advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy.  Specifically, investigators will review with subjects all applicable information about 
pregnancy and lactation in the FDA-approved prescribing information for medications in the 
protocol.  The subject must sign an ICF stating that the above-mentioned risk factors and the 
consequences were discussed with her. 

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9.5.1.7 
Efficacy Assessments 
9.5.1.7.1 Hospitalization and Emergency Room Visit Form 
The HEC form is a subject interview form in which the subject is asked to answer a “yes” or “no” 
question regarding each one of nine settings pertaining to inpatient, emergency room, and crisis 
stabilization treatment.  If the subject answers “yes” to any of the questions, additional information 
regarding the “yes” answer is elicited.  The questions are: 
Did you spend any nights in the following treatment settings:  1) medical program, 2) surgical 
program, 3) psychiatric program, 4) substance use program, 5) nursing home, 6) halfway house 
or staffed residence, 7) emergency room for medical reason, 8) emergency room for psychiatric 
or substance abuse reason, and 9) crisis stabilization for psychiatric or substance abuse reason. 
For “yes” answers, the total number of times and the total number of nights are recorded.  In 
addition, continuing for inpatient care, and the longest duration of the emergency room stay and 
overnight stay status is also recorded. 
9.5.1.7.2 Clinical Global Impression–Severity 
The severity of illness for each subject will be rated using the CGI-S scale.  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. 
9.5.1.7.3 
Brief Psychiatric Rating Scale 
The BPRS is a rating scale that a clinician or researcher may use to measure psychiatric symptoms 
such as depression, anxiety, hallucinations, and unusual behavior.  Each symptom is rated 1 (not 
present) to 7 (extremely severe).  A zero is entered if the item is not assessed. 
9.5.1.8 
Other Assessments – Neuropsychiatric Function 
PREMORBID ADJUSTMENT SCALE 
The Premorbid Adjustment Scale is a rating scale designed to evaluate the degree of achievement 
of developmental goals at each of several periods of a subject's life before the onset of 
schizophrenia.  The Premorbid Adjustment Scale has been found to be useful in identifying 
patients likely to become chronically hospitalized or at high risk for readmission.  
The scale is divided into a general scale and four developmental age periods: 
1. Childhood to age 11 years old 
2. Early adolescence to age 15 years old 

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3. Late adolescence to age 18 years old 
4. Adulthood 
Rating items in childhood, early adolescence, and late adolescence include sociability and social 
withdrawal, peer relationships, scholastic performance, adaption to school, and ability to form 
socio-sexual relationships.  Rating items in adulthood include social relationships, educational 
achievement, and level of interest and enjoyment of major life activities. 
REPEATABLE BATTERY FOR THE ASSESSMENT OF NEUROPSYCHOLOGICAL STATUS 
The RBANS is a brief neurocognitive battery with four alternate forms that measures immediate 
and delayed memory, attention, language, and visuospatial skills.  It is broadly used for clinical 
diagnostic purposes and is increasingly employed as an endpoint in clinical trials of medications 
that may have an impact on neurocognitive status.  The RBANS was developed for two primary 
applications: 
1. As a stand-alone “core” battery for the detection and neurocognitive characterization of 
dementia. 
2. As a brief neurocognitive battery for the detection and tracking of neurocognitive deficits 
in a variety of disorders. 
The RBANS consists of ten subtests that give five scores, one for each of the five domains tested 
(i.e., immediate memory, visuospatial/constructional, language, attention, and delayed memory).  
The RBANS requires approximately 25 minutes to administer, and is a “pencil-and-paper” test, 
with only a stimulus booklet and record form needed for administration and scoring. 
SERVICE UTILIZATION AND RESOURCES FORM 
The SURF questionnaire is comprised of seven domains with 49 questions.  The domains are: 
• Work 
• General Health 
• Outpatient Mental Health Visits 
• Use of Outpatient Medical/Surgical Treatment Services 
• Substance Use 
• Justice System Contacts 
• Insurance Coverage 
All questions in the SURF refer to the 30 days prior to the date of the interview.  The subjects are 
asked questions with either “yes” or “no” answers, a rating scale to circle all that apply, or 

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requesting specific information (e.g., hours worked or total earnings), depending on the domain 
and the information in question. 
9.5.1.9 
Other Assessments – Quality of Life 
HEINRICHS-CARPENTER QUALITY OF LIFE SCALE 
The QLS is a 21-item semi-structured interview designed to be used by trained interviewers to 
assess functioning based on the subject’s self-report and the interviewer’s judgment based on all 
available information.  The QLS combines subjective reports and objective data, and raters are 
instructed to weight their assessment more heavily than the subject’s self-assessment.  The QLS 
assesses four domains:  1) interpersonal relations, 2) instrumental role functioning, 3)  intrapsychic 
foundations (i.e., cognitive-emotional functioning), and 4) common objects and activities (i.e., 
extent of involvement with routine daily life activities).  Each item is rated on a 0 to 6 Likert-type 
scale with a higher score indicating a higher level of functioning.  The QLS has become the 
standard instrument for assessing change in quality of life in clinical trials and, based on our 
preliminary work, provides an optimal balance between subjective and objective perspectives. 
9.5.2 
Pharmacodynamic Assessments 
The dependent measures will include volumes of brain structure (e.g., gray matter, white matter, 
and subcortical regions), white matter integrity assessed using diffusion tensor imaging, and 
indices of fMRI task-based and resting state activity. 
To accomplish scanner stability, each site will purchase and employ the Magphan® Quantitative 
Imaging Phantom, commonly known as the ADNI phantom (http://www.phantomlab.com/ 
products/magphan_adni.php). 
9.5.2.1 
Structural and Diffusion Tensor Imaging 
Each exam will include acquisition of structural images, including a sagittal localizer and 
high-resolution T1-weighted sequence.  In addition, we will collect diffusion-weighted, spin-echo 
echo planar imaging (EPI) scans, and a reference T2-weighted image.  Functional imaging will 
utilize a gradient echo, EPI sequence sensitive to the blood-oxygen-level-dependent signal, 
acquired along the anterior/posterior commissure.  A field map will be collected to control for 
distortions in the EPI images. 
9.5.2.2 
Resting State fMRI Acquisition 
Resting state fMRI will be collected in the absence of task demands and subjects will be instructed 
to keep their eyes open.   This permits the assessment of functional connectivity while the subjects 
are at rest.  

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9.5.2.3 
MRI Assessments 
EDINBURGH HANDEDNESS INVENTORY 
The Edinburgh Handedness Inventory is a scale used to assess the dominance of a person's right 
or left hand in everyday activities.  The inventory will be completed by the patients self-reporting 
hand use.  The inventory will be completed only at the Baseline 2 Visit. 
MRI FORM 
The MRI form will capture patient date of birth, gender, summary of the Edinburgh Handedness 
Inventory, medications taken the day of the scan, and any substances use 24 hours prior to the 
scan. 
9.5.3 
Schedules of Assessments 
The Schedule of Assessments for screening, baseline, and Year 1 of the study is provided in 
Table 3. 
The Schedule of Assessments for Year 2 of the study is provided in Table 4. 

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Table 3: 
Schedule of Assessments Year 1 
Procedure 
Screening 
Baseline Visits 
Visits 1 and 2j 
Month (each visit ± 3 days)k 
~ 1 week 
Up to 4 weeks 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
On-site Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility and demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information interview 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Psychiatric History 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Current medication 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SURF 
 
 
X 
 
 
 
P 
 
 
 
P 
 
 
 
X 
HEC Form 
 
 
X 
 
P 
 
P 
 
X 
 
P 
 
P 
 
X 
Clinical laboratory testinga 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Urine pregnancy testingb 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Body weight, height, BMI, waist 
circumference, temperature, pulse 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Blood pressurec 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
RBANS 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
MRId 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Edinburgh Handedness Inventoryd 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Formd 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Oral aripiprazolee 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Tolerabilityf 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
LAI injectione 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Visit Recordg 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEsh 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Remote Assessmentsl 
SCID-5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BPRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CGI-S 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
C-SSRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Heinrichs-Carpenter QLS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Premorbid Adjustment Scalei 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 

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AE = adverse event, BMI = body mass index, BPRS = Brief Psychiatric Rating Scale, CBC = complete blood count, CGI-S = Clinical Global Impression-Severity, 
C-SSRS = Columbia Suicide Severity Rating Scale, HbA1c = glycosylated hemoglobin, HDL = high-density lipoprotein, HEC = Hospitalization and Emergency Room Visit, 
LAI = long-acting injectable, LDL = low-density lipoprotein, MRI = magnetic resonance imaging, P = phone visit, QLS = Heinrichs-Carpenter Quality of Life Scale, 
RBANS = Repeatable Battery for the Assessment of Neuropsychological Status, SCID-5 = Structured Clinical Interview for DSM-5 Disorders, SURF = Service Utilization and 
Resources Form, TAU = treatment as usual, X = clinic visit 
a:  Clinical laboratory testing includes a fasting lipid panel (i.e., cholesterol:  total, HDL, LDL, and triglycerides), metabolic profile, prolactin and fasting insulin concentrations, 
HbA1c, and a CBC with differential.  Samples for urinalysis tests will be collected and analyzed as clinically indicated. 
b:  Urine pregnancy test for women of childbearing potential only.  If a subject or investigator suspects that the subject may be pregnant, a serum pregnancy test should be 
performed. 
c:  Blood pressure will be measured sitting after 5 minutes, and then standing after 3 minutes. 
d:  For the MRI subset of subjects only. 
e:  At the LAI sites only.  Oral aripiprazole will continue for 14 days after the first aripiprazole once monthly injections. 
f:  The initial aripiprazole injection will be given at some point after the Baseline Visit 1 once tolerability to oral aripiprazole is established.  Future injections of aripiprazole will 
still be administered monthly; however, the injections may not coincide with the scheduled monthly visits. 
g:  The Medication Visit Record will be completed monthly at the LAI sites and whenever a medication visit occurs at the TAU sites. 
h: Adverse events will be elicited and recorded at the 6-, 12-, 18-, and 24-month visits.  Spontaneous reports will be recorded and assessed when the site is notified, per the AE 
reporting section.  Serious AEs will be reported as outlined in Section 9.5.5. 
i:  The Premorbid Adjustment Scale will be administered at Baseline Visit 1 or Baseline Visit 2 for those clients who have a family member or support. 
j:  All Baseline Visit 2 assessments must occur within 4 weeks of Baseline Visit 1.  Baseline Visit 2 will be considered completed when all assessments have been performed. 
k:  Visit windows are for data management purposes only.  Subjects will not be discontinued if visit windows are not adhered to. 
l:  Remote assessments will be conducted by a centralized assessment team from Vanguard Research Group, while the subject is at the clinic. 
 
 
 

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Table 4: 
Schedule of Assessments Year 2 
Procedure 
Month (each visit ± 3 days)h 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24i 
30-day Follow-up 
On-site Assessments 
SURF 
 
 
 
P 
 
 
 
P 
 
 
 
X 
 
HEC Form 
 
P 
 
P 
 
X 
 
P 
 
P 
 
X 
 
Clinical laboratory testinga 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Body weight, height, BMI  
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Blood pressureb 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Urine pregnancy testingc 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
RBANS 
 
 
 
 
 
 
 
 
 
 
 
X 
 
MRId 
 
 
 
 
 
 
 
 
 
 
 
X 
 
MRI Formd 
 
 
 
 
 
 
 
 
 
 
 
X 
 
LAI injectione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medication Visit Recordf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEsg 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Remote Assessmentsj 
BPRS 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CGI-S 
 
 
 
 
 
 
 
 
 
 
 
X 
 
C SSRS 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Heinrichs-Carpenter QLS 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Telephone call 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE = adverse event, BMI = body mass index, BPRS = Brief Psychiatric Rating Scale, CBC = complete blood count, CGI-S = Clinical Global Impression–Severity, C-SSRS = Columbia 
Suicide Severity Rating Scale, HbA1c = glycosylated hemoglobin, HDL = high-density lipoprotein, HEC = Hospitalization and Emergency Room Visit, LAI = long-acting injectable, 
LDL = low-density lipoprotein, MRI = magnetic resonance imaging, P = phone visit, QLS = Heinrichs-Carpenter Quality of Life Scale, RBANS = Repeatable Battery for the Assessment 
of Neuropsychological Status, SURF = Service Utilization and Resources Form, TAU = treatment as usual, X = clinical visit 
a:  Clinical laboratory testing includes a fasting lipid panel (i.e., cholesterol:  total, HDL, LDL, and triglycerides), a metabolic profile, prolactin and fasting insulin concentrations, HbA1c, 
and a CBC with differential.  Samples for urinalysis tests will be collected and analyzed as clinically indicated. 
b:  Blood pressure will be measured after sitting for 5 minutes, and then standing for 3 minutes. 
c:  Urine pregnancy test for women of childbearing potential only.  If a subject or investigator suspects that the subject may be pregnant, a serum pregnancy test should be performed. 
d:  For the MRI subset of subjects only. 
e:  At the LAI sites only. 
f:  The Medication Visit Record will be completed monthly at the LAI sites and whenever a medication visit occurs at the TAU sites. 
g:  Adverse events will be elicited and recorded at the 6-, 12-, 18-, and 24-month visits.  Spontaneous reports will be recorded and assessed when the site is notified, per the AE reporting 
section.  Serious AEs will be reported as outlined in Section 9.5.5. 
h:  Visit windows are for data management purposes only.  Subjects will not be discontinued if visit windows are not adhered to. 
i:  Subjects who terminate early from the study will be asked to complete the Month 24 assessments. 
j:  Remote assessments will be conducted by a centralized assessment team from the Vanguard Research Group, while the subject is in the clinic. 

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9.5.4 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of schizophrenia. 
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, and assessment of AEs, are standard evaluations to ensure subject safety. 
9.5.5 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest 
9.5.5.1 
Reporting of Serious Adverse Events 
All SAEs, regardless of their relationship to study treatment, must be reported to the PI’s study 
manager on a completed SAE form by email or fax as soon as possible but no later than 24 hours 
from the date the investigator becomes aware of the event. 
Deaths and life-threatening events should be reported immediately by telephone.  The immediate 
report should be followed up within 24 hours by emailing or faxing the completed SAE form. 
The SAE is reviewed for completeness, and if necessary, queries are issued to the site for additional 
or corrected information.  Once the SAE form is reviewed by the study manager, the site is 
instructed to enter the SAE information into the electronic database. 
Serious adverse events, regardless of causality assessment, must be collected through the last visit.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  Any SAE 
judged by the investigator to be related to the study treatment should be reported to the sponsor, 
regardless of the length of time that has passed since study completion. 
Report immediately reportable events (SAEs, potential Hy’s Law cases, pregnancies, and 
AEs requiring discontinuation of study drug) to: 
Vanguard Research Group 
Fax:  212-913-9850 
e-mail:  cgomes@nshs.edu 
Tel:  347-804-3605 
It is very important that the SAE report form be filled out as completely as possible at the time of 
the initial report.  This includes the investigator’s assessment of causality. 
As updated information becomes available, an updated SAE form is sent from the site to the study 
manager to review for completeness.  Once reviewed, the study manager informs the site and 
instructs them to enter the data into the electronic database. 
The PI will notify the IRB of the occurrence of the SAE, in writing, if the SAE meets the IRB 
reporting criteria. 

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During the study, all women of childbearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
cycle). 
9.5.6 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason without prejudice.  All 
subjects who discontinue the study are to complete the early discontinuation procedures indicated 
in the Schedule of Assessments (Table 4) whenever possible. 
The investigator will promptly explain to the subject involved that the study will be discontinued 
for that subject and provide appropriate medical treatment and other necessary measures for the 
subject.  A subject who has ceased to return for visits will be followed up by mail, phone, or other 
means to gather information, such as the reason for failure to return, the status of treatment 
compliance, the presence or absence of AEs, and clinical courses of signs and symptoms.  This 
information will be recorded in the CRF. 
Subjects who discontinue early from the study will be discontinued for one of these primary 
reasons:  AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, withdrawal of 
consent, pregnancy, study termination, or other (to be specified).  In addition to the primary reason, 
the subject may indicate one or more secondary reasons for discontinuation. 
A subject removed from the study for any reason may be replaced. 
9.5.7 
Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects to inform site personnel when they are planning to receive 
medical care by another physician.  At each visit, the investigator will ask the subject whether he 
or she has received medical care by another physician since the last visit or is planning to do so in 
the future.  When the subject is going to receive medical care by another physician, the 
investigator, with the consent of the subject, will inform the other physician that the subject is 
participating in the clinical study. 
9.6 
DATA QUALITY ASSURANCE 
9.6.1 
Monitoring 
The investigator has ethical, legal, and scientific obligations to follow this study in a detailed and 
orderly manner in accordance with established research principles, the ICH GCP Guideline, FDA 
regulations and applicable regulatory requirements and local laws.  As part of a concerted effort 
to fulfill these obligations (i.e., maintain current personal knowledge of the progress of the study), 
investigator's monitors may visit the site during the study, as well as communicate frequently via 
telephone and written communications. 
9.6.2 
Auditing 
The OAPI Quality Management Unit, or a representative, may conduct study site audits.  Audits 
will include, but are not be limited to, drug supply, presence of required documents, the informed 

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consent process, and comparison of CRFs with source documents.  The investigator agrees to 
participate with audits. 
Regulatory authorities may inspect the investigator during or after the study.  The investigator will 
cooperate with such inspections and will contact the sponsor and OAPI immediately if such an 
inspection occurs. 
9.6.3 
Data Collection 
The study is expected to start on or about 01 December 2014 and be completed on or about 
15 March 2018.  Data collection will begin when the first subject signs the ICF, on approximately 
01 December 2014, and is complete on the date at which the last subject’s data has been entered 
into the database and no data queries are outstanding, on approximately 01 March 2018. 
9.6.3.1 
Cross-site Data Integration 
Data management for the project will be performed by the Nathan Kline Institute for Psychiatric 
Research.  Data are transmitted to the data center through a secure, password-protected web portal.  
Nathan Kline Institute has an up-to-date information system security plan developed under the 
guidance of federal document NIST Special Publication 800-18:  “Guide for Developing Security 
Plans for Federal Information Systems”.  Nathan Kline Institute has also completed a thorough 
security self-assessment, under the guidance of federal document NIST 800-53A:  “Guide for 
Assessing the Security Controls in Federal Information Systems Questionnaire”. 
9.7 
STATISTICAL METHODS 
The investigator or designee will perform all statistical analyses after the study is completed and 
the database is locked and released.  Statistical analyses will be performed using the Statistical 
Analysis System software or other validated statistical software as required.  Details of the 
statistical analyses will be included in a separate statistical analysis plan (SAP).  Unless otherwise 
stated, all hypothesis tests will be performed at a two-sided 0.05 significance level. 
9.7.1 
Statistical Considerations 
The statistical analyses of study data are described in this section.  Additional details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock. 
9.7.1.1 
Primary Endpoint 
The primary endpoint of the study is: 
• Time to the first hospitalization 
9.7.1.2 
Secondary Endpoints 
Secondary endpoints of the study are: 

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• Change from baseline to the 1- year and 2-year time points in gray matter and white matter 
volume, and cortical thickness.  The 2-year time point is the primary time point. 
• Time to all episodes of psychiatric hospitalization, including total times (e.g., time from 
randomization to first, second, or any subsequent hospitalizations) as well as gap times 
(e.g., time between first and second hospitalization, second and third hospitalization, etc.) 
• Total number of days of inpatient psychiatric hospitalization per quarter for each subject 
for the duration of the study 
• Change from baseline in BPRS and CGI-S 
• Cost of care from the SURF 
• Change from baseline in neuropsychological function (i.e., RBANS) 
• Change from baseline in quality of life (i.e., QLS) 
9.7.1.3 
Definitions of Analysis Sets 
The Safety Analysis Set (SAS) is the group of subjects who received at least one dose of study 
drug and had at least one postdose safety assessment. 
The Full Analysis Set (FAS) is the group of randomized subjects who meet all of the inclusion 
criteria and none of the exclusion criteria. 
The Randomized Set is the group of subjects who were randomized. 
The Per Protocol Set is the group of subjects who sufficiently complied with the protocol.  Details 
of the evaluability criteria will be determined before database lock and will be specified in the 
SAP. 
Subjects at LAI sites who do not agree to an injection of aripiprazole once monthly will be 
continued in the study.  These subjects will be given continued education about aripiprazole once 
monthly and given the opportunity to start aripiprazole once monthly later in the study. 
For subgroup analyses of subjects at LAI sites, two groups are being specified prior to the start of 
data analysis.  The tolerated aripiprazole once monthly group consists of LAI site subjects who the 
prescriber deemed as tolerating aripiprazole once monthly after a maximum of 6 weeks of 
initiating treatment with aripiprazole within the study (i.e., tolerability can be declared at times 
earlier than 6 weeks).  The timely initiation of aripiprazole once monthly group consists of LAI 
site subjects who received at least one injection of aripiprazole once monthly within 3 months of 
the prescriber declaring that the subject tolerates aripiprazole. 

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9.7.1.4 
Subject Disposition 
The summary of subject disposition for all enrolled subjects will be provided for the study overall 
and by site.  The summary will include the number of subjects enrolled, completed, and 
discontinued, including the reason for discontinuation. 
9.7.1.5 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the FAS will be summarized for each treatment 
group using descriptive statistics. 
Continuous variables, such as age, will be summarized by N (i.e., sample size), mean, standard 
deviation, minimum, median, and maximum.  Categorical variables, such as sex, will be 
summarized by frequency counts and percentages. 
9.7.1.6 
Prior and Concomitant Therapy 
Medical history and medication history will be summarized.  The use of aripiprazole in the TAU 
group will be accounted for in the SAP. 
9.7.1.7 
Safety Analyses 
All safety analyses will be performed on the SAS.  Safety data, presented by treatment group, will 
be summarized on an “as treated” basis using descriptive statistics (e.g., n, mean, standard 
deviation, median, minimum, and maximum for continuous variables; n [%] for categorical 
variables).  Safety variables, such as TEAEs, clinical laboratory parameters, and vital signs will 
be summarized.  Study Day 1 for all safety analyses will be defined as the date of the first dose of 
study drug. 
9.7.1.7.1 Extent of Exposure 
Treatment exposure will be characterized according to the number of subjects exposed, the 
duration of exposure, and the dose to which they were exposed. 
9.7.1.7.2 Adverse Events 
The AE verbatim descriptions (i.e., investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 15.1 or higher) lower level 
term closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary system 
organ class are also captured in the database. 
A TEAE is defined as an AE that: 
• Emerges during treatment, having been absent at pretreatment (i.e., baseline) 
• Reemerges during treatment, having been present at pretreatment (i.e., baseline) but 
stopped before treatment 

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• Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous 
Only those AEs that were treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
Treatment-emergent AEs will be summarized by treatment group.  The incidence of TEAEs will 
be reported as the number (i.e., percentage) of subjects with TEAEs by system organ class and PT.  
A subject will be counted only once within a system organ class and PT, even if the subject 
experienced more than one TEAE within a specific system organ class and PT.  The number (i.e., 
percentage) of subjects with TEAEs will also be summarized by maximum severity (i.e., mild, 
moderate, or severe). 
The number (i.e., percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (i.e., possibly related, probably related, and not related). 
The number (i.e., percentage) of subjects with treatment-related TEAEs will be summarized by 
system organ class and PT.  Treatment-related TEAEs include those events considered by the 
investigator to be possibly or probably related to study treatment.  The number (i.e., percentage) 
of subjects with treatment-related TEAEs will also be summarized by maximum severity (i.e., 
mild, moderate, or severe). 
Adverse events will be summarized using the SAS.  The number of AEs and number and incidence 
(%) of subjects with AEs will be summarized by cohort or dose and overall.  To obtain the 
incidence (%), the number of subjects with at least one event and the percentage of subjects with 
AEs by system organ class and by PT will be calculated.  Incidence (%) by causal relationship 
with study drug and by severity will also be calculated.  For clinically significant events, time of 
onset and recovery will be reported. 
The number (i.e., percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA system organ class and PT for each treatment group.  A subject data listing of all AEs 
leading to death will be provided. 
The number (i.e., percentage) of subjects with SAEs will be summarized by MedDRA system 
organ class and PT for each treatment group.  A subject data listing of all SAEs will be provided. 
The number (i.e., percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA system organ class and PT for each treatment group.  A subject 
data listing of all AEs leading to discontinuation from study drug will be provided. 
9.7.1.7.3 Laboratory Values 
Laboratory results will be summarized using Système International units, as appropriate.  For all 
quantitative parameters listed in Section 9.5.1.3 Safety Assessments (Laboratory Measurements), 
the actual value and the change from baseline to each postbaseline visit and to the end of treatment 
(i.e., defined as the last on-treatment value) will be summarized by visit and treatment group using 
descriptive statistics.  Qualitative parameters listed in Section 9.5.1.3 will be summarized using 
frequencies (i.e., number and percentage of subjects), and changes from baseline to each 

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postbaseline visit and to end of treatment will be reported.  Percentages will be based on the 
number of subjects with both nonmissing baseline and relevant postbaseline results. 
Laboratory test results will be assigned a low/normal/high classification according to whether the 
value was below, within, or above the laboratory parameter’s reference range. 
9.7.1.7.4 Blood Pressure 
Descriptive statistics for blood pressure parameters (i.e., diastolic and systolic) and changes from 
baseline will be presented by visit and treatment group. 
9.7.1.8 
Efficacy Analyses 
9.7.1.8.1 Primary Efficacy Analysis 
Hazard functions related to the first hospitalization will be analyzed using competing risk (CR) 
modeling strategies proposed by Fine and Gray49.  The proportional hazards regression (PHREG) 
procedure in the Statistical Analysis System software will be utilized for this analysis.  The newly 
available random effects option in the PHREG procedure will be explored to incorporate the 
within-cluster correlations.  We will also consider a recently proposed population average CR 
regression model for clustered data50 using the crrSC package in R.  Percent CIF macro in the 
Statistical Analysis System software will be used to implement Gray’s method51 for testing 
differences of the cumulative incidence functions between the two treatment groups.  The SRATA 
parameter in the %CIF macro will also be used to perform the stratified version of Gray’s test51.  
In the event that a subject dies from causes unrelated to schizophrenia before a hospitalization, the 
death will be considered a competing event instead of a censoring event.  Subjects discontinued 
without an event (i.e., hospitalization) will be censored on the last known day without an event.  
We will also assess for the misspecification of the regression model for the subdistribution hazard 
of a CR using the diagnostic plots recommended by Latouche et al52. 
9.7.1.8.2 Secondary Efficacy Analysis 
Time to hospitalization and days of inpatient hospitalization will be evaluated as part of the 
secondary efficacy analysis using the following: 
• Time to hospitalizations:  Total times (e.g., time from randomization to first, second, or 
any subsequent hospitalizations) as well as gap times (e.g., time between first and second 
hospitalization, second and third hospitalization, etc.) will be considered.  The conditional 
models of Prentice, Williams, and Peterson will be used, with the risk set for the (k + 1)st 
hospitalization restricted to subjects who already had k hospitalizations, to compare the 
total time endpoints between the treatment groups.  For comparison of gap time endpoints, 
a marginal approach proposed by Wei, Lin, and Weissfeld will be used. 
• Days of inpatient psychiatric hospitalization:  The total number of days of inpatient 
psychiatric hospitalization occurring in each quarter (i.e., every 3 months) of the 2-year 
study period will be counted.  This will generate longitudinal measurements with eight 
time points (i.e., corresponding to eight quarters) for each subject. 

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If the subject drops out partially or completely for any quarter, the outcome for that particular 
quarter will be considered a missing value.  The linear mixed effects model with time x group 
interaction will be used to compare the longitudinal trajectories of number of days of psychiatric 
hospitalization every quarter between the two treatment groups. 
Change from baseline or postbaseline assessments in psychopathology (e.g., BPRS and CGI-S), 
cost of care from the SURF, quality of life from the QLS, and change from baseline at the 1-year 
and 2-year time points in neuropsychological functioning (e.g., RBANS) will be analyzed using 
linear contrasts in a mixed model with a nested design (e.g., subjects nested within clusters).  This 
design will take into account the within-cluster correlations as well as within-subject correlations.  
The treatment effects, treatment differences, and the associated 95% confidence intervals will be 
presented. 
9.7.1.8.3 Pharmacodynamic Analyses 
Change from baseline to the 1-year and 2-year time points in gray matter and white matter volume, 
and cortical thickness will be analyzed using linear contrasts in a mixed model with a nested design 
(e.g., subjects nested within clusters).  This design will take into account the within-cluster 
correlations as well as within-subject correlations.  The 2-year time point will be the primary time 
point for this variable. 
9.7.1.8.4 a priori Analyses 
In addition to an intent-to-treat analysis including all FAS subjects, an a priori sensitivity analyses 
of the data will be conducted.  The first will exclude patients who discontinue for any reason during 
the first 2 months after determination of study eligibility.  The second will exclude patients who 
have a psychiatric emergency room visit or a psychiatric inpatient hospitalization during the first 
2 months after determination of study eligibility.  The third will exclude patients who do not meet 
criteria for inclusion into the timely initiation of aripiprazole once monthly group. 
9.7.2 
Determination of Sample Size 
The total number of subjects will be 500.  There will be approximately 250 subjects in the 
aripiprazole once monthly arm and 250 subjects receiving TAU.  Each group will be further 
divided into a first-episode cohort and an EP cohort. 
In a unique 2-year longitudinal epidemiological study of subjects receiving community-based 
treatment in the US for first-episode psychosis, differences among diagnostic groups in the interval 
from first psychotic symptom to hospitalization were analyzed.  The rate of rehospitalization for 
subjects with schizophrenia followed for 2 years after the first psychiatric admission was 53.5%46, 
which was similar to the 53.7% cited by Robinson et al47 in a previous study.  These 
rehospitalization rates are for subjects recruited at the time of first initiating treatment for 
psychosis.  Subjects for the proposed study include subjects who are slightly more advanced in the 
course of their illness.  Therefore, we project a 60% rehospitalization rate for subjects in our TAU 
treatment group.  In addition, a subset of 114 first-episode and EP subjects at approximately 
10 sites will undergo imaging studies during the 2-year study duration.  The sample size 
calculation was based on the formula provided by Fitzmaurice, Laird, and Ware (2004) for a 
longitudinal study.  We assume that changes in neuroanatomic measures can be expressed in terms 

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of a linear trend over time, in years, and that these effects can be expressed as the difference 
between slopes in the treatment conditions (i.e., δ).  We based our analysis on data provided in 
Bartzokis et al20, which reported study standard deviations for the rate of change in neuroanatomic 
measures ranging from 0.66 to 0.98, for an LAI antipsychotic versus oral administration.  For our 
calculations, we assume that the between-subject standard deviation of the slopes is 0.90 and 
within-subject variability to be 2.0.  With these values, we would be able to detect a minimum 
treatment effect δ of 1.25 (effect size = 0.75) with 80% power (alpha = 0.05), with a sample size 
of 28 in each treatment arm at the 2-year follow-up.  Assuming a 30% drop-out rate, the sample 
size needed at baseline would be 57 per group.  Included in the 30% drop-out rate are dropouts for 
the imaging analyses, subjects who drop out of the study completely (i.e., all study procedures), 
and those that drop out of the imaging component only. 
Sample size calculations were done using the formula developed by Latouche et al48 proportional 
hazards modeling of CR.  The proportion of “failures of interest” (i.e., first hospitalization) was 
set at 60% for the TAU arm.  For the sample size calculation, we hypothesized the corresponding 
proportion in the LAI arm to be 30% so that the overall proportion of the patients hospitalized at 
least once, in both treatment arms combined, is 45%.  The minimum detectable subdistribution 
hazard ratio at 80% power and a 5% significance level with 398 subjects equally allocated in the 
two treatment arms is 148.  Accounting for a 20% drop-out from the rehospitalization analyses, the 
corresponding sample will be 498, or 249 per treatment group.  With 400 completed subjects (i.e., 
200 per group), the cause-specific hazard ratio that could be estimated at 80% power and 5% 
significance level was 1.38.  The 1.38 hazard ratio is conventionally considered to be close to a 
small effect size, but it is large enough that it would influence both prescriber decisions about 
individual patients but also crucially health policy makers’ decisions about the advantages of 
treatment with aripiprazole once monthly. 
The numbers of subjects per site and treatment arm are provided in Table 5. 
Table 5: 
Number of Subjects per Site per Treatment Arm 
Treatment Group 
Number of 
sites 
First-
episodea 
EPb 
Total 
Aripiprazole once monthly (LAI) 
20 
125 
125 
250 
TAU 
20 
125 
125 
250 
Total 
40 
250 
250 
500 
EP = early phase, LAI = long-acting injectable, TAU = treatment as usual 
a:  < 1 year of antipsychotic treatment 
b:  between 1 and 5 years of antipsychotic treatment 
 
9.7.3 
Interim Analysis 
No interim analyses are planned. 
9.7.4 
Multiple Comparison Adjustment 
No multiple comparisons are required as there is only one primary endpoint. 

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9.7.4.1 
Data Safety Monitoring Board 
The study will be monitored by a Data Safety Monitoring Board (DSMB) organized by The Zucker 
Hillside Hospital.  The DSMB will independently review the protocol and consent documents, 
AEs, and outcome data as needed, for the proposed study.  The DSMB will evaluate issues related 
to subject safety and the adequacy and integrity of accumulated data.  The DSMB will meet once 
per year to review the study.  Data reports will be prepared by the central coordinating team and 
the data management center to support the work of the DSMB. 
The data coordinating center will create tables for the DSMB to review every 6 months.  The tables 
will include enrollment, demographic information by treatment arm, abnormal laboratory results, 
SAEs, and missing data.  After each annual meeting, the DSMB will issue a memo documenting 
any action items for the team.  Copies will be provided to OAPI upon request. 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the SAP requires revision after the study starts, the investigator will determine how the revision 
affects the study and how the revision should be implemented.  The details of the revision will be 
documented and described in the clinical study report.  Any changes to the SAP will be sent to the 
DSMB for review. 

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10 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS 
10.1 
CHANGES TO THE PROTOCOL 
Any change to the protocol requires a written protocol amendment or administrative change that 
must be approved by the investigator and OAPI before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the study 
require submission to health or regulatory authorities as well as additional approval by the 
applicable IRBs and the DSMB.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, in the interest of preserving the safety of all subjects 
included in the study.  If the investigator determines that an immediate change to or deviation from 
the protocol is necessary for safety reasons to eliminate an immediate hazard to the subjects, OAPI 
and the IRB for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB, but the health or regulatory authority and 
IRB should be kept informed of such changes, as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB detailing such changes. 
10.2 
ADHERENCE TO THE PROTOCOL 
The investigator will conduct the study in strict accordance with the protocol (refer to ICH E6, 
Section 4.5). 
10.3 
MONITORING PROCEDURES 
The investigator will assure appropriate monitoring of the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The CRFs and 
subject’s corresponding original medical records (i.e., source documents) are to be fully available 
for review by the PI’s representatives at regular intervals.  These reviews verify adherence to study 
protocol and data accuracy in accordance with local regulations.  All records at the site are subject 
to inspection by the local auditing agency and IRB review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to the 
following: 
• Clinic, office, or hospital charts 
• Copies or transcribed health care provider notes that have been certified for accuracy after 
production 
• Recorded data from automated instruments, such as Interactive Voice and Web Response 
System, x-rays, and other imaging reports, (e.g., sonograms, computed tomography scans, 
MRIs, 
radioactive 
images, 
ECGs, 
rhythm 
strips, 
electroencephalographies, 
polysomnographs, and pulmonary function tests) regardless of how these images are 
stored, including microfiche and photographic negatives 

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• Pain, quality of life, or medical history questionnaires completed by subjects 
• Records of telephone contacts 
• Diaries or evaluation checklists 
• Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• Laboratory results and other laboratory test outputs (e.g., urine pregnancy test result 
documentation and urine dip-sticks) 
• Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs 
• CRF components (e.g., questionnaires) that are completed directly by subjects and serve 
as their own source 
10.4 
RECORDING OF DATA 
A CRF is required and must be completed for each subject by qualified and authorized personnel.  
All data on the CRF must reflect the corresponding source document, except when a section of the 
CRF itself is used as the source document.  Any correction to entries made on the CRF must be 
documented in a valid audit trail where the correction is dated, the individual making the correction 
is identified, the reason for the change is stated, and the original data are not obscured.  Only data 
required by the protocol for the purposes of the study should be collected. 
The investigator must sign each CRF. 
10.5 
IDENTIFICATION OF SOURCE DATA 
All data to be recorded on the CRF must reflect the corresponding source documents. 
10.6 
RETENTION OF RECORDS 
The circumstances of completion or termination of the study notwithstanding, the investigator is 
responsible for retaining all study documents including, but not limited to the protocol, copies of 
CRFs, the IB, and regulatory agency registration documents (e.g., Form FDA 1572, ICFs, and IRB 
correspondence).  The site should plan to retain study documents for the length of time agreed 
upon in the study contract. 
It is requested that at the completion of the required retention period, or should the investigator 
retire or relocate, the investigator contact OAPI, allowing OAPI the option of permanently 
retaining the study records. 

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10.7 
REPORTING OF PRODUCT QUALITY COMPLAINTS 
A product quality complaint (PQC) is any written, electronic, or verbal communication by a 
healthcare professional, consumer, subject, medical representative, Competent Authority, 
regulatory agency, partner, affiliate, or other third party that alleges deficiencies or dissatisfaction 
related to identity, quality, labeling, packaging, reliability, safety, durability, tampering, 
counterfeiting, theft, effectiveness, or performance of a drug product or medical device after it is 
released for distribution.  Examples include, but are not limited to, communications involving: 
• Failure/malfunction of a product to meet any of its specifications 
• Incorrect or missing labeling 
• Packaging issues (e.g., damaged, dirty, crushed, missing product) 
• Blister defects (e.g., missing or empty blisters) 
• Bottle defects (e.g., underfill, overfill, no safety seal) 
• Vial defects 
• Product defect (e.g., odor, chipped, broken, embossing illegible) 
• Loss or theft of product 
10.7.1 
Information Required for Reporting Purposes 
All of the following information should be included when reporting a PQC: 
• Description of the complaint(s) 
• Reporting party identification (initial reporting party, e.g., subject, investigator, study 
coordinator) 
• Reporter contact information (e.g., address, telephone number, e-mail address) 
• Product or compound identification; include any product codes if applicable 
• Clinical protocol reference (e.g., collaborative protocol number and title) 
• Dosage form and strength, if known 
• Photographs if available 
• Availability for return 

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10.7.2 
Eliciting and Reporting Quality Complaints 
The investigator or designee must record all PQCs identified through any means from the receipt 
of study drug through and including reconciliation and up to destruction, including subject dosing.  
Identification of a PQC by a subject should be reported to the site investigator, who should report 
the PQC. 
The investigator or designee must notify OAPI Ethics, Quality, and Compliance (EQC) within 
24 hours of becoming aware of the PQC by e-mail or telephone: 
• Online – send the required information to OAPI-EQC ProductComplaints@otsuka-us.com 
• Telephone – Rocky Mountain Call Center – 1-800-438-9927 
10.7.3 
Return Process 
During the PQC reporting process, indicate if the sample under complaint is available for return.  
If the sample is available for return, OAPI-EQC will provide a product retrieval package.  Return 
the sample in the product retrieval package. 
Documentation in the site source documents that a complaint sample for a dispensed product was 
forwarded to OAPI-EQC for complaint investigation. 
Assessment and evaluation of PQCs will be handled by the OAPI-EQC Quality Management 
Group. 
10.8 
DISCONTINUATION OF STUDY 
OAPI reserves the right to discontinue the study for medical reasons or any other reason at any 
time.  If a study is terminated or suspended prematurely, OAPI will promptly inform the 
investigators or institutions and the investigator will inform the regulatory authorities of the 
termination or suspension and the reason(s) for the termination or suspension.  The IRB will also 
be informed promptly and provided the reason(s) for the termination or suspension by the 
investigator or institution, as specified by the applicable regulatory requirement(s). 
The investigator reserves the right to discontinue the study should his or her judgment so dictate.  
If the investigator terminates or suspends a study without prior agreement of OAPI, the investigator 
should inform the institution where applicable, and the investigator or institution should promptly 
inform OAPI and the IRB and provide OAPI and the IRB with a detailed written explanation of 
the termination or suspension.  Study records must be retained as noted above. 

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11 
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45. Lieberman JA, Phillips M, Gu H, Stroup S, Zhang P, Kong L, et al:  Atypical and 
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12 
APPENDICES 
Appendix 1: SIGNATURE PAGE 
Study Protocol Number: 
COL.AOM.2013.005 
Study Protocol Title: 
A Cluster Randomized, Multi-center, Parallel-group, Rater-blind 
Study Comparing Treatment with Aripiprazole Once Monthly and 
Treatment as Usual on Effectiveness in First-Episode and Early 
Phase Illness in Schizophrenia 
Investigational Product 
Name: 
Abilify Maintena®, aripiprazole 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
Feinstein Institute for Medical Research 
Medical Institution 
 
John M. Kane, MD 
  
  
Investigator 
 Signature 
 Date