Conditions: Schizophrenia
Keywords: MRI Imaging Antipsychotic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: yes

Brief summary:
This is a Phase 4, randomized, open-label, parallel group study designed to assess the clinical and biological effects of 12 months of treatment with long acting intramuscular (IM) aripiprazole (Abilify®) as measured by clinical and behavioral measures, and changes on magnetic resonance imaging (MRI) scans in subjects with schizophrenia compared with SOC oral antipsychotic medications and compared with a healthy control group.

Detailed description:
This is a Phase 4, randomized, open-label, parallel group study designed to assess the clinical and biological effects of 12 months of treatment with long acting intramuscular (IM) aripiprazole (Abilify®) as measured by clinical and behavioral measures, and changes on magnetic resonance imaging (MRI) scans in subjects with schizophrenia compared with SOC oral antipsychotic medications and compared with a healthy control group.

It is hypothesized that improved treatment compliance will lead to fewer white matter changes in the brain. Fewer white matter changes will be demonstrated via neuroimaging as increased FA and BPF values in the prefrontal region, and an increase in metabolites in a voxel centered on the anterior cingulate cortex (ACC) as seen with MRS. Therefore, the aim of this study is to examine the structural and metabolic effects of aripiprazole (Abilify®) once monthly in patients with schizophrenia using MRI techniques and to examine these effects in association with cognitive and clinical measures.

Arms:
arm 1: Healthy individuals with no mental health diagnosis arm 2: Individuals with a diagnosis of Schizophrenia undergoing standard of care treatments. arm 3: Individuals with Schizophrenia who are receiving treatment with Aripiprazole once monthly injections.

Interventions: intervention 1: Standard of Care Oral antipsychotics intervention 2: IM aripiprazole once monthly intervention 3: No Treatment
Intervention descriptions: intervention 1: A total of 15 to 20 subjects with schizophrenia will receive SOC oral antipsychotic medications (e.g., aripiprazole (Abilify®), risperidone (Risperdal®), lurasidone HCI (Latuda®), quetiapine fumarate (Seroquel®), olanzapine (Zyprexa®), and ziprasidone HCI(Geodon®)) or once monthly aripiprazole (Abilify®), PO daily, in accordance with their respective product labeling. intervention 2: A total of 30 to 40 subjects with schizophrenia will receive aripiprazole (Abilify®) monthly, at a starting dose of 400 mg IM or an approved dose based on the investigator's judgment and in accordance with product labeling. intervention 3: A total of 15 healthy controls will participate in the study and will not receive medication

Protocol document:
Prot_SAP_000.pdf: 
Protocol  COL.AOM.2013.002 
 
Page 1 of 76 
Final Protocol: 29 July 2013 
1 
TITLE PAGE 
ARIPIPRAZOLE, ABILIFY MAINTENA™ 
CLINICAL PROTOCOL 
A Randomized, Open-Label, Parallel-Group, Study of the Impact of Aripiprazole Once 
Monthly versus Standard of Care Oral Antipsychotic Medications on Changes in 
Brain Structure and Metabolism 
 
Protocol No. COL.AOM.2013.002 
G-Port No.  
CONFIDENTIAL – PROPRIETARY INFORMATION 
Drug Development Phase: 
4 
 
 
Principal Investigator: 
Deborah Yurgelun-Todd, PhD 
Professor of Psychiatry 
Director of Imaging 
The Brain Institute 
Phone:  801-587-1538 
 
 
 
Otsuka Contact: 
Susan N. Legacy, MD 
Associate Director - CNS Medical Affairs 
Otsuka America Pharmaceuticals, Inc. 
Phone:  609-249-6597  
Fax:  609-249-0597 
 
 
Immediately Reportable Event 
Clinical Safety and Pharmacovigilance 
Otsuka Pharmaceutical Development & 
Commercialization, Inc. 
Khaled Bannout, MD 
Phone:  240-683-3115 
Fax:  301-721-7115 
 
 
Issue Date: 
29 July 2013 
 
 


Protocol  COL.AOM.2013.002 
 
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Final Protocol: 29 July 2013 
2 
CLINICAL PROTOCOL SYNOPSIS 
Name of Sponsor:  The Brain Institute 
Name of Product:  Abilify Maintena™, aripiprazole 
Protocol Title: 
A Randomized, Open-Label, Parallel-Group, Study of the Impact of 
Aripiprazole Once Monthly versus Standard of Care Oral Antipsychotic 
Medications on Changes in Brain Structure and Metabolism 
Clinical Phase: 
4 
Treatment Indication:  
Schizophrenia 
Objectives: 
The primary objective of the study is: 
• 
To determine if there are differences in prefrontal white matter 
fractional anisotrophy (FA) in subjects with schizophrenia after 
6 and 12 months of treatment with aripiprazole once monthly 
compared with standard of care (SOC) oral antipsychotic 
medications.  
The secondary objectives of the study are: 
• 
To determine if there are differences in water bound pool fraction 
(BPF) in prefrontal white matter in subjects with schizophrenia 
after 6 and 12 months of treatment with aripiprazole once monthly 
as compared with SOC oral antipsychotic medications. 
• 
To determine if proton metabolites, specifically 
gamma-aminobutyric acid (GABA), glutamine, and glutamate, are 
altered in subjects with schizophrenia after 6 and 12 months of 
treatment with aripiprazole once monthly compared with SOC oral 
antipsychotic medications. 
• 
To determine if there are differences in regional white matter and 
gray matter volume in subjects with schizophrenia after 6 and 
12 months of treatment with aripiprazole once monthly compared 
with SOC oral antipsychotic medications. 
• 
To determine the effect on clinical and behavioral assessments 
after 12 months with aripiprazole once monthly compared with 
SOC oral antipsychotic medications in subjects with 
schizophrenia. 
The exploratory objective of the study is: 
• 
To determine if there is a demonstrated association between 
clinical and neurocognitive variables and FA, BPF, and proton 
metabolite concentrations in subjects with schizophrenia receiving 
SOC oral antipsychotic medications or once monthly aripiprazole. 


Protocol  COL.AOM.2013.002 
 
Page 3 of 76 
Final Protocol: 29 July 2013 
Name of Sponsor:  The Brain Institute 
Name of Product:  Abilify Maintena™, aripiprazole 
Study Design: 
This is a Phase 4, randomized, open-label, parallel-group study designed to 
assess the clinical and biological effects of 12 months of treatment with 
long-acting intramuscular (IM) aripiprazole as measured by clinical and 
behavioral measures, and changes on magnetic resonance imaging (MRI) 
scans in subjects with schizophrenia compared with SOC oral antipsychotic 
medications and compared with a healthy control group.  A total of 
80 subjects are planned to be enrolled in the study in a 3:1 subjects with 
schizophrenia:control ratio, to allow for an expected 60 completed subjects:  
approximately 45 subjects with Diagnostic and Statistical Manual, Fourth 
Edition – Text Revision (DSM-IV-TR) schizophrenia, and approximately 
15 healthy control subjects.  Attempts will be made to age-, gender-, and 
education-match the healthy control group with the schizophrenia group.  
Prospective subjects will undergo a thorough psychiatric and clinical 
screening phase, including a physical and neurological exam, 12-lead 
electrocardiogram (ECG), and baseline clinical laboratory testing.   
After screening, subjects with schizophrenia will be randomized in a 
2:1 aripiprazole once monthly:oral SOC antipsychotics ratio to the 
aripiprazole once monthly arm or the SOC oral antipsychotic arm of the 
study.  Subjects with schizophrenia who are randomized to the aripiprazole 
once monthly arm and are not currently receiving oral aripiprazole 
monotherapy will undergo a medication washout and a conversion (Phase 
A) to oral aripiprazole monotherapy.  In addition, any subject who is still 
taking a prohibited medication will enter Phase A for the appropriate 
washout.  All subjects with schizophrenia will proceed to Phase B 
(Stabilization) directly after screening, or after Phase A if conversion to 
oral aripiprazole or washout from prohibited medications is required.  Once 
stable on SOC oral antipsychotic medications for 2 consecutive visits, the 
subjects will proceed into Phase C (Treatment).  Control subjects will also 
enter Phase C.  All subjects with schizophrenia will undergo 
neuropsychological testing, clinical ratings, and multimodal MRI 
acquisition.  The MRI scanning protocol includes high-resolution MRI, 
diffusion tensor (DT)-MRI, water-BPF, and magnetic resonance 
spectroscopy (MRS). Neuropsychological testing, clinical ratings, and 
multimodal MRI acquisitions will be performed after 6 and 12 months of 
treatment.  The subjects will be assessed at regularly scheduled visits 
according to the schedule of assessments (Table 4 through Table 7).  Six 
and 12-month MRI indices in subjects receiving once monthly aripiprazole 
will be compared with baseline data, the data from subjects with 
schizophrenia who are receiving SOC oral antipsychotic medications, and 
the healthy control subjects.   
Instruments for the assessment of clinical and behavioral changes are: 
Clinical assessments including suicidality, mood, extrapyramidal side 
effects (EPS), and adverse drug effects are:  Abnormal Involuntary 
Movement Scale (AIMS), Barnes Akathesia Rating Scale (BARS), Clinical 
and Global Impression – Improvement (CGI-I), Clinical and Global 
Impression – Severity (CGI-S), Clinical and Global Impression -  Severity 
of Suicidality (CGI-SS), Columbia Suicide Severity Rating Scale (C-
SSRS), Hamilton Anxiety Scale (HAM-A), Hamilton Depression Rating 
Scale (HAM-D), Medication Adherence Questionnaire (MAQ), Monitoring 
of Side Effects Scale (MOSES), Positive and Negative Symptom Scale 
(PANSS), Profile of Mood States (POMS), and Simpson Angus Scale 
(SAS). 
 


Protocol  COL.AOM.2013.002 
 
Page 4 of 76 
Final Protocol: 29 July 2013 
Name of Sponsor:  The Brain Institute 
Name of Product:  Abilify Maintena™, aripiprazole 
Study Design continued: 
In addition to completion of formal rating scales used to assess suicidal 
ideation and behaviors, suicidal symptomology will be monitored using 
structured interview questions and follow-up queries.   
Neuropsychological testing will include:  The CogState tests which include 
Simple Reaction Time, Choice Reaction Time, One-back Working 
memory, Two-back Working Memory, and Set Shifting. Other 
neuropsychological tests will be the TrailMaking Test, Tower of London, 
Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test 
(WCST). 
Functional assessments will include:  Functional Assessment Test (FAST), 
Quality of Life Scale (QOLS), Social and Occupational Functioning 
Assessment Scale (SOFAS), and Life Functioning Questionnaire (LFQ). 
Healthy control subjects will not receive any investigational medicinal 
product (IMP); however these subjects will undergo all of the study 
procedures for comparison with the subjects with schizophrenia. 
Compliance with SOC drug will be managed using medication possession 
ratio (MPR) for prescription refills and the MAQ. 
Subject Population: 
A total of 80 subjects, aged 18 to 35 years will be enrolled to provide for an 
approximate 60 subjects who complete the study, 45 subjects with 
DSM-IV-TR schizophrenia and 15 healthy volunteers  
Study Drug, Dose, 
Formulation, Mode of 
Administration: 
Aripiprazole, administered once monthly via gluteal IM injection, as 
outlined in the product labeling. 
Oral antipsychotics – (SOC), which includes but is not limited to per oral 
(PO) administration of the following drugs as prescribed for the treatment 
of schizophrenia: 
• 
aripiprazole (Abilify®) 10 to 30 mg daily  
• 
risperidone (Risperdal®) 2 to 8 mg daily 
• 
lurasidone HCl (Latuda®) 40 to 160 mg daily 
• 
quetiapine fumarate (Seroquel®) 300 to 800 mg daily 
• 
olanzapine (Zyprexa®) 10 to 30 mg daily 
• 
ziprasidone HCl (Geodon®) 40 to 160 mg daily 
All SOC oral antipsychotics will be prescribed according to the 
recommendations contained in their respective product labeling. 


Protocol  COL.AOM.2013.002 
 
Page 5 of 76 
Final Protocol: 29 July 2013 
Name of Sponsor:  The Brain Institute 
Name of Product:  Abilify Maintena™, aripiprazole 
Criteria for Evaluation: 
Primary Outcome Variables: 
Efficacy:  The primary endpoint is FA by DT-MRI. 
 
Secondary Outcome Variables: 
Efficacy:  The secondary endpoints are: 
• 
Volumes by high-resolution MRI 
• 
Water-BPF by MRI 
• 
Schizophrenia-related instrument scores including suicidality 
(CGI-SS and C-SSRS), clinical assessment (CGI-I, GAF), 
symptomology (CGI-I, CGI-S, HAM-A, HAM-D, PANSS, 
POMS), medication adherence (MAQ, MPR), neuropsychological 
assessment (Simple Reaction Time, Choice Reaction Time, 
One-back Working Memory, Set Shifting, TrailMaking Test, 
Tower of London, CPT, WCST), functional outcomes (FAST, 
QOLS, SOFAS, LFQ, Hollignshead Index), and side effects 
(MOSES) 
• 
Proton metabolite measurements by MRS 
 
Study Duration: 
The clinical trial duration is expected to be approximately 2 years.  
For subjects who do not require conversion to aripiprazole, the study 
duration including screening, stabilization, and the treatment phase is 
expected to be 13 months. For subjects who will require conversion to oral 
aripiprazole, the duration is expected to be 14.5 months. 
 


Protocol  COL.AOM.2013.002 
 
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Final Protocol: 29 July 2013 
3 
TABLE OF CONTENTS 
1	  
TITLE PAGE ....................................................................................................................... 1	  
2	  
CLINICAL PROTOCOL SYNOPSIS ................................................................................ 2	  
3	  
TABLE OF CONTENTS .................................................................................................... 6	  
LIST OF IN-TEXT TABLES ............................................................................................ 10	  
LIST OF IN-TEXT FIGURES .......................................................................................... 10	  
LIST OF APPENDICES ................................................... Error! Bookmark not defined.	  
4	  
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 11	  
5	  
ETHICS ............................................................................................................................. 13	  
5.1	  
Informed consent ................................................................................................... 13	  
6	  
INVESTIGATORS AND STUDY PERSONNEL ........................................................... 14	  
7	  
INTRODUCTION ............................................................................................................. 15	  
7.1	  
Novel approaches to Understanding Brain Changes Associated with 
Medications ........................................................................................................... 15	  
7.2	  
ABILIFY
® (aripiprazole) ........................................................................................ 17	  
7.3	  
Relevant Nonclinical Studies ................................................................................ 17	  
7.4	  
Relevant Clinical Studies ...................................................................................... 18	  
7.4.1	   Schizophrenia Studies with Oral Aripiprazole .......................................... 18	  
7.4.2	   Agitation Studies with Injectable Aripiprazole ......................................... 19	  
7.4.3	   Clinical Studies in Schizophrenia with Aripiprazole IM .......................... 19	  
7.4.4	   Known and Potential Risks and Benefits .................................................. 20	  
7.5	  
Study Rationale ..................................................................................................... 22	  
8	  
STUDY OBJECTIVES ..................................................................................................... 23	  
8.1	  
Primary Objective(s) ............................................................................................. 23	  
8.2	  
Secondary Objective(s) ......................................................................................... 23	  
8.3	  
Exploratory Objective(s) ....................................................................................... 23	  
9	  
INVESTIGATIONAL PLAN ........................................................................................... 24	  
9.1	  
Overall Study Design and Plan .............................................................................. 24	  
9.1.1	   Screening Period ........................................................................................ 27	  
9.1.2	   Baseline ..................................................................................................... 28	  
9.1.3	   Randomization ........................................................................................... 29	  
9.1.3.1	  
Overall Treatment ................................................................. 29	  
9.1.3.2	  
Phase A – Conversion ............................................................ 29	  
9.1.3.3	  
Phase B – Stabilization .......................................................... 30	  
9.1.3.4	  
Phase C – Treatment ............................................................. 30	  
9.1.4	   Follow-Up Period ...................................................................................... 30	  
9.2	  
Discussion of Study Design, Including Choice of Control Groups ....................... 30	  
9.3	  
Selection of Study Population ............................................................................... 31	  
9.3.1	   Inclusion Criteria ....................................................................................... 31	  
9.3.1.1	  
Inclusion Criteria for All Subjects ........................................... 31	  
9.3.1.2	  
Inclusion Criteria for Subjects with Schizophrenia ................. 31	  
9.3.2	   Exclusion Criteria ...................................................................................... 32	  
9.3.2.1	  
Exclusion Criteria All Subjects ............................................... 32	  


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Final Protocol: 29 July 2013 
9.3.2.2	  
Exclusion Criteria for Subjects with Schizophrenia ................ 32	  
9.3.3	   Removal of Subjects From Therapy or Assessment .................................. 33	  
9.3.3.1	  
Entire Study or Treatment Arm(s) ........................................... 33	  
9.3.3.2	  
Individual Center ..................................................................... 33	  
9.3.3.3	  
Individual Subject .................................................................... 33	  
9.4	  
Treatments ............................................................................................................. 34	  
9.4.1	   Treatments Administered .......................................................................... 34	  
9.4.1.1	  
Dosage Adjustments for Missed Doses of Aripiprazole 
Once Monthly .......................................................................... 34	  
9.4.2	   Identity and Storage of Investigational Product(s) .................................... 35	  
9.4.3	   Method of Assigning Subjects to Treatment Groups ................................ 35	  
9.4.4	   Blinding ..................................................................................................... 35	  
9.4.5	   Prohibited Medication ............................................................................... 35	  
9.4.6	   Treatment Compliance .............................................................................. 36	  
9.4.7	   Accountability ........................................................................................... 36	  
9.5	  
Study Assessments ................................................................................................ 37	  
9.5.1	   Assessments ............................................................................................... 37	  
9.5.1.1	  
Demographics .......................................................................... 37	  
9.5.1.2	  
Screening Assessments ............................................................ 38	  
9.5.1.3	  
Safety Assessments ................................................................. 38	  
9.5.1.3.1	   Clinical Laboratory Tests ............................................ 38	  
9.5.1.3.2	   Physical Examination .................................................. 39	  
9.5.1.3.3	   ECG Assessments ........................................................ 39	  
9.5.1.4	  
Adverse Events and Other Events of Interest .......................... 39	  
9.5.1.5	  
Serious Adverse Events and Other Events of Interest ............. 42	  
9.5.1.6	  
Other Safety Assessments ....................................................... 43	  
9.5.1.6.1	   Injection Site Evaluation ............................................. 43	  
9.5.1.6.2	   Body Mass Index and Waist Circumference ............... 43	  
9.5.1.6.3	   Vital Signs ................................................................... 43	  
9.5.1.6.4	   Schizophrenia Assessments ......................................... 43	  
9.5.1.6.5	   Suicidality .................................................................... 44	  
9.5.1.6.6	   Pregnancy Test ............................................................ 45	  
9.5.1.6.7	   Urine Screen for Drugs of Abuse ................................ 45	  
9.5.1.6.8	   Monitoring of Side Effects Scale (MOSES) ............... 46	  
9.5.1.7	  
Efficacy Assessments – Clinical Outcome .............................. 46	  
9.5.1.7.1	   Clinical Global Impression – Improvement ................ 46	  
9.5.1.7.2	   Clinical Global Impression – Severity ........................ 46	  
9.5.1.7.3	   Positive and Negative Syndrome Scale 
(PANSS) ...................................................................... 46	  
9.5.1.8	  
Efficacy Assessments – Extrapyramidal Symptoms ............... 47	  
9.5.1.8.1	   Abnormal Involuntary Movement Scale (AIMS) ........ 47	  
9.5.1.8.2	   Barnes Akathisia Rating Scale (BARS) ...................... 47	  
9.5.1.8.3	   Simpson Angus Scale (SAS) ....................................... 47	  
9.5.1.9	  
Efficacy Assessments – Mood ................................................. 47	  
9.5.1.9.1	   The Hamilton Anxiety Scale (HAM-A) ...................... 47	  


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9.5.1.9.2	   The Hamilton Depression Rating Scale (HAM-
D) ................................................................................. 48	  
9.5.1.9.3	   The Profile of Mood States (POMS) ........................... 48	  
9.5.1.10	  
Efficacy Assessments – Medication Adherence ...................... 48	  
9.5.1.10.1	   Medication Adherence Questionnaire (MAQ) ............ 48	  
9.5.1.10.2	   Medication Possession Ratio (MPR) ........................... 48	  
9.5.1.11	  
Other Assessments ................................................................... 48	  
9.5.1.11.1	   Neuropsychological Measures ..................................... 48	  
9.5.1.11.2	   Functional Outcomes and Quality of Life ................... 50	  
9.5.1.12	  
Pharmacokinetic/Pharmacodynamic Assessments .................. 51	  
9.5.2	   Schedules of Assessments ......................................................................... 52	  
9.5.3	   Appropriateness of Measurements ............................................................ 59	  
9.5.4	   Reporting of Serious Adverse Events, Pregnancy, and Other 
Events of Interest ....................................................................................... 59	  
9.5.4.1	  
Reporting of Serious Adverse Events ...................................... 59	  
9.5.4.2	  
Immediately Reportable Events (IRE) .................................... 60	  
9.5.4.3	  
Reporting of Pregnancy and Exposure to Study Drug 
Through Breastfeeding ............................................................ 61	  
9.5.4.4	  
Reporting of Safety Information and Other Events of 
Interest ..................................................................................... 61	  
9.5.4.5	  
Regulatory Reporting of Adverse Events ................................ 63	  
9.5.5	   Database Reconciliation ............................................................................ 63	  
9.5.6	   Completion/Discontinuation of Subjects ................................................... 63	  
9.5.7	   Confirmation of Medical Care by Another Physician ............................... 64	  
9.6	  
Data Quality Assurance ......................................................................................... 64	  
9.6.1	   Monitoring ................................................................................................. 64	  
9.6.2	   Auditing ..................................................................................................... 64	  
9.6.3	   Data Collection Duration ........................................................................... 64	  
9.7	  
Statistical Methods ................................................................................................ 64	  
9.7.1	   Statistical and Analytical Plans ................................................................. 64	  
9.7.1.1	  
Primary Endpoint(s) ................................................................ 65	  
9.7.1.2	  
Exploratory Endpoint(s) .......................................................... 65	  
9.7.1.3	  
Definitions of Analysis Sets .................................................... 65	  
9.7.1.4	  
Subject Disposition .................................................................. 65	  
9.7.1.5	  
Demographic and Other Baseline Characteristics ................... 65	  
9.7.1.6	  
Prior and Concomitant Therapy .............................................. 66	  
9.7.1.7	  
Safety Analyses ....................................................................... 66	  
9.7.1.7.1	   Extent of Exposure ...................................................... 66	  
9.7.1.7.2	   Adverse Events ............................................................ 66	  
9.7.1.7.3	   Laboratory Values ....................................................... 67	  
9.7.1.7.4	   Physical Examination and Vital Signs ........................ 67	  
9.7.1.7.5	   Electrocardiograms ...................................................... 67	  
9.7.1.7.6	   Other Safety Analyses ................................................. 68	  
9.7.1.8	  
Efficacy Analyses .................................................................... 68	  
9.7.1.8.1	   Primary Efficacy Analysis ........................................... 68	  
9.7.1.8.2	   Secondary Efficacy Analyses ...................................... 68	  


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9.7.1.8.3	   Exploratory Efficacy Analyses .................................... 68	  
9.7.1.9	  
Pharmacokinetic/Pharmacodynamic Analyses ........................ 68	  
9.7.1.9.1	   Pharmacokinetic Analyses ........................................... 68	  
9.7.1.9.2	   Pharmacodynamic Analyses ........................................ 68	  
9.7.2	   Determination of Sample Size ................................................................... 68	  
9.7.3	   Interim Analysis ........................................................................................ 69	  
9.7.3.1	  
Data Safety Monitoring Board ................................................ 69	  
9.7.3.1.1	   Functions of the Data and Safety Monitoring 
Board ........................................................................... 69	  
9.7.3.1.2	   Monitoring of Data Quality by the DSMB .................. 69	  
9.7.4	   Other Statistical/Analytical Issues ............................................................. 69	  
9.7.5	   Procedure for Revising the Statistical Analysis Plan ................................ 69	  
10	  
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS ...................................... 70	  
10.1	  
Changes to the Protocol ......................................................................................... 70	  
10.2	  
Adherence to the Protocol ..................................................................................... 70	  
10.3	  
Monitoring Procedures .......................................................................................... 70	  
10.4	  
Recording of Data .................................................................................................. 71	  
10.5	  
Identification of Source Data ................................................................................. 71	  
10.6	  
Retention of Records ............................................................................................. 71	  
10.7	  
Auditing Procedures and Inspection ...................................................................... 71	  
10.8	  
Reporting and Publication of Results .................................................................... 72	  
10.9	  
Disclosure and Confidentiality .............................................................................. 72	  
10.10	   Discontinuation of Study ....................................................................................... 72	  
11	  
REFERENCE LIST ........................................................................................................... 73	  
12	  
APPENDICES ................................................ ERROR! BOOKMARK NOT DEFINED.	  
 
 


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Final Protocol: 29 July 2013 
LIST OF IN-TEXT TABLES 
Table 1:	  
Estimated Enrollment - Subjects Completed Per Year .......................................... 31	  
Table 2:	  
Prohibited and Restricted Medications .................................................................. 36	  
Table 3.	  
Safety Clinical Laboratory Tests ........................................................................... 39	  
Table 4	  
Schedule of Assessments – Phase A – Screening and Conversion Phase ............. 53	  
Table 5:	  
Schedule of Assessments Phase B – Oral Stabilization Phase .............................. 55	  
Table 6:	  
Schedule of Assessments Phase C - Treatment Phase ........................................... 57	  
Table 7:	  
Neuropsychological Measures for the Treatment Phase (Phase C) ....................... 59	  
 
LIST OF IN-TEXT FIGURES 
Figure 1	  
Study Schematic .................................................................................................... 26	  
 


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Final Protocol: 29 July 2013 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
2-D 
two-dimensional 
ACC 
anterior cingulate cortex 
ADC 
apparent diffusion coefficient 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BARS 
Barnes Akathesia Rating Scale 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BPF 
bound pool fraction 
BUN 
blood urea nitrogen 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical and Global Impression - Severity 
CGI-S 
Clinical and Global Impression - Schizophrenia 
CGI-SS 
Clinical and Global Impression - Severity of Suicidality 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CPT 
Continuous Performance Test 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DCF 
data clarification form 
DSM-IV-TR 
Diagnostic and Statistical Manual, Fourth Edition – Text Revision 
DSMB 
Data Safety Monitoring Board 
DT 
diffusion tensor 
EC 
Ethics Committee 
ECG 
electrocardiogram 
EPI 
echo-planar imaging 
EPS 
extrapyramidal side effects 
FA 
fractional anisotrophy 
FAST 
Functional Assessment Test 
FDA 
Food and Drug Administration 
fMRI 
functional magnetic resonance imaging 
GABA 
gamma-aminobutyric acid 
GAF 
DSM-IV-TR Global Assessment of Functioning 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLX 
glutamate/glutamine 
HAM-A 
Hamilton Anxiety Scale 
HAM-D 
Hamilton Depression Rating Scale 


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ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IM 
intramuscular 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRE 
immediately reportable event 
IUD 
intrauterine device 
LDH 
lactate dehydrogenase 
LFQ 
Life Functioning Questionnaire 
MAQ 
Medication Adherence Questionnaire 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MD 
mean diffusivity 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOSES 
Monitoring of Side Effects Scale 
MPR 
medication possession ratio 
MPRAGE 
magnetization prepared rapid acquisition gradient echo 
MRI 
magnetic resonance imaging 
MRS 
magnetic resonance spectroscopy 
NAA 
N-acetyl aspartate 
OAPI 
Otsuka America Pharmaceutical, Inc. 
OPC 
Otsuka Pharmaceutical Company 
PANSS 
Positive and Negative Syndrome Scale 
PD 
pharmacodynamic 
PO 
per oral 
POMS 
Profile of Mood States 
QOLS 
Quality of Life Scale 
RBC 
red blood cell 
SAE 
serious adverse event 
SAS 
Simpson Angus Scale 
SCID-P 
Structured Clinical Interview for DSM-N patient version 
SOC 
standard of care 
SOFAS 
Social and Occupational Functioning Assessment Scale 
TE 
echo time 
TEAE 
treatment-emergent adverse event 
TR 
repetition time 
VAS 
visual analog scale 
WBC 
white blood cell 
WCST 
Wisconsin Card Sorting Test 
 


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5 
ETHICS 
This study must be conducted in compliance with the protocol, FDA regulations, the ICH GCP 
Guideline, and all other applicable local laws and regulatory requirements.  Each study site will 
seek approval by an IRB according to regional requirements.  The IRB will evaluate the ethical, 
scientific and medical appropriateness of the study.  Further, in preparing and handling 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.  If a subject consents to participation in this study, the subject will review and sign the 
informed consent form (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 Institutional Review Board (IRB) that approves this protocol.  
Each ICF will comply with the Food and Drug Administration (FDA) regulations in Title 21 
Code of Federal Regulations (CFR) Part 50, International Conference on Harmonisation (ICH), 
Good Clinical Practices (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 determining 
eligibility for this study, including withdrawal from current medication(s). 
Once 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 (investigator 
or designee), as well as by any other parties required by the IRB.  The subject will receive a copy 
of the signed informed consent form; the original shall be kept on file by the investigator. 


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6 
INVESTIGATORS AND STUDY PERSONNEL 
This is an investigator initiated study that will be conducted at The Brain Institute, University of 
Utah, 36 South Wasatch Drive, Salt Lake City, UT  84112. 
Principal Investigator: 
Sub-Investigator 
Deborah Yurgelun-Todd, PhD 
Professor of Psychiatry 
University of Utah School of Medicine 
Director of Cognitive Neuroimaging 
The Brain Institute 
383 Colorow Road Room 308 
Associate Director, VISN 19 MIRECC  
(Mental Illness Research and Clinical Center) 
Phone:  801-587-1538 
e-mail:  Deborah.Yurgelun-Todd@hsc.utah.edu 
 
Melissa Lopez-Larson, MD 
Assistant Professor 
University of Utah School of Medicine 
The Brain Institute 
383 Colorow Raod 
Phone:  801-587-1554 
e-mail:  melissa.lopez-larson@hsc.utah.edu 
 
 
 
Data Safety Monitoring Board: 
Laboratory for Drugs of Abuse Testing: 
Douglas Kondo, MD 
Assistant Professor  
University of Utah 
Reporting of SAEs: 
USAMRMC ORP, HRPO 
 
Immediate report: 
Phone:  301-619-2165 
e-mail:  hsrrb@emedd.army.mil 
Fax:  301-619-7803 
 
Written Follow-up: 
USAMRMC 
Attn:  MCMR-ZB-P 
504 Scott Street 
Fort Detrick, MD 21701-5012 
 
ARUP Laboratories 
500 Chipeta Way 
Salt Lake City, UT 84108-1221 
(800) 242-2787 
(801) 583-2787  
(800) 522-2706 (fax) 
 
 


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7 
INTRODUCTION 
Aripiprazole is the first non-D2 receptor antagonist with clear antipsychotic effects and 
represents a novel treatment development for psychotic disorders.  Aripiprazole possesses 
serotonergic properties, including partial 5-HT1A agonism, 5-HT2A antagonism, and affinity for 
the 5-HT2C, 5-HT6, and 5-HT7 receptors.  Aripiprazole is effective, safe, well tolerated, and has 
shown efficacy in the treatment of both the positive and negative symptoms of schizophrenia and 
schizoaffective disorder.  Its unique mechanism of action may account for its sustained efficacy 
and favorable safety and tolerability profile, including a low risk for extrapyramidal symptoms 
(EPS), 
cardiac 
effects, 
hyperprolactinemia, 
weight 
gain, 
and 
other 
metabolic 
disturbances.  Despite the improved side-effect profile of this agent, medication compliance in 
individuals with schizophrenia is still problematic and may impact symptomatic and cognitive 
recovery.  Improved adherence to psychotropic treatment via long-acting injectable formulations 
may therefore lead to greater symptomatic improvements in this patient population, which may 
be detectible not only clinically but via current neuroimaging techniques as well.  Therefore, the 
aim of this study is to examine the structural and metabolic effects of long-acting intramuscular 
(IM) aripiprazole once monthly and standard of care (SOC) oral antipsychotic medications in 
subjects with schizophrenia using magnetic resonance imaging (MRI) techniques and to examine 
these effects in association with cognitive and clinical measures. 
Schizophrenia is a chronic illness associated with progressive brain changes over time1.  The 
process underlying tissue loss has been attributed to the course of the illness.  However, a study 
in primates found that loss of gray matter in schizophrenia may be related to antipsychotic 
medications2. In human studies of schizophrenia, volume losses have been reported for typical 
antipsychotic medications and volume gains for patients treated with atypical antipsychotic 
medications3-5.  A recent investigation of long-acting depot risperidone versus oral risperidone 
in first-episode schizophrenia patients found that white matter volume remained stable over the 
6-month trial in the long-acting depot patients, while it declined in those individuals taking oral 
risperidone.  Interestingly, the increase in white matter was associated with improved cognitive 
performance.  The authors suggested that the long-acting preparation changed the trajectory of 
myelination secondary to improved compliance6.  Treatment with long-acting atypical 
antipsychotics has also been associated with improved clinical outcomes, including decreased 
hospitalizations and duration of hospital stays.  
7.1 NOVEL APPROACHES TO UNDERSTANDING BRAIN CHANGES ASSOCIATED 
WITH MEDICATIONS 
While conventional magnetic resonance imaging (MRI) allows for adequate visualization of 
brain structures and the detection of white matter lesions and hyperintensities, white matter tracts 
are not readily distinguishable.  Diffusion tensor (DT)-MRI is a relatively new MRI modality 
designed to measure differences in constraints on water diffusion in various types of tissue7.  
Diffusion tensor imaging has proven effective for observing the relationship between cognitive 
deficits and structural connectivity in white matter.  For example, fractional anisotropy (FA), 
reflective of tissue organization, degree of myelination, and water mobility, has been extensively 
used to correlate measures of diffusion with cognitive ability8.  In a study of cognitive aging and 
executive function, Grieve et al. administered a battery of executive tasks and gathered DT-MRI 
data in a sample of 87 healthy subjects (aged 20 to 73 years) and found a significant negative 
association between age and average FA values in the frontal, parietal, and temporal lobes9.  


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Fractional anisotropy was shown to decrease at a rate of approximately 3% per decade in the 
prefrontal regions of the frontal lobe.  Additionally, decreased FA was associated with poorer 
cognitive performance in executive maze and attention-shifting tasks9.  These findings are 
consistent with earlier correlational work showing a negative association between age and FA 
values and a positive correlation between FA values and cognitive performance10.  
Determining the precise macromolecular content in neural tissue is crucial for accurately 
investigating white matter changes associated with anomalous brain development in the central 
nervous system (CNS)11.  Recent imaging modalities, such as DT-MRI, provide useful, potential 
complementary tools that may aid in this process, but they are not without their limitations.  For 
instance, DT-MRI indices, which measure the directionality of water diffusion in white matter 
through measures of FA, apparent diffusion coefficient (ADC) and mean diffusivity (MD), may 
or may not in fact be indicative of compromised brain tissue.  Furthermore, there is still some 
disagreement over what exactly FA and ADC measure.  Nevertheless, DT-MRI and other 
techniques have yielded promising findings, which may be aided by other novel approaches, 
such as T1 bound pool fraction (BPF).  Bound pool fraction, a T1 measurement, may hold 
particular utility in the assessment of white matter tissue integrity, as it is a more direct measure 
of myelin content12.  There is already convincing evidence, including some from the 
demyelinating disease, multiple sclerosis, that BPF is directly linked to the composition and 
density of myelin13-15, a dielectric material that enables rapid and efficient conduction of neural 
signals16-18.  Relevant to this proposal, Soellinger and colleagues’ recent work demonstrated that, 
at 3 Tesla, BPF showed high repeatability and low variance in several investigated regions and 
thus appears to be a useful tool in investigating changes in myelin content or microstructural 
changes in brain tissue longitudinally11.  The potential for BPF and DT-MRI to complement each 
other in such investigations was recently demonstrated by Stikov, et al12.  In their study, they 
combined BPF macromolecular content estimates with measurements of diffusivity within 
human white matter tracts and found modest correlations between BPF and the diffusion indices 
FA and radial diffusivity.  These findings suggest that the two techniques may, in fact, constitute 
complementary findings, which will clarify the mechanisms underlying white matter changes 
associated with the atypical antipsychotic agent, aripiprazole. 
Magnetic resonance spectroscopy (MRS) methods allow identification and quantification of 
chemical compounds in tissue.  The application of proton (1H) MRS is widely used for in vivo 
measurement of human brain chemistry because nearly all metabolites contain protons, allowing 
for a large number of important neurochemicals to be detected and measured.  Proton (1H) MRS 
can measure cerebral concentrations of N-acetyl aspartate (NAA), choline (Cho)-containing 
compounds, glutamate/glutamine (Glx), myo-inositol (mI), lactate, and gamma-aminobutyric 
acid (GABA), which plays a central role in maintaining inhibitory function19.  The primary 
inhibitory neurotransmitter, GABA, is distributed ubiquitously throughout the mammalian CNS.  
Altered GABAergic neurotransmission has been implicated in a wide range of human CNS 
disorders including epilepsy, schizophrenia, anxiety, and substance abuse disorders20.  The 
pharmacological manipulation of GABAergic neurotransmission is a common target for many of 
these disorders and Proton (1H) MRS approaches have successfully demonstrated normalized 
post-treatment GABA levels in depression21, epilepsy22, and substance abuse disorders23.  To 
date, there have been no studies on the relationship between brain GABA levels and aripiprazole 
treatment in humans, which constitutes an important gap in the MRS literature.  However, a 
recent study evaluating the effect of a variety of psychotropic drugs, including aripiprazole, on 


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rat brain metabolites found increased NAA concentrations (a marker of neuronal viability and 
activity) in the frontal cortex and striatum24. 
Seminal work completed by Koenig et al.13 has provided strong evidence that BPF is directly 
linked to the local density of myelin and is thought to reflect efficient neuronal signal 
conduction.  This method complements DT-MRI-based tractography, which allows for the 
evaluation of the integrity of specific white matter tracts and their connectivity25.  Furthermore, 
the application of two-dimensional  MRS provides a technique for the simultaneous 
measurement of localized neuronal metabolites, including GABA, glutamate, glutamine, and 
lactate26.  Taken together these methods are ideally suited for evaluating changes in the structure 
and chemistry of the brain in relation to aripiprazole treatment.  Although DT-MRI approaches 
have begun to examine aberrant white matter connectivity, changes accompanied by alterations 
in the macromolecular content of tissue are not observable using DT-MRI or conventional MRI.  
To our knowledge, no previous investigation has explored the impact of aripiprazole on the 
relationship between macromolecular content of white matter, DT-MRI measures of white matter 
integrity, and concentration of neuronal metabolites in the brain.  In addition, we propose to 
examine the relationship between white matter integrity and neurocognitive and functional 
outcomes in relation to changes in brain structure and metabolic function.  
7.2 ABILIFY
® (ARIPIPRAZOLE) 
Aripiprazole (ABILIFY®) is a dopamine partial agonist discovered by Otsuka Pharmaceutical 
Company (OPC) and co-developed by Bristol-Myers Squibb and OPC.  Otsuka Pharmaceutical 
Company and H. Lundbeck A/S are jointly developing the IM once monthly 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 (dispersible) tablets have been approved and marketed in 
the US and EU.  The favorable side effect profile of oral aripiprazole, including its low incidence 
of extrapyramidal symptoms (EPS), low risk of prolactin elevation, decreased adrenergic and 
anticholinergic side effects, and minimal weight gain, makes it an excellent candidate for a long-
acting once monthly formulation.  The aripiprazole IM 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 aripiprazole’s effectiveness 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 


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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 extrapyramidal symptoms 
(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)27 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.  The studies of subjects with an acute exacerbation of schizophrenia established 
the effectiveness of aripiprazole in the treatment of schizophrenia, including positive and 
negative symptoms.  These studies also demonstrated its early onset of action.  The long-term 
studies showed that aripiprazole treatment maintained stability in subjects with schizophrenia. 
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 10, 
15, 20, and 30 mg for the treatment of acute relapse of schizophrenia or schizoaffective disorder.  
The two 4-week studies (31-97-20128 and 31-97-202)29 each included 2 fixed doses of 
aripiprazole (15 mg and 30 mg for 31-97-201 and 20 mg and 30 mg for 31-97-202), an active 
comparator, for comparison of safety profiles, and placebo.  Review of the data from these 
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 (CN138001)30 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 CN13804731,32 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 (CGI-I) score ≥	 5, PANSS scores for hostility or 
uncooperativeness ≥	 5, or ≥	 20% increase in PANSS total score.  The results indicated that 


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subjects treated with aripiprazole 15 mg daily experienced a significantly longer time to relapse 
over the 26-week assessment period compared with those receiving placebo.  Two 52-week 
studies (Studies 31-98-217 and 31-98-304-01)33,34 of aripiprazole 30 mg versus haloperidol 
10 mg were conducted in acutely relapsing schizophrenic subjects with the intention of pooling 
the data for analysis.  On the primary efficacy measure (time to failure to maintain response in 
responders) no difference was seen between aripiprazole and haloperidol.  However, analysis of 
secondary efficacy measures showed that aripiprazole 30 mg was superior to haloperidol for 
negative symptoms, depressive symptoms, and discontinuation for any reason. 
The subject-rated and investigator-rated acceptability of aripiprazole treatment was examined in 
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 study (CN138087 and CN138100)35.  A separate open-label study (CN138152)36,37 
compared aripiprazole (10 to 30 mg daily) with SOC treatment (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 tolerability38. 
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-a-day schedule without regard to 
meals.  Aripiprazole has been systematically evaluated and shown to be effective in a dose range 
of 10 mg to 30 mg/day; however, there is no evidence that doses higher than 15 mg per day are 
associated with increased efficacy.  Additional details of results of clinical studies with 
aripiprazole in other indications are provided in the Investigator’s Brochure.27 
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 (24-hour) placebo-controlled studies39.  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 IM 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 IM 
Protocol CN138020, a clinical study conducted by Bristol-Myers Squibb, assessed the safety, 
tolerability, and PK of single doses of the aripiprazole IM once monthly formulation.  This was 
an open-label, 2-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 based on no significant adverse events (AEs) 


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or clinical laboratory abnormalities received a single dose of 15, 50, 100, 200, 300, or 400 mg of 
aripiprazole IM once monthly formulation, followed by safety and PK monitoring.  The IM once 
monthly 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 AEs 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), attempted suicide and exacerbation of schizophrenia, which were 
considered to be unrelated to study-drug. 
Otsuka Pharmaceutical Development & Commercialization, Inc. conducted a phase 1B study 
(Protocol 31-05-244) to assess the safety, tolerability, and PK of multiple doses of the 
aripiprazole IM once monthly formulation in subjects with schizophrenia.  The results showed 
that once-monthly administration of the 400-mg and 300-mg IM once monthly injections 
resulted in mean aripiprazole trough and average plasma concentrations that were comparable to 
the therapeutic concentrations of 10-mg to 30-mg oral aripiprazole administered daily to 
schizophrenic subjects.  All 3 doses of aripiprazole IM once monthly (200, 300, and 400 mg) 
demonstrated acceptable safety, tolerability, and potential effectiveness40. 
A phase 3 study (Protocol 31-07-246) was conducted to evaluate the efficacy and safety of 
aripiprazole IM once monthly compared with placebo in schizophrenic subjects who had 
maintained stability on aripiprazole IM once monthly for at least 12 weeks.  Aripiprazole IM 
once monthly 400 or 300 mg administered as monthly injections was effective for the 
maintenance treatment of schizophrenia in adults as demonstrated by a statistically significant 
difference, 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 IM once monthly group than in the placebo group.  The maintenance of 
stability was also demonstrated by statistically significant differences favoring aripiprazole IM 
once monthly in PANSS and CGI scores that remained significant throughout the double-blind, 
placebo-controlled phase.  In addition, the Personal and Social Performance Scale (PSP) total 
score, cognitive function assessments, and IAQ score were supportive of the efficacy of 
aripiprazole IM once monthly treatment.  Aripiprazole IM once monthly was well tolerated by 
adult subjects with schizophrenia as demonstrated by an AE profile similar to placebo.  Most 
treatment-emergent adverse events (TEAEs) were either mild or moderate in severity.  The only 
TEAE reported by ≥ 5% of subjects receiving aripiprazole IM once monthly and at least twice 
the incidence of placebo was tremor.  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 patients were treated with aripiprazole oral tablet formulation in 
Phase 2, 3, and 4 studies (representing 8577 patient-exposure years).  Of these, 3901 (25.9%) 
patients were treated with aripiprazole for 180 days or longer; 2259 (15.0%) patients received 


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aripiprazole for at least 360 days, with 933 (6.2%) patients continuing 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.  Akathesia was the only commonly observed AE that 
occurred in ≥ 5% of aripiprazole-treated subjects and at an incidence more than twice that of 
placebo (8% vs 4%, respectively).  Aripiprazole was well-tolerated in the long-term studies.  
Changes in body weight, fasting glucose, lipid profile, and serum prolactin levels were similar 
between aripiprazole- and placebo-treated subjects.  No clinically relevant changes in QTc were 
observed in either group32.  
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%)34.  
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 elevation41. 
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.  Because aripiprazole was not marketed at the time these studies were 
performed, it is not known if aripiprazole is associated with this increased risk.  Precise risk 
estimates for hyperglycemia-related AEs in subjects treated with atypical 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 


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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 of these studies, 
a 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 postmarketing 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 (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 United States (US) package insert. 
7.5 STUDY RATIONALE 
Aripiprazole is a second-generation antipsychotic with a mechanism of action that may be 
attributed to a partial agonism at dopamine D2 receptors. Aripiprazole also possesses 
serotonergic properties, including partial 5-HT1A agonism, 5-HT2A antagonism, and affinity for 
the 5-HT2C, 5HT6, and 5HT7 receptors. Its unique mechanism of action may account for its 
sustained efficacy and favorable safety and tolerability profile, including a low risk for EPS, 
cardiac effects, hyperprolactinemia, weight gain, and other metabolic disturbances.  Despite the 
improved side-effect profile of this agent, compliance in individuals with schizophrenia is 
problematic and may impact recovery.  Improved adherence to psychotropic treatment may 
therefore lead to greater symptomatic improvements in this patient population. By nature of the 
method of administration, once monthly aripiprazole should produce improved treatment 
compliance compared with oral antipsychotics.    
It is hypothesized that improved treatment compliance will lead to fewer white matter changes in 
the brain.  Fewer white matter changes will be demonstrated via neuroimaging as increased FA 
and BPF values in the prefrontal region, and an increase in metabolites in a voxel centered on the 
anterior cingulate cortex (ACC) as seen with MRS.  Therefore, the aim of this study is to 
examine the structural and metabolic effects of aripiprazole once monthly in patients with 
schizophrenia using MRI techniques and to examine these effects in association with cognitive 
and clinical measures. 


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8 
STUDY OBJECTIVES 
8.1 PRIMARY OBJECTIVE(S) 
The primary objective of the study is: 
• 
To determine if there are differences from baseline in prefrontal white matter FA after 
6 and 12 months of treatment with once monthly aripiprazole in subjects with 
schizophrenia compared with SOC oral antipsychotic medications.  
8.2 SECONDARY OBJECTIVE(S) 
The secondary objectives of the study are: 
• 
To determine if there are differences from baseline in water BPF in prefrontal white 
matter after 6 and 12 months of treatment with once monthly aripiprazole in subjects with 
schizophrenia compared with SOC oral antipsychotic medications. 
• 
To determine if proton metabolites, specifically GABA, glutamine, and glutamate, are 
altered after 6 and 12 months of treatment with once monthly aripiprazole in subjects 
with schizophrenia compared with SOC oral antipsychotic medications, compared with 
baseline. 
• 
To determine if there are differences from baseline in regional white and gray matter 
volume after 6 and 12 months of treatment with once monthly aripiprazole in subjects 
with schizophrenia compared with SOC oral antipsychotic medications. 
• 
To determine the effect on clinical and behavioral assessments of schizophrenia after 12 
months with aripiprazole once monthly compared with SOC oral antipsychotic 
medications, compared with baseline. 
8.3 EXPLORATORY OBJECTIVE(S) 
The exploratory objective of the study is: 
• 
To determine if there is a demonstrated association between clinical and neurocognitive 
variables and FA, BPF, and metabolite concentrations in subjects with schizophrenia 
receiving SOC oral antipsychotic medications or once monthly aripiprazole. 


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9 
INVESTIGATIONAL PLAN 
9.1 OVERALL STUDY DESIGN AND PLAN 
This is a Phase 4, randomized, open-label, parallel-group study designed to assess the clinical 
and biological effects of 12 months of treatment with aripiprazole once monthly as measured by 
clinical and behavioral measures, and changes on MRI scans in subjects with schizophrenia, 
compared with standard of care (SOC) oral antipsychotic therapy.  A total of 80 subjects are 
planned to be enrolled in the study in a 3:1 subjects with schizophrenia:control ratio, to allow for 
60 completed subjects:  45 subjects with Diagnostic and Statistical Manual of Mental Disease – 
Fourth Edition, Text Revised (DSM-IV-TR) schizophrenia, and 15 age-, gender-, and 
education-matched healthy control subjects.  Prospective subjects will undergo a thorough 
psychiatric and clinical screening phase, including a physical and neurological examination, 
12-lead electrocardiogram (ECG), and clinical laboratory testing.  All subjects with 
schizophrenia will be evaluated using appropriate rating scales for psychosis, negative 
symptoms, depression, suicidality, and psychosocial functioning.   
After screening, subjects with schizophrenia will be randomized in a 2:1 aripiprazole once 
monthly:oral SOC antipsychotics ratio to the aripiprazole once monthly arm or the SOC oral 
antipsychotics arm of the study.  Subjects with schizophrenia who are randomized to the 
aripiprazole once monthly arm of the study and are not currently receiving oral aripiprazole 
monotherapy will undergo a medication washout and a conversion (Phase A) to oral aripiprazole 
monotherapy.  In addition, any subject who is still taking prohibited medication will enter Phase 
A for the appropriate washout.  All subjects with schizophrenia will proceed to Phase B 
(Stabilization) directly after screening, or after Phase A if conversion to oral aripiprazole or 
washout from prohibited medications is required.  For those subjects in the oral SOC 
antipsychotic arm, once stable on SOC oral antipsychotic medications for 2 consecutive visits, 
the subjects will proceed into Phase C (Treatment).  Control subjects will enter Phase C directly 
after screening.  All subjects with schizophrenia will undergo neuropsychological testing, 
clinical ratings, and multimodal MRI acquisition.  The MRI scanning protocol includes 
high-resolution MR, diffusion tensor (DT)-MRI, water-BPF, and magnetic resonance 
spectroscopy (MRS).  Neuropsychological testing, clinical ratings, and multimodal MRI 
acquisitions will be performed after 6 and 12 months of treatment.  The subjects will be assessed 
at regularly scheduled visits according to the schedules of assessments (Table 4 through 
Table 7).  Six and 12-month MRI indices in subjects receiving once monthly aripiprazole will be 
compared with baseline data, the data from subjects with schizophrenia who are receiving SOC 
oral antipsychotic medications, and the healthy control subjects.   
Clinical assessments including suicidality, mood, extrapyramidal side effects (EPS), and adverse 
drug effects are:  Abnormal Involuntary Movement Scale (AIMS), Barnes Akathesia Rating 
Scale (BARS), Clinical and Global Impression – Improvement (CGI-I), Clinical and Global 
Impression – Severity (CGI-S), Clinical and Global Impression -  Severity of Suicidality (CGI-
SS), Columbia Suicide Severity Rating Scale (C-SSRS), Hamilton Anxiety Scale (HAM-A), 
Hamilton Depression Rating Scale (HAM-D), Medication Adherence Questionnaire (MAQ), 
Monitoring of Side Effects Scale (MOSES), Positive and Negative Symptom Scale (PANSS), 
Profile of Mood States (POMS), and Simpson Angus Scale (SAS). 


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In addition to completion of formal rating scales used to assess suicidal ideation and behaviors, 
suicidal symptomology will be monitored through structured interview questions and follow-up 
queries.  During the initial structured interview, subjects will be asked about historical and 
current suicidal thoughts and self-directed violence.  During study conduct, subjects will be 
asked during each call and at each visit if they had experienced a wish to die, or had any 
intention of engaging in self-directed violence.  Additionally, subjects will be queried regarding 
feelings of sadness, helplessness, and hopelessness, as each of these have been related to suicidal 
ideation and suicide attempts.  Expression of suicidal ideation or behaviors will be followed up 
verbally or, depending on the severity, through further clinical action. 
Neuropsychological testing will include:  The CogState tests which include Simple Reaction 
Time, Choice Reaction Time, One-back Working memory, Two-back Working Memory, and Set 
Shifting. Other neuropsychological tests will be the TrailMaking Test, Tower of London, 
Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST). 
Functional assessments will include:  Functional Assessment Test (FAST), Quality of Life Scale 
(QOLS), Social and Occupational Functioning Assessment Scale (SOFAS), and Life Functioning 
Questionnaire (LFQ). 
Healthy control subjects will not receive any study drug; however these subjects will undergo 
MRI imaging for comparison with the subjects with schizophrenia. 
Compliance with SOC antipsychotic drugs will be managed using medication possession ratio 
(MPR) for prescription refills, and the self-reported MAQ. 
The trial schematic is provided in Figure 1. 


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Final Protocol: 29 July 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 
Study Schematic 
 
Screening 
Randomization 
Phase A  
(Conversion) 
Phase B 
(Stabilization) 
Phase C  
(Treatment) 
Total 60 
subjects with 
schizophrenia 
Days -7 to -2 
Aripiprazole once 
monthly NOT on oral 
aripiprazole 
monotherapy 
Day -1 
Aripiprazole once 
monthly on oral 
aripiprazole 
monotherapy 
Oral SOC antipsychotics 
Weekly visits, minimum 
4 weeks, maximum  
6 weeks 
Bi-weekly visits 
for up to 12 weeks.  
Subjects must meet 
stability criteria for 
two consecutive 
visits. 
4 to 6 weeks 
4 to 12 weeks 
Subjects who meet 
stability criteria.  
Treatment with 
aripiprazole once 
monthly or SOC 
antipsychotics. 
12 months 
Total 20 healthy  
control subjects 
These subjects do not receive  
any study drug.  All other Phase C 
assessments will be completed. 


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9.1.1 Screening Period 
All recruitment methods will conform to the guidelines of the IRB at the clinical site.  Study 
recruitment materials will be posted at all included treatment facilities.  Contact between subjects 
and clinical research staff will be initiated by the subjects.  An initial pre-screening visit will be 
held to describe the study and, if interested, subjects will be asked to sign a study ICF.  
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 briefing subjects on the reasons for the research, their rights 
as a subject and the risks involved, they will be given the opportunity to ask questions.  Subjects 
will be asked to paraphrase the ICF.  When ready, subjects will be asked to give written consent 
to participate in the study.  After the ICF is signed by both the subject and the investigator, each 
subject will be given a copy of the signed ICF.  The PI will have full responsibility for all issues 
pertaining to assent and informed consent. 
 
The Screening Visit will occur on Days -7 to -2.  Eligibility for the study will be determined via 
the following: 
• 
Review of the inclusion and exclusion criteria 
• 
Complete medical history and demographic data 
• 
Assessment of current antipsychotic treatment and the stability of the current medication 
regimen 
• 
Structured Clinical Interview for DSM-IV Patient Version (SCID-P) to determine Axis I 
disorders including substance use/dependence disorders 
• 
Serum beta human chorionic gonadatropin (βhCG) pregnancy test for all women of 
childbearing potential to ensure that individuals are appropriate for imaging. Subjects 
who are found to be pregnant or have metal implants, pacemakers, prosthetic devices, or 
other situations or conditions that preclude the ability to participate in the imaging studies 
will not be entered into the study. 
• 
Physical examination, including height and weight, and vital signs (body temperature, 
supine and sitting blood pressure, and heart rate) measurements 
• 
Baseline clinical laboratory tests (See Section 9.5.1.3.1 for a complete list) 
• 
Serum prolactin concentration 
• 
12-lead electrocardiogram (ECG) 
• 
Urine drugs of abuse screen 
• 
Blood alcohol content 


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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) will be recorded.   
Washout from prohibited concomitant medications will begin, if applicable. 
9.1.2 Baseline 
Screening and the first baseline visit can occur on the same day if appropriate, and the 
assessments to be completed for the baseline visits will occur as outlined in Table 4, Table 5, and 
Table 6. For subjects who enter Phase A after screening, the baseline visit for Phase B will occur 
during the last visit for Phase A; all other subjects will have their baseline visit for Phase B either 
at the screening visit or on Day 1 of Phase B. At the Baseline Visits, the inclusion and exclusion 
criteria, current antipsychotic therapy, and concomitant medication use will be reviewed and 
recorded. Vital signs and body weight will be measured and body mass index (BMI) will be 
calculated. 
The following core measures will be assessed: 
1. Clinical Outcomes  
a. Positive and Negative Syndrome Scale (PANSS) 
b. Medication Adherence Questionnaire (MAQ) 
c. Clinical and Global Impression - Severity (CGI-S) 
d. Clinical and Global Impression - Severity of Suicidality (CGI-SS) 
e. Clinical and Global Impression – Improvement (CGI-I) 
f. Columbia Suicide Severity Rating Scale (C-SSRS) 
g. DSM-IV-TR Global Assessment of Functioning (GAF) 
2. Mood  
a. Profile of Mood States (POMS) 
b. Hamilton Anxiety Scale (HAM-A) 
c. Hamilton Depression Rating Scale (HAM-D) 
3. Extrapyramidal Side Effects 
a. Simpson Angus Scale (SAS) 
b. Abnormal Involuntary Movement Scale (AIMS) 
c. Barnes Akathesia Rating Scale (BARS) 
4. Adverse Drug Effects 


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a. Monitoring of Side Effects Scale (MOSES) 
Subjects will be given prescriptions for their oral SOC antipsychotic medications. 
At the end of the baseline visit, for subjects who were randomized to aripiprazole once monthly 
who were not receiving oral aripiprazole monotherapy, cross-titration will begin (Phase A).  In 
addition, any subjects who must undergo a washout from prohibited medications (see 
Section 9.4.5Error! Reference source not found.) will enter Phase A to complete the washout.  
Subjects with schizophrenia who are randomized to the SOC oral antipsychotic arm who do not 
need to undergo washout from prohibited medications will move directly into Phase B.  
9.1.3 Randomization 
All subjects with schizophrenia will be randomized to the aripiprazole once monthly arm or the 
SOC oral antipsychotic arm in a 2:1 ratio at screening.  Blocking will be used to ensure relatively 
equal distribution of subjects in each arm.  It is expected that 80 subjects will be enrolled to 
compensate for any subjects that are lost-to-follow up, discontinue the study, or fail to meet 
conversion or stability criteria. 
This will be an open-label study.  All clinical personnel, investigators, and subjects will be 
knowledgeable regarding the study treatment.  
9.1.3.1 Overall Treatment 
● Aripiprazole once monthly at an approved dose based on the investigator’s judgment and 
in accordance with product labeling, administered via gluteal IM injection once monthly.   
● SOC oral antipsychotic medications (PO) will be prescribed by the study physician based 
on the investigator’s judgment and in accordance with product labeling and include but 
are not limited to aripiprazole (Abilify®), risperidone (Risperdal®), lurasidone HCl 
(Latuda®), quetiapine fumarate (Seroquel®), olanzapine (Zyprexa®), and ziprasidone HCl 
(Geodon®). 
9.1.3.2 Phase A – Conversion 
During Phase A, all subjects randomized to aripiprazole once monthly that are not currently 
receiving aripiprazole monotherapy will undergo cross-titration to receive oral aripiprazole 
monotherapy, 10 to 20 mg PO, daily. 
Subjects receiving SOC aripiprazole monotherapy can receive oral aripiprazole at doses ranging 
from 10 to 30 mg PO daily. 
In addition, any subject requiring washout from prohibited medications will enter Phase A and 
prohibited medications will be withdrawn on a schedule based on the investigator’s judgment. 


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9.1.3.3 Phase B – Stabilization 
During Phase B, all enrolled subjects will be receiving SOC oral antipsychotic medication until 
stability criteria are met for two consecutive visits.  All oral antipsychotic medications will be 
prescribed using doses consistent with their respective product labeling. 
9.1.3.4 Phase C – Treatment 
During Phase C: 
● A total of 30 to 40 subjects with schizophrenia will receive aripiprazole once monthly, at 
a starting dose of 400 mg IM or an approved dose based on the investigator’s judgment 
and in accordance with product labeling.  In addition, these subjects will continue to 
receive oral aripiprazole at the dose (10 to 20 mg PO, daily) given prior to Phase C for 
14 days. 
● A total of 15 to 20 subjects will receive SOC oral antipsychotic medications, PO daily, in 
accordance with their respective product labeling. 
9.1.4 Follow-Up Period 
All subjects who receive at least one dose of study drug and who are discontinued from the study 
for any reason will be followed for safety reasons for 30 days following the last dose of drug. 
9.2 DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL GROUPS 
The study design is based on published findings with respect to long-acting injectable 
neuroleptic medications and was selected based on prior imaging findings for competitor 
compounds4,5.  Prior investigations suggest that the effect sizes will be large enough to see 
differences in imaging parameters between oral and once monthly injectable medication with the 
sample size proposed in this protocol6.  Imaging findings in patients treated with aripiprazole 
will be compared to those observed in patients treated as usual with oral antipsychotic 
medications.  The study will also include a non-psychiatric control group as normal aging has 
been shown to be associated with progressive brain structural changes including changes in 
white matter fiber tracts43.  This study is not powered to provide evidence for or against clinical 
inferiority of the depot preparation.  Choice of both primary and secondary endpoints for this 
study is consistent with published reports of changes in brain white matter integrity, localized 
brain volumes, and cognition after treatment with neuroleptic medications4-6. 
A data safety monitoring board (DSMB) will oversee the current study.  Monitoring will include 
completion of a site initiation visit, interim monitoring visits, submission of monitoring reports, 
oversight of regulatory paperwork, and oversight of IRE/SAE review of monthly enrollment 
logs. 
The scanning methods to be employed in this study are superior to those utilized in previous 
investigations as the current protocol will use higher magnetic resonance imaging field strength 
to collect data and more advanced analytical strategies for image analysis.  As such, the effect 
sizes are expected to be larger and, because multimodal imaging protocols will be implemented, 
it is expected that this study will produce a number of significant, complimentary clinical 
findings. 


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This is an open-label study.  Randomization is used in the study to mitigate the potential for bias 
in allocation of study drug. 
9.3 SELECTION OF STUDY POPULATION 
Approximately 80 subjects are planned for enrollment into the study at the Brain Institute.  There 
will be up to 60 subjects with a diagnosis of DSM-IV-TR schizophrenia and 15 to 20 age-, 
gender-, and education-matched healthy control subjects enrolled in a 3:1 subjects with 
schizophrenia:control subjects ratio.  This, accounting for drop-outs, will allow for 60 completed 
subjects:  45 subjects with schizophrenia and 15 healthy control subjects.  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.  After screening, subjects with schizophrenia will be randomized in a 2:1 
aripiprazole once monthly:SOC oral antipsychotics ratio. 
The enrollment estimates for the study are provided in Table 1: 
Table 1: 
Estimated Enrollment - Subjects Completed Per Year 
Subject type 
Year 1 
Year 2 
Total 
n 
Healthy controls 
7 
8 
15 
SCZ subjects treated with depot aripiprazole 
15 
15 
30 
SCZ subjects treated with SOC oral antipsychotics 
7 
8 
15 
Total 
29 
31 
60 
SCZ = schizophrenia, SOC = standard of care 
 
9.3.1 Inclusion Criteria 
9.3.1.1 Inclusion Criteria for All Subjects 
1 
Are able to provide written informed consent. 
2 
Are male and female subjects 18 to 35 years of age, inclusive, at time of informed 
consent. 
9.3.1.2 Inclusion Criteria for Subjects with Schizophrenia 
1. 
Have a current diagnosis of schizophrenia as defined by DSM-IV-TR criteria and a 
history of the illness for at least 1 year prior to screening and at least two prior psychotic 
episodes based on medical records or a qualified and reliable health care provider. 
2. 
Require, in the investigator's judgment, chronic treatment with an antipsychotic 
medication. 
3. 
Are able to understand the nature of the study and follow protocol requirements, 
including the prescribed dosage regimens, tablet ingestion, IM depot injection, and 
discontinuation of prohibited concomitant medications, read and understand the written 


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Final Protocol: 29 July 2013 
word in order to complete subject-reported outcomes measures, and be reliably rated on 
assessment scales. 
4. 
Are male and female subjects who are surgically sterile (i.e., have undergone 
orchiectomy or hysterectomy, respectively; female subjects who have been 
postmenopausal for at least 12 consecutive months; or male and female subjects who 
agree to remain abstinent or to practice double-barrier forms of birth control from trial 
screening through 30 days (for females) and 90 days (for males) from the last dose of 
IMP for SOC oral antipsychotics and 150 days for females and 180 days for males for 
aripiprazole depot.  If employing birth control, two of the following precautions must be 
used:  vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, 
birth control implant, birth control depot injections, condom, or sponge with spermicide.  
9.3.2 Exclusion Criteria 
9.3.2.1 Exclusion Criteria All Subjects 
1. 
Presence of any metal implants, pacemakers, unremovable prosthetic device, or other 
device or situation that may preclude imaging 
2. 
History of a head injury with loss of consciousness > 5 minutes 
3. 
Has a significant medical condition that would expose the subject to undue risk or 
interfere with study assessments. 
9.3.2.2 Exclusion Criteria for Subjects with Schizophrenia 
 
1. 
Has a current DSM-IV-TR diagnosis other than schizophrenia, including 
schizophreniform disorder, schizoaffective disorder, major depressive disorder, bipolar 
disorder, delirium, dementia, amnestic or other cognitive disorders.  Also excluded are 
subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial 
personality disorder. 
2. 
Is considered resistant/refractory to antipsychotic treatment by history (failed two prior 
antipsychotic medication trials) or response only to clozapine. 
3. 
Has a significant risk of violent behavior or a significant risk of committing suicide based 
on history or investigator's discretion. 
4. 
Has met DSM-IV-TR criteria for any significant substance use disorder within 3 months 
prior to screening, excluding caffeine, nicotine, or marijuana. 
5. 
Is known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or 
other quinolinones, or hypersensitivity to antipsychotic agents, including aripiprazole. 


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6. 
Has a history of neuroleptic malignant syndrome or clinically significant tardive 
dyskinesia at screening per the investigator’s discretion. 
7. 
Has a history of seizures or any other medical condition that would expose the subject to 
undue risk or interfere with study assessments. 
8. 
Is involuntarily incarcerated. 
9. 
Has undergone electroconvulsive therapy in the 2 years prior to enrollment in the study. 
10. 
Has used an investigational agent or has participated in a clinical study with aripiprazole 
IM depot or any other antipsychotic depot preparation within 30 days of screening. 
11. 
Has clinically significant abnormalities in laboratory test results, vital signs, or ECG 
results. 
12. 
Requires more than one benzodiazepine beyond screening (e.g., lorazepam and 
oxazepam). 
13. 
Fails to washout from prohibited concomitant medications, including the use of or 
CYP3A4 inducers, a second antipsychotic, antidepressants (including monoamine 
oxidase inhibitors), and mood stabilizers. 
9.3.3 Removal of Subjects From Therapy or Assessment 
9.3.3.1 Entire Study or Treatment Arm(s) 
If the investigator terminates or suspends the study for safety or unanticipated other reasons, 
prompt notification will be given to OAPI, IRBs, and regulatory authorities in accordance with 
regulatory requirements. 
9.3.3.2 Individual Center 
The investigator will notify OAPI promptly if the study is terminated by the investigator or the 
IRB at the site. 
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 investigators 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 the following criteria must be withdrawn from the 
study: 


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1. occurrence of any AE, intercurrent illness or abnormality in a laboratory assessment 
which, in the opinion of the investigator, warrants the subject’s permanent withdrawal 
from the study; 
2. treatment with a prohibited concomitant medication other than the use of appropriate 
medications for the treatment of adverse events under direction of the investigator; 
3. subject noncompliance, defined as refusal or inability to adhere to the study schedule or 
procedures per the investigator’s discretion; 
4. at the request of the subject, investigator, OAPI or designee, or regulatory authority 
5. subject becomes pregnant; or 
6. subject is lost to follow-up. 
The Investigator will notify OAPI promptly when a subject is withdrawn. 
9.4 TREATMENTS 
9.4.1 Treatments Administered 
Aripiprazole once monthly and oral aripiprazole from commercial sources will be prescribed and 
administered according to recommendations contained in their respective product labeling, 
including dosing adjustments based on CYP2D6 status and concomitant medication use.  All 
other SOC oral antipsychotic medications 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 (IM), 300 or 400 mg administered via gluteal injection, once monthly. 
• SOC oral antipsychotic medications (PO) including but not limited to: 
o Aripiprazole (Abilify®), 10 mg to 30 mg, daily 
o Risperidone (Risperdal®), 2 to 8 mg daily 
o lurasidone HCl (Latuda®), 40 to 160 mg daily 
o quietapine fumarate (Seroquel®), 300 to 800 mg daily 
o olanzapine (Zyprexa®) 10 to 30 mg daily 
o ziprasidone HCl (Geodon®) 40 to 160 mg daily 
9.4.1.1 Dosage Adjustments for Missed Doses of Aripiprazole Once Monthly 
If the second or third doses are missed: 


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● 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 will not be stored at the clinical site.  If, on occasion, study drug is stored at the site 
for any reason, all drug will be securely locked in a cabinet or enclosure 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 80 subjects are planned to be enrolled in the study in a 3:1 subjects with 
schizophrenia:control ratio, to allow for 60 completed subjects:  45 subjects with schizophrenia, 
and 15 age-, gender-, and education-matched healthy control subjects.  
9.4.4 Blinding 
The study will not be blinded. 
9.4.5 Prohibited Medication 
Medications that are prohibited or restricted prior to screening and/or during the study are listed 
in Table 2. 


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Table 2: 
Prohibited and Restricted Medications 
Medication 
Prohibition or Restriction 
Antipsychotics 
No more than one SOC antipsychotic allowed 
Antidepressants including MAOIs 
Not allowed 
Benzodiazapine 
The use of one benzodiazapine is allowed.  
Mood stabilizers 
Not allowed 
Non-benzodiazapine sleep aidsa 
Allowed 
Anitcholinergics 
≤ 4 mg/day benztropine or equivalent; not within 12 
hours of any rating scales. 
Propanolol for akathisia or tremor 
Maximum 60 mg/day; not within 8 hours of any 
rating scales.  Subjects receiving propanolol for heart 
disease may remain on stable, pre-study doses, as 
needed as long as the dose does not exceed 60 
mg/day. 
Varenicline 
Not allowed 
Nutritional supplements and non-
prescription herbal preparations with 
CNS effects (e.g., St. John’s Wort, 
omega-3 fatty acids, kava extracts, 
GABA supplements) 
Not allowed 
CYP3A4 or CYP2D6 inhibitors or 
CYP3A4 inducers 
CYP3A4 or CYP2D6 inhibitors are allowed, 
however, the investigator may adjust the dose of the 
study drug per the prescribing instructions. 
CYP3A4 inducers are not allowed 
Hydroxyzine and diphenhydramine  
Not allowed for the treatment of agitation, anxiety, 
insomnia, or EPS; Allowed for the treatment of 
allergy. 
AE – adverse event, CNS = central nervous system, CYP = cytochrome P450, EPS = extrapyramidal side 
effects, GABA = gamma aminobutyric acid, IM = intramuscular, MAOI = monoamine oxidase inhibitor 
a:  Zolpidem 5 to 10 mg/day, zolpidem extended-release 12.5 mg/day, zaleplon 5 to 10 mg/day, zopiclone 
3.75 to 7.5 mg/day, or eszopiclone 1 to 3 mg/day is permitted, but not in addition to a benzodiazepine for 
insomnia. 
 
9.4.6 Treatment Compliance 
Compliance with SOC drug will be managed using the MPR (Section Error! Reference source 
not found.) for prescription refills and the MAQ (Section Error! Reference source not found.). 
9.4.7 Accountability 
Study drug will not be prescribed or administered until the following documentation has been 
provided by the investigator to OAPI: 
● A signed and dated confidentiality agreement 


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● 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 
● The IRB membership list and statutes or Health and Human Services Assurance number 
● A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol 
● An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable 
● Financial Disclosure form(s) for the investigator and all subinvestigators listed on Form 
FDA 1572, where applicable 
● A signed and dated curriculum vitae (CV) of the investigator including a copy of the 
investigator’s current medical license or medical registration number on the CV 
● A signed and dated clinical studies agreement 
The investigator and the study staff will be responsible for the accountability of all study drugs 
(dispensing, inventory, and record keeping) following the, and adherence to, Good Clinical 
Practice (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 administered or prescribed to any individual 
who is not enrolled in the study.   
The investigator, or designee, must maintain an inventory record of trial 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 (or age), sex, race or ethnicity. 


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9.5.1.2 Screening Assessments 
MEDICAL HISTORY 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All relevant medical and surgical history within 10 years must be noted in the CRF. 
PSYCHIATRIC HISTORY 
A review of the subject’s psychiatric history will be performed including all antipsychotic 
medications used within the 6 months prior to screening.  Confirmation of the diagnosis of 
schizophrenia, as defined by DSM-IV-TR criteria. 
9.5.1.3 Safety Assessments 
Safety will be assessed by adverse event (AE) reporting, clinical laboratory tests (hematology 
and fasting clinical chemistry), urinalysis, 12-lead ECG, vital signs, and physical examination.  
In addition, body weight, BMI, and serum prolactin concentrations will be monitored. 
The MOSES will be utilized to assess for side effects, and the following scales will be used to 
assess for EPS:  AIMS, SAS, and BARS. 
For subjects receiving an injection, the investigator, or qualified designee, will assess the 
injection site for localized pain, redness, swelling, and induration. 
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 4 through Table 6, 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.  If non-fasting blood samples are obtained initially for determining eligibility for the 
study, a fasting blood sample should be drawn prior to enrollment.  The clinical laboratory tests 
performed during the study are provided in Table 3. 


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Table 3. 
Safety Clinical Laboratory Tests 
Hematology: 
 
White Blood Cell (WBC) count with differential  
Red Blood Cell (RBC) count  
Hematocrit  
Hemoglobin 
Mean Corpuscular Volume (MCV) 
Mean Corpuscular Hemoglobin Concentration 
(MCHC) 
 
Serum Chemistry: 
 
Alanine Transaminase (ALT) 
Alkaline Phosphatase (ALP) 
Aspartate Transaminase (AST) 
Bilirubin, Total 
Blood Urea Nitrogen (BUN)  
Calcium 
Cholesterol 
Creatinine  
Gamma Glutamyl Transferase (GGT) 
Glucose 
Lactic Dehydrogenase (LDH) 
Potassium 
Protein, Total 
Sodium  
Triglycerides 
 
Urinalysis: 
Color 
Appearance 
pH 
Specific gravity 
Microscopic Analysis of RBC/WBC (per high 
powered field)] 
Additional Tests: 
 
Urine β-hCGa for women of child-bearing potential  
 
Serum prolactin 
 
β-hCG = beta human chorionic gonadatropin 
a:  Serum β-hCG will be performed if the subject or investigator suspects that the subject may be pregnant. 
 
9.5.1.3.2 Physical Examination 
Physical examinations (comprehensive or symptom directed) will be performed as designated on 
the Schedules of Assessments (Table 4 through Table 6).  A comprehensive physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest (including 
heart and lungs), abdomen, limbs, skin, and a complete neurological examination.  A urogenital 
examination will only be required in the presence of clinical symptoms related to this region.  
Documentation of the physical examination will be included in the source documentation.  
Significant findings at the Screening Visit will be recorded on the CRF.  Changes from screening 
physical examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF. ECG Assessments 
A 12-lead ECG will be performed in triplicate while the subject is in a supine position and after 
having rested for 5 minutes.Adverse Events and Other Events of Interest 
An adverse event (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 product.  For this study, the study drugs are aripiprazole once 
monthly and SOC oral antipsychotics. 
The criteria for identifying AEs are: 


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● 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 
● Recurrence of an intermittent medical condition (e.g., headache) not present pretreatment 
(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. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 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 and CGI-SS 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 and 
CGI-SS). 


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Every effort must be made by the investigator to categorize each AE according to its severity and 
its relationship to the study treatment. 
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). 
Assessing Severity of Adverse Events 
Standard Text 
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
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 
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 (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 there is 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. 
 


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9.5.1.5 Serious Adverse Events and Other Events of Interest 
A serious adverse event (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 adverse event 
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/incapacity 
● Is a congenital anomaly/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 
may require intervention to prevent one of the outcomes in the definition of SAE listed above 
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  
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
● Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 


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9.5.1.6 Other Safety Assessments 
9.5.1.6.1 Injection Site Evaluation 
For subjects receiving an injection, two assessments of the most recent injection site will be 
completed at each visit at which an injection is administered:  an investigator assessment and a 
subject-rated visual analog scale (VAS) assessment of the pain at the injection site. 
For the investigator assessment, the investigator, or qualified designee, will assess the injection 
site for localized pain, redness, swelling, and induration.  For the subject-rated VAS assessment, 
the subject will mark the scale with one vertical line across the bar of the VAS to indicate the 
degree of injection site discomfort. 
These assessments will occur as the last evaluations of the visit, approximately 1 hour 
(± 15 minutes) after the gluteal IM once monthly injection. 
For the subject-rated assessment of pain at the injection site, the subject will complete the VAS 
approximately 1 hour (± 15 minutes) post-injection to assess the injection site. 
The evaluations must be completed on the same day (i.e., the day the injection is administered). 
9.5.1.6.2 Body Mass Index and Waist Circumference 
An assessment for potential of prolactin-related effects will be performed via determination of 
BMI, and measurement of waist circumference. 
The calculation for BMI is: 
weight (kg) 
[height (m)]2 
 
9.5.1.6.3 Vital Signs 
Vital sign measurements (i.e., systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated on the Schedules of Assessments (Table 4 through 
Table 6) by a validated method.  Blood pressure and pulse will be measured after the subject has 
been supine for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person. 
9.5.1.6.4 Schizophrenia Assessments 
DSM-IV-TR Global Assessment of Functioning (GAF) 
The GAF is used to assess global functioning using a scale from 1 (worst) to 100 (best).  An 
intraclass correlation coefficient of 0.81 has been reported. 
Structured Clinical Interview for DSM-IV, Patient Version (SCID-P) 


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The SCID-P is a semi-structured interview for making the major DSM-IV Axis I diagnoses.  The 
instrument is designed to be administered by a clinician or trained mental health professional.  
The SCID-P 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. However, to be sensitive to subthreshold syndromes we will 
query further even if the entry questions appears negative.  For all diagnoses symptoms are 
coded as present, subthreshold, or absent.  
9.5.1.6.5 Suicidality 
Clinical Global Impression – Severity of Suicidality (CGI-SS) 
The CGI-SS is a two-part scale that assesses severity of suicidality over the week prior to the 
evaluation. 
The CGI-SS Part 1 has 5 levels of severity of suicidality: 1   =   not at all suicidal, 2   =   mildly 
suicidal, 3   =   moderately suicidal, 4   =   severely suicidal, and 5   =   attempted suicide. 
The CGI-SS Part 2 has 7 levels of change in suicidality: 1 = very much improved since the 
initiation of treatment, 2 = much improved, 3 = minimally improved, 4 = no change since the 
initiation of treatment, 5=minimally worse, 6= much worse, 7=very much worse since the 
initiation of treatment. 
All evaluations for Part 2 of the CGI-SS will use the baseline of the appropriate phase as a 
reference for judging change in suicidality.  For the purpose of this study, a score of 4 (severely 
suicidal) or 5 (attempted suicide) on Part 1 and/or a score of 6 (much worse) or 7 (very much 
worse) on Part 2 will be considered an exacerbation of psychotic symptoms/impending relapse 
and may result in immediate withdrawal from the study at the investigator’s discretion. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS was designed to distinguish the domains of suicidal ideation and suicidal behavior.  
The C-SSRS scale consists of a baseline evaluation that assesses the lifetime experience of the 
subject with suicide events and suicidal ideation and a post-baseline/”Since Last Visit” 
evaluation that focuses on suicidality since the last study visit.  The baseline C-SSRS form will 
be completed at baseline of Phase 1.  The “Since Last Visit” C-SSRS form will be completed at 
all subsequent visits. 
Four constructs are measured: 
1. The severity of ideation (the “severity subscale”), which is rated on a 5-point ordinal 
scale in which 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 (the “intensity subscale”), which comprises 5 items, 
each rated on a 5-point ordinal scale: frequency, duration, controllability, deterrents, and 
reason for ideation.  


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3. The behavior subscale, which is rated on a nominal scale that includes actual, aborted, 
and interrupted attempts; preparatory behavior; and nonsuicidal self-injurious behavior.  
4. The lethality subscale, which 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. 
9.5.1.6.6 Pregnancy Test 
Women of childbearing potential and men who are sexually active must use an effective method 
of birth control during the course of the trial and for and for 30 days for a female subject and 
90 days for a male subject after the last dose of SOC oral antipsychotics and 150 days for a 
female subject and 180 days for a male subject after the last dose of aripiprazole once monthly, 
in a manner such that risk of failure is minimized.  Unless the subject and his/her partner(s) are 
sterile (i.e., women who have had an oophorectomy and/or hysterectomy or have been 
postmenopausal for at least 12 consecutive months; or men who have had orchiectomy) or 
remain abstinent, two of the following precautions must be used: vasectomy, tubal ligation, 
vaginal diaphragm, IUD, birth control pills, birth control depot injection, birth control implant, 
condom, or sponge with spermicide.  Any single method of birth control, including vasectomy 
and tubal ligation, may fail, leading to pregnancy. 
Before enrolling women of child-bearing potential in this clinical study, investigators must 
review guidelines about trial participation for women of childbearing potential.  The topics 
should generally include: 
• General information 
• Informed consent form 
• Pregnancy prevention information 
• Drug interactions with hormonal contraceptives 
• Contraceptives in current use 
• Guidelines for the follow-up of a reported pregnancy. 
Prior to study enrollment, women of childbearing potential must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an ICF stating that the above-mentioned risk factors and the 
consequences were discussed with her. 
9.5.1.6.7 Urine Screen for Drugs of Abuse 
A 30-mL urine sample will be collected at designated time points as specified in the Schedules of 
Assessments (Table 4 through Table 6).  This sample will be tested for drugs of abuse: e.g., 
marijuana, 
cocaine, 
opiates, 
oxycodone, 
phencyclidine, 
amphetamines, 
barbiturates, 
benzodiazapines, methadone, and propoxyphene (ARUP laboratories; see Section 6).  An aliquot 


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of the urine sample will be prepared and shipped for confirmation and quantification of drug 
levels via enzyme immunoassay/gas chromatography-mass spectrometry/liquid chromatography-
tandem mass spectrometry. 
In addition, a blood sample will be obtained to test for blood alcohol content. 
9.5.1.6.8 Monitoring of Side Effects Scale (MOSES) 
The MOSES scale is a Division of Social and Health Services Scale consisting of seven body 
system symptom domains: ears, eyes, head; mouth; nose, throat, chest; gastrointestinal; 
musculoskeletal and neurological; skin; and urinary and genital; and one psychological symptom 
domain, in which the examiner will check boxes for symptoms present on a scale of 0 to 4 in 
which 0 = none and 4 = severe. 
9.5.1.7 Efficacy Assessments – Clinical Outcome 
9.5.1.7.1 Clinical Global Impression – Improvement 
The efficacy of study medication will be rated for each subject using the CGI-I scale.  The rater 
or investigator will rate the subject’s total improvement whether or not it is due entirely to drug 
treatment.  All responses will be compared to the subject’s condition at baseline of the 
appropriate phase.  The CGI-I during Phase B should be assessed relative to the subject’s 
condition at the Phase B baseline visit.  Response choices include:  0 = not assessed; 1 = very 
much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally 
worse; 6 = much worse; and 7 = very much worse.  
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 Positive and Negative Syndrome Scale (PANSS) 
The PANSS consists of three subscales containing a total of 30 symptom constructs.  For each 
symptom construct, severity is rated on a 7-point scale, with a score of 1 indicating the absence 
of symptoms and a score of 7 indicating extremely severe symptoms.  The symptom constructs 
for each subscale are as follows: 
Positive Subscale (7 positive symptom constructs:  delusions, conceptual disorganization, 
hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility), 
Negative Subscale (7 negative symptom constructs:  blunted affect, emotional withdrawal, poor 
rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow 
of conversation, stereotyped thinking),  


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General Psychopathology Subscale (16 symptom constructs:  somatic concern, anxiety, guilt 
feelings, tension, mannerism and posturing, depression, motor retardation, uncooperative, 
unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance 
of volition, poor impulse control, preoccupation, and active social avoidance). 
All efforts are to be made to ensure that the same rater administers the PANSS for a given 
subject.  The number of raters within each study center is to be kept to a minimum.  Instructions 
for administering this instrument will be provided to the site.  A copy of the PANSS assessment 
with complete rating criteria is required as source documentation.  
9.5.1.8 Efficacy Assessments – Extrapyramidal Symptoms 
9.5.1.8.1 Abnormal Involuntary Movement Scale (AIMS) 
The AIMS assessment consists of 10 items describing symptoms of dyskinesia.  Facial and oral 
movements (items 1 through 4), extremity movements (items 5 and 6), and trunk movements 
(item 7) will be observed unobtrusively while the subject is at rest (e.g., in the waiting room), 
and the investigator will also make global judgments on the subject’s dyskinesias (items 8 
through 10).  Each item will be rated on a 5-point scale, with a score of 0 representing absence of 
symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 
10, awareness/severe distress). 
9.5.1.8.2 Barnes Akathisia Rating Scale (BARS) 
The BARS assessment consists of 4 items related to akathisia: objective observation of akathisia 
by the investigator, subjective feelings of restlessness by the subject, subject distress due to 
akathisia, and global evaluation of akathisia.  The first 3 items will be rated on a 4-point scale, 
with a score of 0 representing absence of symptoms and a score of 3 representing a severe 
condition.  The global clinical evaluation will be made on a 6-point scale, with 0 representing 
absence of symptoms and a score of 5 representing severe akathisia. 
9.5.1.8.3 Simpson Angus Scale (SAS) 
The SAS assessment consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, 
shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, 
and akathisia).  Each item is rated on a 5-point scale, with a score of 1 representing absence of 
symptoms, and a score of 5 representing a severe condition.  The SAS Total Score is the sum of 
the scores for all 10 items. 
9.5.1.9 Efficacy Assessments – Mood 
9.5.1.9.1 The Hamilton Anxiety Scale (HAM-A) 
Rating scale developed to quantify the severity of anxiety symptomatology, often used in 
psychotropic drug evaluations. 


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9.5.1.9.2 The Hamilton Depression Rating Scale (HAM-D) 
Proven useful for determining the level of depression before, during, and after treatment32.  It is 
based on the clinician's interview with the patient and probes symptoms such as depressed mood, 
guilty feelings, suicidal ideation, sleep disturbances, anxiety levels and weight loss.  Research 
has demonstrated a validity coefficient of .85. 
9.5.1.9.3 The Profile of Mood States (POMS) 
Self-report inventory in which respondents rate a series of mood states.  The POMS Standard 
form contains 65 items and takes approximately 10 minutes to complete. Internal consistency 
scores have ranged from .84 to .95. 
9.5.1.10 Efficacy Assessments – Medication Adherence 
9.5.1.10.1 Medication Adherence Questionnaire (MAQ) 
The MAQ is a validated, 4-item, self-reported measure to determine adherence to treatment.  The 
four behavioral questions of the MAQ are designed to assess different sources of noncompliance 
(e.g., forgetfulness, carelessness, symptom driven compliance), with positive responses 
indicating nonadherence to medication regimens.  Responses to each question will be “Yes” 
(score of 1) or “No” (score of 0), thus the MAQ total score will range from 0 to 4. 
9.5.1.10.2 Medication Possession Ratio (MPR) 
Medication Possession Ratio (MPR) measures the percentage of time a subject has access to 
medication.   
9.5.1.11 Other Assessments 
9.5.1.11.1 Neuropsychological Measures 
COGSTATE COMPUTERIZED TESTING 
Simple Reaction Time 
Simple reaction time will be assessed by means of the Detection Task section of the CogState 
computerized assessment.  This task is used to assess psychomotor functioning as well as speed 
of processing.  During this task a face down deck of cards is presented electronically to the 
subject.  The card on the top of the pile is then flipped over to reveal the face of the card.  The 
subject is asked to indicate when this has happened by pressing a “yes” button.  Subjects are 
instructed to make this indication as quickly as possible.  If the subject fails to make an 
indication, or presses the button prior to the face of the card becoming visible, an error sound is 
heard. 
Choice Reaction Time 
Choice reaction time will be assessed by means of the Identification Task section of the CogState 
computerized assessment.  This task is used to assess visual attention as well as vigilance.  This 
task is presented similar to the simple reaction time task with the additional instruction that the 


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subject only presses the “yes” button when the card presented is red.  As with the previous task, 
subjects are instructed to make this indication as quickly as possible. 
One-back Working Memory 
The one back task is a CogState task that will be used to assess attention and working memory.  
During this task, subjects are presented with an electronic deck of cards face down.  A card is 
turned over revealing the face of the card and then is returned to the deck.  Following each card, 
the subject is instructed to indicate whether or not the most recent card is identical to the 
previous card by pressing either “yes” or “no” on the keyboard.  The subject is encouraged to 
work quickly and accurately. 
Set Shifting 
This test is a Cog State test designed to determine executive function.  During this task, the 
subject is presented with a playing card in the center of the computer screen.  The subject is 
asked to guess whether the card is the “target” or “correct” card.  A target card is a card which 
contains a color or a number.  If the guess is correct the card is flipped over. If not correct, an 
error noise will sound and the card will not flip over.  At this point, the subject must guess again. 
Once the subject has made their way through a set of cards, the target or correct stimulus 
dimensions changes without the subject’s knowledge and the subject must relearn the rule.  
There are multiple set shifts within the task, and the order of the set shifts is pseudo-randomized 
to create multiple alternate forms of the task. 
Unit of measurement: total number of errors.  Accuracy of performance and total number of 
errors across five rounds are measured; a lower score = better performance 
OTHER NEUROPSYCHOLOGICAL TESTS 
TrailMaking Test 
This test is designed to measure visual conceptual and visual-motor tracking, as well as 
maintenance of cognitive set.  The subject must first draw lines to connect consecutively 
numbered circles on one work sheet (Part A) and then connect the same number of consecutively 
numbered and lettered circles on another work sheet by alternating between the two sequences 
(Part B).  TrailMaking B is the more sensitive of the two tests -- particularly to frontal-lobe 
dysfunction -- as scores on this section are indicative of the subject's ability to shift sets and 
process concurrent stimuli. 
Tower of London 
The Tower of London task will be used to assess executive function.  This assessment will be 
presented electronically during with the subject will be presented with a screenshot containing 
three balls of differing colors on three pegs.  The subject will be asked the amount of times the 
balls in one picture must be moved in order to match a second image.  The complexity of the task 
will increase over the course of the trials. 
Continuous Performance Test (CPT) 


Protocol  COL.AOM.2013.002 
 
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Computerized test of sustained attention.  The test requires subjects to attend vigilantly to a 
series of target and distracter stimuli for 14-minutes.  Generated scores include reaction time, 
omission errors, commission errors, and an index of overall performance.  An alpha score of .84 
has been reported along with an intraclass correlation coefficient of .91. 
Wisconsin Card Sorting Test 
Assesses a person’s ability to form abstract concepts, utilize feedback, and shift and maintain set.  
This test has been shown to be sensitive to frontal lobe dysfunction.  Dependent variables include 
total number of categories correct (color, form, or number) and perseverative errors.  The 
measure has a test retest generalizability coefficient of > 90. 
9.5.1.11.2 Functional Outcomes and Quality of Life 
FUNCTIONING ASSESSMENT SHORT TEST (FAST):  
The FAST is a 24-item, clinician administered assessment used to assess functional impairment 
with a focus on the main problems experienced by psychiatric populations.  The timeframe for 
this measure refers to the subjects last 15 days before assessment.  The assessment is broken 
down into 6 specific areas of functioning including:  autonomy, occupational functioning, 
cognitive functioning, financial issues, interpersonal relationships, and leisure time. 
QUALITY OF LIFE SCALE (QOLS):  
The QOLS is a measure designed to determine the impact of health care.  This measure consists 
of 16 questions (the original 15 QOLS questions, with the addition of a chronic illness 
component) delivered as a self-report measure.  The QOLS assesses factors related to (1) 
relationships and material well-being, (2) personal, social and community commitment, and (3) 
health and functioning. 
SOCIAL AND OCCUPATIONAL FUNCTIONING ASSESSMENT SCALE (SOFAS):  
The SOFAS is a new scale that assesses a subject’s individual level of social and occupational 
functioning.  Similar to the GAF, the SOFAS is a scaled score that ranges from 0 to 100, but 
differs from the GAF such that it is specific to social and occupational functioning and is not 
directly influenced by a subject’s psychiatric illness symptom severity.  This scale can be used in 
terms of current functioning, but can also be used over a timeframe detailing highest and lowest 
level of social and occupational functioning. 
LIFE FUNCTIONING QUESTIONNAIRE (LFQ):  
The LFQ is a 14-item, gender-neutral, self-report questionnaire used to assess functional 
outcome in patients with psychiatric illness in terms of role function.  The assessment measures 
four domains, which include:  workplace, duties at home, leisure time with family, and leisure 
time with friends. 
HOLLINGSHEAD FOUR FACTOR INDEX OF SOCIAL POSITION:  
The Hollingshead Index is a report of socioeconomic status, used with modifications.  
Intermeasure correlations range from r = .86 to .91. 


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9.5.1.12 Pharmacokinetic/Pharmacodynamic Assessments 
PHARMACOKINETIC ASSESSMENTS 
Not applicable. 
PHARMACODYNAMIC ASSESSMENTS 
Measurements of FA, BPF, and proton metabolites will occur using imaging techniques as 
described below.  All structural scans will be read and interpreted by a clinical neuroradiologist.  
Structural data will be utilized in three ways: to ensure specific regions of interest are visible and 
localized for correlation with T1 mapping of the BPF, DT-MRI and MRS data.  In addition, 
cortical reconstruction and volumetric segmentation and parcellation will be performed with the 
FreeSurfer image analysis suite, which is documented and available for download online 
(http://surfer.nmr.mgh.harvard.edu/), to obtain volumetric and cortical thickness measures for 
brain regions of interest, including the cingulum.  
Magnetic Resonance Imaging 
All subjects will undergo an MRI protocol on a Siemens Trio 3 Tesla Scanner at baseline, 6 
months, and 12 months during Phase C.  This protocol includes a high-resolution structural MRI 
protocol.  The structural acquisitions include a T1-weighted 3D magnetization prepared rapid 
acquisition gradient echo (MPRAGE) sequence acquired sagittally, with TE/TR/TI = 
3.38ms/2.0s/1.1s, 8°flip, 256 x 256 acquisition matrix, 256 mm2 field of vision, 160 slices, 1.0 
mm slice thickness.   
Diffusion Tensor Imaging (DT-MRI)  
A single-shot spin-echo echo-planar imaging (EPI) sequence with diffusion-weighting will be 
used to acquire diffusion tensor images.  To describe the intensity and direction of diffusion 
anisotropy, MR images with 25 non-collinear diffusion gradients and without diffusion gradient 
will be acquired.  B-factor will be set to be 1000 sec/mm2.  Acquisition parameters include FOV 
= 256 mm, matrix = 128 x 128, resulting 2-mm isotropic in-plane resolution.  TR/TE = 7000/84, 
pixel bandwidth = 1346 Hz, and averages = 4.  
Magnetic Resonance Spectroscopic (MRS) Imaging  
Proton (1H) magnetic resonance spectroscopic imaging measurements will be acquired using a 
3.0 Tesla Siemens (Erlangen, Germany) VerioTM whole-body MRI scanner.  
1H-MRS spectra will be acquired using a manufacturer-supplied 12-channel head coil, following 
high-resolution MPRAGE image acquisition to facilitate accurate voxel positioning. A modified 
point-resolved spectroscopy  sequence (two-dimensional J-resolved spectroscopy) is used:  
repetition time/echo time (TR/TE) range 2400/31 to 229 ms; 100 TE steps; Vector size 2048; 
Bandwidth 2000/500 Hz) acquires MRS spectra with 128 and 4 signal averages per TE step for 
metabolite and water non-suppressed data. An 18.75 mL (2.5 x 2.5 x 3.0 cm3) voxel is placed at 
the ACC and the parietal-occipital cortex. Parietal occipital cortex data serves as a control 
region. Automated and manual shimming ensures unsuppressed water signal linewidths of <9 
Hz. 


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9.5.2 Schedules of Assessments 
Table 4 provides the Schedule of Assessments for Phase A of the study.  Table 5 provides the 
Schedule of Assessments for Phase B of the study.  Table 6 provides the Schedule of 
Assessments for Phase C of the study.  Table 7 provides the neurological assessments to be 
completed During Phase C. 
 


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Table 4 
Schedule of Assessments – Phase A – Screening and Conversion Phase 
Assessments 
STUDY VISIT 
Screening 
(Days -7 to -
2) 
Conversion to Oral Aripiprazole (Phase A) 
Baseline 
Day 1i 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6g 
± 2 days 
STANDARD STUDY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
Review inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
X 
Medical history 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Physical examination, 
including height 
X 
 
 
 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and waist 
circumference 
 
X 
 
 
 
 
 
X 
Calculate BMIa 
 
X 
 
 
 
 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
X 
Clinical laboratory testsb 
X 
 
 
 
 
 
 
X 
Prolactin level 
X 
 
 
 
 
 
 
X 
Urine βhCGc 
X 
 
 
 
 
 
 
X 
Screen for drugs of abused 
X 
 
 
 
 
 
 
X 
Prior medication history 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
SCHIZOPHRENIA-RELATED ASSESSMENTS 
SCID-P 
X 
 
 
 
 
 
 
 
Current antipsychotic 
therapye 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Outcome 
CGI-I, CGI-S , CGI-SS, C-
SSRS, GAF, MAQ, 
PANSS 
X 
X 
X 
X 
X 
X 
X 
X 
Mood 
HAM-A, HAM-B, POMS 
X 
X 
X 
X 
X 
X 
X 
X 
Extrapyramidal Side Effects 
AIMS, BARS, SAS 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 4 
Schedule of Assessments – Phase A – Screening and Conversion Phase 
Assessments 
STUDY VISIT 
Screening 
(Days -7 to -
2) 
Conversion to Oral Aripiprazole (Phase A) 
Baseline 
Day 1i 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6g 
± 2 days 
Adverse Drug Effects 
MOSES 
X 
X 
X 
X 
X 
X 
X 
X 
CONVERSION TO ARIPIPRAZOLEg 
Dispense oral aripiprazoleh 
 
X 
X 
X 
X 
X 
X 
X 
Cross-titrationh 
 
X 
X 
X 
X 
X 
X 
 
Taper off other 
psychotropic medicationsf 
 
X 
X 
X 
X 
X 
X 
X 
Assess eligibility for Phase 
B 
 
 
 
X 
X 
X 
X 
X 
AIMS = Abnormal Involuntary Movement Scale, ALT = alanine aminotransferase, AST = aspartate aminotransferase, βhCG = human chorionic gonadotropin, BARS = Barnes 
Akathesia Rating Scale, BMI = body mass index, BUN = blood urea nitrogen, CGI-I = clinical and global Impression – Improvement, CGI-S = Clinical and Global Impression – 
Severity, CGI-SS = Clinical and Global Impression for Severity of Suicidality, C-SSRS = Columbia Suicide Severity Rating Scale, CYP = cytochrome P, DSM = Diagnostic and 
Statistical Manual, ECG = electrocardiogram, GAF = DSM-IV-TR Global Assessment of Functioning, GGT = gamma glutamyltransferase, HAM-A = Hamilton Anxiety Scale, 
HAM-D = Hamilton Depression Rating Scale, LDH – lactate dehydrogenase, MAQ = Medication Adherence Questionnaire, MOSES = Monitoring of Side Effects Scale,  
PANSS = Positive and Negative Symptom Scale, POMS = Profile of Mood States, RBC = red blood cell, SAS = Simpson Angus Scale, SCID-P = structured clinical interview for 
DSM-IV Patient Version, WBC = white blood cell 
a:  BMI is calculated as:  mass (kg)/height (m2) 
b:  clinical laboratory tests include hematology (WBC with differential, RBC, hemoglobin, hematocrit, mean corpuscular volume and mean corpuscular hemoglobin 
concentration), serum chemistry (ALT, alkaline phosphatase, AST, total bilirubin, BUN, calcium, cholesterol, creatinine, GGT, glucose, LDH, potassium, total protein, sodium, 
and triglycerides), and urinalysis (color, appearance, specific gravity, pH, microscopic for RBCs and WBCs per high-powered field. 
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:  Urine will be collected for drugs of abuse testing for:  marijuana, cocaine, opiates, oxycodone, phencyclidine, amphetamines, barbiturates, benzodiazapines, methadone, and 
propoxyphene on the day of MR imaging (ARUP Drugs of Abuse Panel 9:  ARUP Laboratories, Salt Lake City, UT).  An aliquot of this urine sample will also be sent for 
confirmation and quantification of drug levels via Enzyme Immunoassay/Gas Chromatography-Mass Spectrometry/Liquid Chromatography-Tandem Mass Spectrometry.  Note:  
the presence of benzodiazapines in the results of the drugs of abuse screening will not be cause for the discontinuation of the subject from the study if they are part of the subject’s 
treatment regimen; subjects will be excluded for significant substance use per the investigator’s discretion. In addition, blood will be collected to test for blood alcohol content. 
e:  Subjects with schizophrenia only 
f:  Subjects on SOC oral antipsychotic medications that areparticipating in Phase A due to  washout from more than one benzodiazepine, or prohibited concomitant medications 
such as CYP3A4 inducers, antidepressants including monamine oxidase inhibitors, and mood stabilizers, will also be evaluated during Phase A.  
g:  The final visit of Phase A will be the baseline for Phase B for those subjects whoparticpated in Phase A. 
h:  For subjects with schizophrenia only, who were randomized to the aripiprazole once monthly arm in Phase C and aren’t currently receiving oral aripiprazole monotherapy. 
i:  Screening and baseline can occur on the same day if appropriate. 


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Final Protocol: 29 July 2013 
Table 5: 
Schedule of Assessments Phase B – Oral Stabilization Phase 
Assessments 
Baselinea 
Week 2b 
Week 4h 
Week  
6c,h 
Week 8c,h 
Week 10c,h 
Week 12c,h 
(± 1 day) 
STANDARD STUDY ASSESSMENTS 
Confirm inclusion/exclusion criteria 
X 
 
 
 
 
 
X 
Physical examination, including height  
X 
 
 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
X 
Body weight and waist circumference 
X 
X 
X 
X 
X 
X 
X 
Calculate BMId 
X 
 
X 
 
X 
 
X 
Clinical laboratory testse 
X 
 
 
 
 
 
X 
Prolactin concentration 
X 
 
 
 
 
 
X 
Urine βhCGf 
X 
 
X 
 
X 
 
X 
Screen for drugs of abuseg 
X 
 
X 
 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events  
X 
X 
X 
X 
X 
X 
X 
SCHIZOPHRENIA-RELATED STUDY ASSESSMENTS 
CLINICAL OUTCOME 
CGI-I, MAQ, PANSS  
X 
X 
X 
X 
X 
X 
X 
MOOD SCALES 
HAM-A, HAM-D, POMS 
 
 
 
 
 
 
 
EXTRAPYRAMIDAL SIDE EFFECTS 
AIMS, BARS, SAS 
 
 
 
 
 
 
 
ADVERSE DRUG EFFECTS 
MOSES 
 
 
 
 
 
 
 
BASELINE ASSESSMENTS FOR PHASE C 
Neuropsychological Testingi 
 
 
 
 
 
 
 
Functional Outcomes Assessmentsj 
 
 
 
 
 
 
 
STUDY MANAGEMENT 
Assess stability criteria 
 
X 
X 
X 
X 
X 
X 
Drug accountability (MPR) 
 
X 
X 
X 
X 
X 
X 
Administer aripiprazole once monthlyc,i 
 
 
 
 
 
 
X 
Evaluate injection sitej 
 
 
 
 
 
 
X 
AIMS = Abnormal Involuntary Movement Scale, ALT = alanine aminotransferase, AST = aspartate aminotransferase, βhCG = human chorionic gonadotropin,  
BARS = Barnes Akathisia Rating Scale, BMI = body mass index, BUN = blood urea nitrogen, CGI-I = Clinical and Global Impression – Improvement,  
C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, GGT = gamma glutamyltransferase, HAM-A = Hamilton Anxiety Scale,  
HAM-D =  Hamilton Depression Rating Scale, IM = intramuscular, LDH – lactate dehydrogenase,  


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Table 5: 
Schedule of Assessments Phase B – Oral Stabilization Phase 
MAQ = Medication Adherence Questionnaire, MPR = medicine possession ratio, MOSES =  Monitoring of Side Effects Scale, MRI = magnetic resonance 
imaging, PANSS = Positive and Negative Syndrome Scale,POMS = Profile of Mood States, RBC = red blood cell, SAS = Simpson Angus Scale, VAS = visual 
analog scale, WBC = white blood cell 
a:  For subjects not converting to oral aripirazole, subjects move directly to Phase B after screening. Screening and baseline can occur on the same day if 
appropriate. 
b:  For subjects who participated in Phase A, baseline assessments are completed during the last visit of Phase A; Week 1 is the first visit of Phase B 
c:  Subjects who are stable for 2 consecutive visits can be moved directly into Phase C; subjects unable to be stabilized after 12 weeks will be discontinued from 
the study 
d:  BMI is calculated as:  mass (kg)/height (m2) 
e:  Clinical laboratory tests include hematology (WBC with differential, RBC, hemoglobin, hematocrit, mean corpuscular volume and mean corpuscular 
hemoglobin concentration), serum chemistry (ALT, alkaline phosphatase, AST, total bilirubin, BUN, calcium, cholesterol, creatinine, GGT, glucose, LDH, 
potassium, total protein, sodium, and triglycerides), and urinalysis (color, appearance, specific gravity, pH, microscopic for RBCs and WBCs per high-powered 
field). 
f:  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. 
g:  Urine will be collected for drugs of abuse testing for:  marijuana, cocaine, opiates, oxycodone, phencyclidine, amphetamines, barbiturates, benzodiazapines, 
methadone, and propoxyphene on the day of MR imaging (ARUP Drugs of Abuse Panel 9:  ARUP Laboratories, Salt Lake City, UT).  An aliquot of this urine 
sample will also be sent for confirmation and quantification of drug levels via Enzyme Immunoassay/Gas Chromatography-Mass Spectrometry/Liquid 
Chromatography-Tandem Mass Spectrometry.  Note:  the presence of benzodiazapines in the results of the drugs of abuse screening will not be cause for the 
discontinuation of the subject from the study if they are part of the subject’s treatment regimen.  A subject will be excluded for significant substance use per the 
investigators discretion.  In addition, blood will be collected to test for blood alcohol content. 
h:  The final visit of Phase B will be the Baseline visit for Phase C.  Neuropsychological testing, functional outcomes testing, and the first dose of aripiprazole 
depot will be administered.  MRI will be completed. 
i:  Neuropsychological testing includes:  CogState testing (simple reaction time, choice reaction time, one-back working memory, two-back working memory, and 
set shifting), TrailMaking Test, Tower of London, Continuous Performance Test, and Wisconsin Card Sorting Test.  See Table 7. 
j:  Functional outcomes assessments include:  Functional Assessment Test, Quality of Life Scale, Social and Occupational Functioning Assessment Scale, Life 
Functioning Questionnaire 
k:  For subjects who are entering into Phase C and are randomized to aripiprazole once monthly, the first dose of aripiprazole once monthly will be administered 
IM at the last visit in Phase B.  All study drug will be administered at the end of the visit. 
 
 
 


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Final Protocol: 29 July 2013 
Table 6: 
Schedule of Assessments Phase C - Treatment Phase 
Assessments 
Study Week 
1 
2 
3 
4 
6 
8 
10 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
(± 3 days) 
STANDARD STUDY ASSESSMENTS 
Physical examination 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and waist 
circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMIa 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Clinical laboratory testsb 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Prolactin level 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Urine Pregnancy testc 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screen for drugs of abused 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
VAS pain at injection sitee 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator rating of injection 
sitee 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SCHIZOPHRENIA-RELATED ASSESSMENTS 
CLINICAL OUTCOME 
CGI-I, CGI-S , CGI-SS, C-
SSRS, GAF, MAQ, PANSS 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
MOOD SCALES 
HAM-A, HAM-D, POMS 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EXTRAPYRAMIDAL SIDE EFFECTS 
AIMS, BARS, SAS 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADVERSE DRUG EFFECTS 
MOSES 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STUDY-SPECIFIC ASSESSMENTS AND MANAGEMENT 
Assess stability criteriag 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MRI Imaging 
Xi 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Administer IM once monthly 
aripiprazoleh 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug accountability with SOC 
oral anti-psychotics (MPR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 6: 
Schedule of Assessments Phase C - Treatment Phase 
Assessments 
Study Week 
1 
2 
3 
4 
6 
8 
10 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
(± 3 days) 
AIMS = Abnormal Involuntary Movement Scale, ALT = alanine aminotransferase, AST = aspartate aminotransferase, βhCG = human chorionic gonadotropin, BARS = Barnes 
Akathesia Rating Scale, BMI = body mass index, BUN = blood urea nitrogen, CGI-I = clinical and global Impression – Improvement, CGI-S = Clinical and Global Impression – 
Severity, CGI-SS = Clinical and Global Impression for Severity of Suicidality, C-SSRS = Columbia Suicide Severity Rating Scale, DSM = Diagnostic and Statistical Manual, 
DT-MRI = diffusion tensor magnetic resonance imaging, ECG = electrocardiogram, EPS = extrapyramidal side effects, fMRI = functional magnetic resonance imaging, GGT = 
gamma glutamyltransferase, HAM-A = Hamilton Anxiety Scale, HAM-D = Hamilton Depression Rating Scale, LDH – lactose dehydrogenase, MAQ = Medication Adherence 
Questionnaire, MOSES = Monitoring of Side Effects Scale, MPR = medication possession ratio, MRI = magnetic resonance imaging, MRS = magnetic resonance spectroscopy, 
PANSS = Positive and Negative Symptom Scale, POMS = Profile of Mood States, RBC = red blood cell, SAS = Simpson Angus Scale, WBC = white blood cell 
a:  BMI is calculated as:  mass (kg)/height (m2)  
b:  clinical laboratory tests include hematology (WBC with differential, RBC, hemoglobin, hematocrit, mean corpuscular volume and mean corpuscular hemoglobin 
concentration), serum chemistry (ALT, alkaline phosphatase, AST, total bilirubin, BUN, calcium, cholesterol, creatinine, GGT, glucose, LDH, potassium, total protein, sodium, 
and triglycerides), and urinalysis (color, appearance, specific gravity, pH, microscopic for RBCs and WBCs per high-powered field. 
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:  Drug screen for drugs of abuse includes:  amphetamines, barbiturates, benzodiazapines, cannabinoids, cocaine metabolites, opiates, ethanol, and methadone.  Note:  the 
presence of benzodiazapines in the results of the drugs of abuse screening will not be cause for the discontinuation of the subject from the study if they are part of the subject’s 
treatment regimen. 
e:  For subjects administered once monthly aripiprazole only.  For visits at which no injection is administered, the assessments are done once, using the most recent injection site.  
For visits in which an injection is administered, the area of the most recent injection will be assessed approximately 30 minutes prior to the injection (or in the case of the first 
injection, the area to be injected), and one hour (± 15 minutes) after the injection.  On injection days, these assessments will be the last assessments completed. 
f:  Neuropsychological testing includes: CogState testing (simple reaction time, choice reaction time, one-back working memory, two-back working memory, and set shifting), 
TrailMaking Test, Tower of London, Cognitive Performance Test, and Wisconsin Card Sorting Test.  See Table 7. 
g:  Functional outcomes assessments include:  Functional Assessment Test, Quality of Life Scale, Social and Occupational Functioning Assessment Scale, Life functioning 
Questionnaire 
h:  aripiprazole will be administered at the end of the visit 
i:  MRI imaging includes MRI, MRS, fMRI, DT-MRI 


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Table 7: 
Neuropsychological Measures for the Treatment Phase 
(Phase C) 
Neuropsychological Measure 
Baseline 
6 Months 
12 Months 
CogState Tests 
Simple Reaction Time 
X 
X 
X 
Choice Reaction Time 
X 
X 
X 
One-back Working Memory 
X 
X 
X 
Two-back Working Memory 
X 
X 
X 
Set-Shifting 
X 
X 
X 
Other Neuropsychological Tests 
TrailMaking Test 
X 
X 
X 
Tower of London 
X 
X 
X 
CPT 
X 
X 
X 
WCST 
X 
X 
X 
CPT = Continuous Performance Test, WCST = Wisconsin Card Sorting Test 
 
 
9.5.3 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, urinalysis, and assessment of AEs, are standard evaluations to ensure subject 
safety. 
9.5.4 Reporting of Serious Adverse Events, Pregnancy, and Other Events of Interest 
9.5.4.1 Reporting of Serious Adverse Events 
All serious adverse events, regardless of their relationship to study treatment, must be reported to 
OAPI 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. 
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. 
The detailed contact information for reporting of SAEs is provided in the Investigator Study File. 
Report IREs (serious adverse events, potential Hy’s Law cases, pregnancies and adverse 
events requiring discontinuation of trial drug) to: 
Clinical Safety and Pharmacovigilance 
Otsuka Pharmaceutical Development & Commercialization, Inc.  
Khaled Bannout, MD 


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2440 Research Boulevard  
Rockville, Maryland  20850, United States 
Hotline:  240-683-3115 
Fax:  301-721-7115  
For Medical Emergencies (use only if Otsuka personnel listed above are unavailable):  
301-990-0030 
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. 
Any follow-up information received on SAEs should be forwarded within 1 business day of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by the 
sponsor. 
The investigator must notify his/her IRB of the occurrence of the SAE, in writing, if required by 
their institution.  A copy of this communication must be forwarded to the OAPI to be filed in the 
OAPI Study Master File. 
9.5.4.2 Immediately Reportable Events (IRE) 
Immediately Reportable Event (IRE): 
• Any SAE 
• Any AE that necessitates discontinuation of study drug 
• Potential Hy’s Law cases (any increase of AST or ALT ≥ 3 times the upper normal limit 
or screening value with an increase in total bilirubin ≥ 2 times the upper normal limit or 
screening value)  
• Pregnancies are also defined as IREs, although normal pregnancy is not an AE, it will 
mandate study drug discontinuation and must be reported on an immediately reportable 
event (IRE) form to OAPI.  Pregnancy will only be documented on the AE-CRF if there 
is an abnormality or complication. 
The investigator must immediately report any serious adverse event (SAE), potential Hy’s law 
cases, or confirmed pregnancy, by telephone or by fax to OAPI as outlined in Section 9.5.4.1 
after either the investigator or site personnel become aware of the event.  An IRE form must be 
completed and sent by fax or overnight courier to OAPI within 24 hours of knowledge of the 
event by the site.  (Please note that the IRE form is NOT the AE CRF.) 
Non-serious events that require discontinuation of study drug (including laboratory 
abnormalities) should be reported to OAPI within 3 working days.  The IRE form must be 
completed and sent by fax or overnight courier to OAPI. 


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Subjects experiencing SAEs should be followed clinically until their health has returned to 
baseline status, or until all parameters have returned to normal, or have otherwise been 
explained.  It is expected that the investigator will provide or arrange appropriate supportive care 
for the subject. 
POTENTIAL HY’S LAW CASES 
For a subject that experiences an elevation in AST or ALT that is ≥ 3 times the upper limit of 
normal (ULN) or whose levels increase ≥ 3 times their initial screening value, a total bilirubin 
level should also be evaluated.  If the total bilirubin is ≥ 2 times the ULN or ≥ 2 times their 
screening value, complete an IRE form with all values listed and also report as an AE on the 
CRF. 
9.5.4.3 Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
During the trial, all women of childbearing potential should be instructed to contact the 
investigator immediately, but no later than 3 days, if they suspect they might be pregnant (e.g., 
missed or late menstrual cycle). 
If a subject or investigator suspects that the subject may be pregnant prior to study drug 
administration, the study drug administration must be withheld until the results of serum 
pregnancy tests are available.  If the pregnancy is confirmed, the subject must not receive the 
study drug and must not be enrolled in the study.  If pregnancy is suspected while the subject is 
taking study drug, the study drug must be withheld immediately (if reasonable, taking into 
consideration any potential withdrawal risks) until the result of the pregnancy is known.  If 
pregnancy is confirmed, the study drug will be permanently discontinued in an appropriate 
manner (e.g., dose tapering if necessary for subject safety) and the subject withdrawn from the 
study.  Exceptions to study discontinuation may be considered for life-threatening conditions 
only after consultations with OAPI’s Clinical Safety and Pharmacovigilance Department (see 
Section 9.5.4.1 for contact information). 
The investigator must immediately notify OAPI of any pregnancy associated with study drug 
exposure, including for 30 days for a female subject and 90 days for a male subject after the last 
dose of SOC oral antipsychotics and 150 days for a female subject and 180 days for a male 
subject after the last dose of aripiprazole once monthly, and record the event on the IRE form 
and forward it to OAPI.  The OAPI contact will forward Pregnancy Surveillance Form(s) for 
monitoring the outcome of the pregnancy. 
Protocol required procedures for trial discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies).  Other appropriate pregnancy 
follow-up procedures should be considered if indicated.  In addition, the investigator must report 
to OAPI, on appropriate Pregnancy Surveillance Form(s), follow-up information regarding the 
course of the pregnancy, including perinatal and neonatal outcome.  Infants will be followed for 
a minimum of 6 months. 
9.5.4.4 Reporting of Safety Information and Other Events of Interest 
All non-serious AEs will be reported to OAPI at the end of the study or at the request of OAPI. 


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REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Safety Information is defined as any information from any source containing information such 
as: 
● Adverse event or suspicion thereof 
● Lack of efficacy 
● Overdose, abuse, misuse (even without resulting adverse reaction) 
● Medication error 
● Exposure during pregnancy or lactation (including uneventful) and reports where the 
embryo or fetus may have been exposed to medicinal products (either through maternal 
exposure or transmission of a medicinal product via semen following paternal exposure) 
● Counterfeit product 
● Transfer of infectious disease by the medicinal product concerned 
● Product complaint report which includes medically important information 
● Pediatric use 
● Occupational exposure  
● Off-label use 
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer to 
AEs associated with uses of the study drug outside of that specified by the protocol.  Overdose, 
misuse, abuse, and medication error are defined as follows: 
Overdose 
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose  
Misuse 
Intentional and inappropriate use of study drug not in accordance with 
the prescribed or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a prescription  
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, procedures, and 
systems including prescribing; order communication; product labeling, 


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packaging, and nomenclature; compounding; dispensing; distribution; 
administration; education; monitoring; and use. 
All AEs associated with an overdose should be captured on the CRF.  Adverse events associated 
with overdose, misuse, abuse, or medication error should be reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet 
serious criteria.  Abuse is always to be captured as an AE.  If the AE associated with an 
overdose, misuse, abuse, or medication error does not meet serious criteria, it must still be 
reported using the SAE form and in an expedited manner but should be noted as nonserious on 
the SAE form and the CRF. 
9.5.4.5 Regulatory Reporting of Adverse Events 
Adverse events will be reported by the investigator or a third party acting on behalf of the 
investigator to regulatory authorities in compliance with the law and established guidance and 
will be reported to OAPI at least 2 weeks prior to submission of an aggregate safety report.  The 
format of these reports will be dictated by the local requirements. 
9.5.5 Database Reconciliation 
The investigator or designee will request contact information for the OAPI safety officer to 
whom this protocol is assigned.  The safety officer will provide listings of SAES and non-serious 
AEs from OAPI to the investigator or designee for review and potential reconciliation of the 
safety data.  This review will occur at specified time points and at the end of the study for final 
reconciliation.   
The OAPI contact will be copied on all correspondence regarding attempts to reconcile the safety 
database.   
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 study’s early discontinuation procedures 
indicated in the Schedules of Assessments (Table 4 through Table 7) 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 terminated, 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. 


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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/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 OAPI has ethical, legal, and scientific obligations to follow this trial 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 (maintain current personal knowledge of the progress of the trial), 
OAPI's monitors may visit the site during the trial, as well as communicate frequently via 
telephone and written communications.   
9.6.2 Auditing 
The OAPI Quality Management Unit (or representative) may conduct trial site audits.  Audits 
will include, but are not be limited to, drug supply, presence of required documents, the informed 
consent process, and comparison of CRFs with source documents.  The investigator agrees to 
participate with audits. 
Regulatory authorities may inspect the investigator during or after the trial.  The investigator will 
cooperate with such inspections and will contact the sponsor immediately if such an inspection 
occurs. 
9.6.3 Data Collection Duration 
Data collection begins when the first subject signs the ICF 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. 
9.7 STATISTICAL METHODS 
All statistical analyses will be performed by the investigator or designee after the study is 
completed and the database is locked and released and randomization codes have been released.  
Statistical analyses will be performed using SAS software or other validated statistical software 
as required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP). 
9.7.1 Statistical and Analytical Plans 
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. 


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9.7.1.1 Primary Endpoint(s) 
The primary efficacy endpoint is change from Phase C baseline in prefrontal white matter FA 
measured by DT-MRI. The primary time point will be the Week 52 assessment.  Secondary 
Endpoint(s) 
The secondary efficacy endpoints will include: 
• 
Change from Phase C baseline in volumes by high-resolution MRI.  This variable will be 
analyzed using the methods employed for the primary endpoint. 
• 
Change from Phase C baseline in Water-BPF by MRI.  This variable will be analyzed 
using the methods employed for the primary endpoint. 
• 
Changes from Phase C baseline in schizophrenia-related instrument scores, if appropriate.  
These variables will be analyzed using the methods employed for the primary endpoint. 
• 
Changes from Phase C baseline in neuropsychological measures.  These variables will be 
analyzed using the methods employed for the primary endpoint. 
9.7.1.2 Exploratory Endpoint(s) 
Exploratory endpoints such as proton metabolite measurements by MRS will be analyzed as 
appropriate.  Additional analyses will be performed as appropriate. 
9.7.1.3 Definitions of Analysis Sets 
Three analysis populations will be considered in this study, safety, intent-to-treat (ITT), and per 
protocol (PP) populations.   
• 
Safety population:  includes all subjects with any safety assessments 
• 
ITT population:  includes all subjects with some Phase C baseline and post-baseline 
efficacy assessments 
• 
PP population includes:  all ITT subjects without major protocol deviations 
Unless otherwise stated, the primary safety analyses will be based on the safety population and 
the primary efficacy and pharmacodynamic analyses will be based on the ITT population.  
The primary comparisons will be made between the SOC oral antipsychotic arm and the 
aripiprazole depot arm during Phase C. 
9.7.1.4 Subject Disposition 
Descriptive statistics will be utilized.  By-subject listings and summary tables will be provided. 
9.7.1.5 Demographic and Other Baseline Characteristics 
Descriptive statistics will be utilized.  By-subject listings and summary tables will be provided. 


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9.7.1.6 Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number (percentage) of 
subjects who took prior and concomitant medications will be summarized by treatment group, 
Anatomical Therapeutic Chemical (ATC) class (i.e., nervous system class and therapeutic class), 
and WHO DD preferred term.  Prior medications will be defined as medications that stopped 
before the first dose of study drug.  Concomitant medications will be defined as medications that 
(1) started before the first dose of study drug and were continuing at the time of the first dose of 
study drug, or (2) started on or after the date of the first dose of study drug up to 30 days after the 
subject’s last dose.  All medications will be presented in subject data listings. 
9.7.1.7 Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  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, maximum for continuous variables; n [%] for 
categorical variables).  Safety variables include physical examinations, neurologic evaluations, 
treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, 12-lead 
ECG results, and injection site reactions.  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 
By-subject listings and summary tables will be provided. 
9.7.1.7.2 Adverse Events 
The AE verbatim descriptions (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 lower level term (LLT) closest to the 
verbatim term.  The linked MedDRA preferred term (PT) and primary system organ class (SOC) 
are also captured in the database. 
A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment 
(Baseline) or  
● Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
● 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 (TEAEs) will be summarized by treatment group and overall.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and PT.  A subject will be counted only once within a SOC and PT, even if the subject 


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experienced more than one TEAE within a specific SOC and PT.  The number (percentage) of 
subjects with TEAEs will also be summarized by maximum severity (mild, moderate, or severe). 
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (possibly related, probably related, and not related). 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by SOC 
and PT.  Treatment-related TEAEs include those events considered by the investigator to be 
possibly or probably related to study treatment.  The number (percentage) of subjects with 
treatment-related TEAEs will also be summarized by maximum severity (mild, moderate, or 
severe). 
Adverse events will be summarized using the Safety Analysis Set.  The number of AEs and 
number and incidence (%) of subjects with AEs will be summarized by cohort/dose level and 
overall.  To obtain the incidence (%), the number of subjects with at least 1 event and the 
percentage of subjects with AEs by system organ class (SOC) and by preferred term (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 (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided. 
The number (percentage) of subjects with SAEs will be summarized by MedDRA SOC and PT 
for each treatment group.  A subject data listing of all SAEs will be provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC 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 
Summary statistics for changes from baseline and the incidence of potentially clinically 
significant values in the routine clinical laboratory measurements will be provided. 
9.7.1.7.4 Physical Examination and Vital Signs 
By-subject listings will be provided for physical examination. Summary statistics for change 
from baseline and incidence of potentially clinically significant results in vital signs will be 
provided. 
9.7.1.7.5 Electrocardiograms 
Mean change from baseline and incidence of clinically significant changes in ECG parameters 
will be calculated. 


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9.7.1.7.6 Other Safety Analyses 
Summary statistics will be provided for the change from baseline in SAS, AIMS, and BARS 
when applicable.  Summary statistics for VAS score and injection site reaction will be provided 
when applicable.  Suicidality data collected on the C-SSRS will be summarized as appropriate. 
9.7.1.8 Efficacy Analyses 
9.7.1.8.1 Primary Efficacy Analysis 
The primary endpoint will be analyzed by an analysis of variance (ANOVA) model with 
treatment effect.  The treatment effects, treatment differences, and the 95% confidence intervals 
of the treatment differences will be presented. 
9.7.1.8.2 Secondary Efficacy Analyses 
The secondary endpoints will be analyzed by an analysis of variance (ANOVA) model with 
treatment effect.  The treatment effects, treatment differences, and the 95% confidence intervals 
of the treatment differences will be presented. 
Correlations between the imaging parameters, especially the primary endpoints and the 
neuropsychological measures (e.g., reaction time) will be analyzed. 
9.7.1.8.3 Exploratory Efficacy Analyses 
Exploratory endpoints such as proton metabolite measurements by MRS will be analyzed as 
appropriate.  Additional analyses will be performed as appropriate. 
9.7.1.9 Pharmacokinetic/Pharmacodynamic Analyses 
9.7.1.9.1 Pharmacokinetic Analyses 
Not applicable. 
9.7.1.9.2 Pharmacodynamic Analyses 
The PD endpoints will be analyzed by an analysis of variance (ANOVA) model with treatment 
effect.  The treatment effects, treatment differences, and the 95% confidence intervals of the 
treatment differences will be presented. 
9.7.2 Determination of Sample Size 
After screening subjects with schizophrenia will be randomized in a 2:1 (aripiprazole once 
monthly:/SOC oral antipsychotics) ratio to the aripiprazole once monthly arm or the SOC oral 
antipsychotic arm of the study.  A sample size of 42 (28 in the depot arm and 14 in the oral arm) 
will provide 90% power to detect a treatment difference for the primary endpoint at a two-sided 
5% significance level.  In the sample size calculation, it was assumed a treatment difference of 
0.7 and a common standard deviation of 0.64.  Approximately 60 subjects with schizophrenia 
will be randomized (40 in the depot arm and 20 in the oral arm) to account for the expected 
dropouts.  Up to 20 normal healthy subjects will also be enrolled to serve as the control. 


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9.7.3 Interim Analysis 
No interim analysis is planned. 
9.7.3.1 Data Safety Monitoring Board  
In addition, a DSMB will be created in compliance with the University of Utah IRBs guidances.  
9.7.3.1.1 
Functions of the Data and Safety Monitoring Board 
The DSMB will function as an independent body charged with monitoring the safety of subjects, 
and ensuring that the scientific goals of the study are met.  To support these goals, the DSMB 
will review proposed amendments to the study protocol, monitor AEs and report to the IRB, 
review subject withdrawals and the reasons for withdrawal, determine whether study procedures 
should be changed or the study should be stopped for reasons related to subject safety, and 
conduct reviews of the completeness and validity of study data.  The DSMB will also monitor 
subject privacy and data confidentiality, and will recommend added protections if necessary. 
9.7.3.1.2 
Monitoring of Data Quality by the DSMB 
On a quarterly basis, the DSMB will receive a report prepared by the research team on data 
quality and completeness.  This will include an overview of recruitment and retention, a 
summary report describing subject adherence to the protocol’s procedures and study-drug 
compliance, and a summary of the completeness and quality of the data elements needed to 
characterize the subjects and their primary and secondary outcomes.  These reports will be used 
by the DSMB to evaluate the adequacy of the research team’s data capture and management to 
support scientifically valid analysis.  The DSMB will make recommendations to improve data 
management as needed. 
The PI will review all unanticipated problems involving risk to subjects or others, SAEs, and any 
subject deaths; and provide an unbiased written report of the event within 5 calendar days. The 
medical monitor will comment on the outcome of the AEs and relationship of the event to the 
study drug.  
9.7.4 Other Statistical/Analytical Issues 
Not applicable. 
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 impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report. 


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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.  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 (source documents) are to be fully available for 
review by the sponsor’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 which have been certified for accuracy 
after production 
● Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (e.g., sonograms, CT scans, magnetic resonance images, radioactive images, 
ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless of 
how these images are stored, including microfiche and photographic negatives 
● Pain, quality of life, or medical history questionnaires completed by subjects 
● Records of telephone contacts 


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● 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 correct 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 Investigator's Brochure, 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. 
10.7 AUDITING PROCEDURES AND INSPECTION 
In addition to the routine monitoring procedures, the OAPI Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with OAPI’s SOPs to 
evaluate compliance with the principles of ICH GCP and all applicable local regulations.  If a 
government regulatory authority requests an inspection during the study or after its completion, 
the investigator must inform OAPI immediately. 


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10.8 REPORTING AND PUBLICATION OF RESULTS 
A clinical study report will be finalized within one year of the end of data collection. 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by OAPI in advance of submission pursuant to the 
terms and conditions set forth in the executed Clinical Study Agreement between OAPI and the 
institution/investigator.  The review is aimed at protecting OAPI's proprietary information 
existing either at the date of the commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between the investigator and OAPI, as appropriate. 
10.9 DISCLOSURE AND CONFIDENTIALITY 
The contents of this protocol and any amendments and results obtained during the study should 
be kept confidential by the investigator, the investigator’s staff, and the IRB and will not be 
disclosed in whole or in part to others, or used for any purpose other than reviewing or 
performing the study, without the written consent of OAPI.  No data collected as part of this 
study will be used in any written work, including publications, without the written consent of 
OAPI.  These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in either the Confidentiality Agreement or Clinical Study Agreement 
executed between OAPI and the institution/investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Study 
Agreement executed between the institution/investigator and OAPI. 
10.10 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 prematurely terminated or suspended, OAPI will promptly inform the 
investigators/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/institution, as specified by the applicable regulatory requirement(s). 
The investigator reserves the right to discontinue the study should his/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/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 REFERENCE LIST 
1 
DeLisi LE, Sakuma M, Tew W, Kushner M, Hoff AL, Grimson R.  Schizophrenia as a 
chronic active brain process: a study of progressive brain structural change subsequent to 
the onset of schizophrenia. Psychiatry Res.  Jul 4 1997; 74(3):129-140. 
2 
Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA.  The influence 
of chronic exposure to antipsychotic medications on brain size before and after tissue 
fixation: a comparison of haloperidol and olanzapine in macaque monkeys. 
Neuropsychopharmacology.  Sep 2005; 30(9):1649-1661. 
3 
van Haren NE, Hulshoff Pol HE, Schnack HG, et al.  Focal gray matter changes in 
schizophrenia across the course of the illness: a 5-year follow-up study. 
Neuropsychopharmacology.  Oct 2007; 32(10):2057-2066. 
4 
Molina V, Reig S, Sanz J, et al.  Increase in gray matter and decrease in white matter 
volumes in the cortex during treatment with atypical neuroleptics in schizophrenia. 
Schizophr Res.  Dec 1 2005; 80(1):61-71. 
5 
Lieberman JA, Tollefson GD, Charles C, et al.  Antipsychotic drug effects on brain 
morphology in first-episode psychosis. Arch Gen Psychiatry.  Apr 2005; 62(4):361-370. 
6 
Bartzokis G, Lu PH, Amar CP, et al.  Long acting injection versus oral risperidone in 
first-episode schizophrenia: differential impact on white matter myelination trajectory. 
Schizophr Res.  Oct 2011; 132(1):35-41. 
7 
Kennedy KM, Raz N.  Aging white matter and cognition: Differential effects of regional 
variations in diffusion properties on memory, executive functions, and speed. 
Neuropsychologia.  Feb 2009; 47(3):916-927. 
8 
Gulani V, Sundgren PC.  Diffusion tensor magnetic resonance imaging. J 
Neuroophthalmol.  Mar 2006; 26(1):51-60. 
9 
Grieve SM, Williams LM, Paul RH, Clark CR, Gordon E.  Cognitive aging, executive 
function, and fractional anisotropy: a diffusion tensor MR imaging study. AJNR Am J 
Neuroradiol.  Feb 2007; 28(2):226-235. 
10 
Madden DJ, Whiting WL, Huettel SA, White LE, MacFall JR, Provenzale JM.  Diffusion 
tensor imaging of adult age differences in cerebral white matter: relation to response 
time. Neuroimage.  Mar 2004; 21(3):1174-1181. 
11 
Soellinger M, Langkammer C, Seifert-Held T, Fazekas F, Ropele S.  Fast bound pool 
fraction mapping using stimulated echoes.  Magn Reson Med. Sep 2011; 66(3):717-724. 


Protocol  COL.AOM.2013.002 
 
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12 
Stikov N, Perry LM, Mezer A, et al.  Bound pool fractions complement diffusion 
measures to describe white matter micro and macrostructure.  Neuroimage.  Jan 15 2011; 
54(2):1112-1121. 
13 
Koenig SH, Brown RD, 3rd, Spiller M, Lundbom N.  Relaxometry of brain: why white 
matter appears bright in MRI. Magn Reson Med.  Jun 1990; 14(3):482-495. 
14 
Ou X, Sun SW, Liang HF, Song SK, Gochberg DF.  Quantitative magnetization transfer 
measured pool-size ratio reflects optic nerve myelin content in ex vivo mice.  Magn 
Reson Med.  Feb 2009; 61(2):364-371. 
15 
Schmierer K, Tozer DJ, Scaravilli F, et al.  Quantitative magnetization transfer imaging 
in postmortem multiple sclerosis brain.  J Magn Reson Imaging.  Jul 2007; 26(1):41-51. 
16 
Rushton WA. A theory of the effects of fibre size in medullated nerve.  J  Physiol. Sep 
1951; 115(1):101-122. 
17 
Waxman SG.  Integrative properties and design principles of axons.  Int Rev Neurobiol. 
1975; 18:1-40. 
18 
Baumann N, Pham-Dinh D.  Biology of oligodendrocyte and myelin in the mammalian 
central nervous system.  Physiol Rev. Apr 2001; 81(2):871-927. 
19 
Dager SR, Corrigan NM, Richards TL, Posse S.  Research applications of magnetic 
resonance spectroscopy to investigate psychiatric disorders.  Topics in magnetic 
resonance imaging :  TMRI.  Apr 2008; 19(2):81-96. 
20 
Wong CG, Bottiglieri T, Snead OC, 3rd.  GABA, gamma-hydroxybutyric acid, and 
neurological disease.  Annals of neurology.  2003; 54 Suppl 6:S3-12. 
21 
Sanacora G, Mason GF, Rothman DL, Krystal JH.  Increased occipital cortex GABA 
concentrations in depressed patients after therapy with selective serotonin reuptake 
inhibitors.  Am J Psychiatry. Apr 2002; 159(4):663-665. 
22 
Petroff OA, Errante LD, Rothman DL, Kim JH, Spencer DD.  Neuronal and glial 
metabolite content of the epileptogenic human hippocampus.  Annals of neurology. Nov 
2002; 52(5):635-642. 
23 
Streeter CC, Hennen J, Ke Y, et al. Prefrontal GABA levels in cocaine-dependent 
subjects increase with pramipexole and venlafaxine treatment. Psychopharmacology 
(Berl). Nov 2005;182(4):516-526. 
24 
McLoughlin GA, Ma D, Tsang TM, et al.  Analyzing the effects of psychotropic drugs on 
metabolite profiles in rat brain using 1H NMR spectroscopy.  J Proteome Res. Apr 2009; 
8(4):1943-1952. 


Protocol  COL.AOM.2013.002 
 
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Final Protocol: 29 July 2013 
25 
Chanraud S, Zahr N, Sullivan EV, Pfefferbaum A. MR diffusion tensor imaging: a 
window into white matter integrity of the working brain. Neuropsychol Rev. Jun 
2010;20(2):209-225. 
26 
Prescot AP, Locatelli AE, Renshaw PF, Yurgelun-Todd DA.  Neurochemical alterations 
in adolescent chronic marijuana smokers: a proton MRS study. Neuroimage.  Jul 1 2011; 
57(1):69-75. 
27 
Aripiprazole Investigator Brochure Version No. 13.  BMS Document Control, 2009. 
15(0920002092 11.0). 
28 
Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, et al.  
Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with 
schizophrenia and schizoaffective disorder.  J Clin Psychiatry. 2002; 63:763-71 
29 
Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, et al.  Aripiprazole,  an 
antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients 
with schizophrenia and schizoaffective disorder.  Arch Gen Psychiatry.  2003; 60:681-90 
30 
Carson WH.  A multicenter, randomized, double-blind, placebo-controlled study of three 
fixed doses of aripiprazole in the treatment of patients with acute schizophrenia.  Bristol-
Myers Squibb Company Study No. CN138001/Report BMS Document Control No. 
930000317, 2001 
31 
Carson, WH. A multicenter, randomized, double-blind, placebo-controlled, 26 week 
study of a fixed dose of aripiprazole in the treatment of stabilized patients with chronic 
schizophrenia.  Bristol-Myers Squibb Company Study No. CN138047/Report BMS 
Document Control No. 930000855, 2001 
32 
Pigott TA, C.W., Saha AR, Torbeyns AF, Stock EG, Ingenito GG, et al. Aripiprazole for 
the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-
controlled 26-week study. J Clin Psychiatry.  2003. 64(1046-56). 
33 
A multicenter, randomized, double-blind, active-controlled study to compare the long-
term maintenance effects and safety of aripiprazole and haloperidol following acute 
relapse in schizophrenic patients.  Otsuka Study Nos. 31-98-217 and 31-98-304- 01, 
BMS Document Control No. 930000732, Report issued 08 Oct 2001 
34 
Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, et al.  Efficacy and 
safety of aripiprazole vs. haloperidol for long-term maintenance treatment following 
acute relapse of schizophrenia.  Int J Neuropsychopharmacol.  2003; 6:325-7. 
35 
Marcus R.  A Prospective, Multicenter, Open-Label Study of Aripiprazole in the 
Management of Patients with Schizophrenia in General Psychiatric Practices (Broad 


Protocol  COL.AOM.2013.002 
 
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Effectiveness Trial with Aripiprazole - BETA).  Bristol-Myers Squibb Company Study 
No. CN138100, 2005 
36 
A multicenter, randomized, naturalistic, open-label study between aripiprazole and 
standard of care in the management of community-treated schizophrenic patients.  Study 
No. CN38152. Bristol-Myers Squibb Company 2006. No. 930015051. 
37 
Kerwin R, M.B., Herman E, Banki CM, Lublin H, Pans M, et al.  A multicentre, 
randomized, naturalistic, open-label study between aripiprazole and standard of care in 
the management of community-treated schizophrenic patients Schizophrenia Trial of 
Aripiprazole:  (STAR) study. . Eur Psychiatry, 2007. 22(433-43). 
38 
Tandon R, D.R., Han J, Li H, Frangou S, Dursun S for the IAQ Validation Study Group.  
Validation of the Investigator's Assessment Questionnaire, a new clinical tool for relative 
assessment of response to antipsychotics in patients with schizophrenia and 
schizoaffective disorder.  Psychiatry Research, 2005.  136(211-21). 
39 
Tran-Johnson TK, S.D., Marcus RN, Auby P, McQuade RD, Oren DA.  Efficacy and 
safety of intramuscular aripiprazole in patients with acute agitation:  A randomized, 
double-blind, placebo-controlled trial. J Clin Psychiatry, 2007. 68:111. 
40 
Nyalis M, Mallikaarjun S.  An open-label parallel arm multiple dose tolerability, 
pharmacokinetics and safety study in adult patients with schizophrenia following 
administration of aripiprazole IM depot formulation once every four weeks.  Otsuka 
Clinical Study Report for Protocol 31-05-244, issued 27 May 2009, amended 17 Jul 2009 
41 
Vieta E, Bourin M, Sanchez R, Marcus R, Stock E, McQuade R.  Effectiveness of 
aripiprazole v. haloperidol in acute bipolar mania:  Double-blind, randomised, 
comparative 12-week trial.  Br J Psychiatry.  2005; 187:235-42. 
42 
.Schulte RF and Boesiger P.  ProFit:  two-dimensional prior-knowledge fitting of 
J-resolved spectra.  NMR Biomed.  2006 Apr; 19(2):255-63. 
43 
Teipel SJ, Meindl T, Wagner M, Stieltjes B, Reuter S, Hauenstein S, et al.  Longitudinal 
changes in fiber tract integrity in healthy aging and mild cognitive impairment:  a DTI 
follow-up study.  J Alzheimers Dis.  2010; 22(2):507-22. 
 
 
 

ICF_001.pdf: 
Deborah Yurgelun-Todd, Ph.D. 
 
Page 1 of 15 
[A Randomized, Open-Label, Parallel-Group, Study of the Impact of Aripiprazole Once Monthly versus Standard of Care Oral Antipsychotic 
Medications on Changes in Brain Structure And Metabolism 
Version: June 2017, 4.0  
 
FOOTER FOR IRB USE ONLY 
Version: 102513 
 
 
University of Utah 
Institutional Review Board 
Approved 5/24/2017 
Expires 5/23/2018 11:59 PM 
IRB_00073657 
 
Consent and Authorization Document 
 
BACKGROUND 
You are being asked to take part in a research study. Before you decide, it is important for you to 
understand why the research is being done and what it will involve. Please take time to read the 
following information carefully and discuss it with friends and relatives if you wish. This form describes 
the purpose, procedures, benefits, recognized or known risks, discomforts, and precautions of the study 
including the duration and nature of your participation. It also describes recognized or known 
alternative therapies that may be available and your right to withdraw from the study at any time. No 
guarantees or assurances can be made as to the results of the study. Ask the research doctor or staff if 
there is anything that is not clear or if you would like more information. Take time to decide whether or 
not to volunteer to take part in this research study.   
 
The purpose of the study is to evaluate the effects of 12 months of treatment with long-acting 
intramuscular (IM) aripiprazole in subjects with schizophrenia compared with standard of care (SOC) 
oral antipsychotic medications and compared with a healthy control group. Both the long-acting 
intramuscular (IM) aripiprazole and the oral antipsychotic medications are FDA approved standardly 
available treatments. You are being asked to participate in this study because you are a male or female 
between the ages of 18 and 35, and have a current diagnosis of schizophrenia. Long-acting IM 
aripiprazole and SOC oral antipsychotic medications are treatments used for schizophrenia. Otsuka 
America Pharmaceuticals, Inc. is paying the study center, the University of Utah, and the study doctor, 
Dr. Deborah Yurgelun-Todd, to conduct this study. 
 
This is a Phase IV study. Phase IV studies are done after a drug or treatment has been marketed to 
gather information on the drug’s effect in various populations and any side effects associated with long 
term use.  
 
STUDY MEDICATION 
This study involves the administration of long-acting IM aripiprazole and SOC oral antipsychotic 
medications. Study medication 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 (IM), 300 or 400 mg administered via gluteal injection, once monthly 
• 
SOC oral antipsychotic medications, per oral (PO) including but not limited to: 
o Aripiprazole (Abilify®), 10 mg to 30 mg, daily 
o Risperidone (Risperdal®), 2 to 8 mg daily 
o Lurasidone HCl (Latuda ®), 40 to 160 mg daily 
o Quetiapine Fumarate (Seroquel®), 300 to 800 mg daily 
o Olanzapine (Zyprexa®), 10 to 30 mg daily 
o Ziprasidone HCl (Geodon®), 40 to 160 mg daily 
 


Deborah Yurgelun-Todd, Ph.D. 
 
Page 2 of 15 
[A Randomized, Open-Label, Parallel-Group, Study of the Impact of Aripiprazole Once Monthly versus Standard of Care Oral Antipsychotic 
Medications on Changes in Brain Structure And Metabolism 
Version: June 2017, 4.0  
 
FOOTER FOR IRB USE ONLY 
Version: 102513 
 
 
University of Utah 
Institutional Review Board 
Approved 5/24/2017 
Expires 5/23/2018 11:59 PM 
IRB_00073657 
 
 
 
STUDY PROCEDURES 
There will be up to 80 participants in this study:  approximately 60 males and females with schizophrenia 
and 20 healthy male and female controls. This is a randomized, open-label, parallel-group trial. 
“Randomized” means that participants are assigned to different groups by chance. “Open-label” means 
that both the researchers and participants know which treatment is being administered. “Parallel-
group” means each participant is assigned to receive only one of the study treatments.   
 
You will be asked to attend a Screening Visit, Baseline Visits, Conversion Phase (if applicable), 
Stabilization Phase, Treatment Period, and Follow-up Visit. Your participation is expected to last up to 
14.5 months.  
 
Screening Period 
The Screening Visit will occur within 7 days prior to the receiving study drug.  At the Screening Visit you 
will receive a full physical examination, and you will be asked some questions about your medical and 
social history, any medications you are taking, and your mood and personality. During your physical 
examination we will draw your blood and collect a urine sample for routine laboratory tests, to screen 
for drugs and alcohol, and test for pregnancy (in women of childbearing age); measure 
electrocardiogram (ECG) [a painless tracing of the electrical activity of the heart] recordings and your 
vital signs (blood pressure, heart rate, body temperature and breathing rate); and record your waist 
circumference, weight, height and body mass index (an estimate of your body fat based on your height 
and weight). 
 
Randomization 
After screening, you will be randomized to either the aripiprazole once monthly group or the SOC oral 
antipsychotic group in a 2:1 ratio. 
• 
Aripiprazole once monthly group: Subjects in this group will receive aripiprazole once monthly 
at an approved dose based on the investigator’s judgment and in accordance with product 
labeling administered via gluteal IM injection once monthly. 
• 
SOC oral antipsychotic group: Subjects in this group will receive SOC oral antipsychotic 
medications prescribed by the study physician based on the investigator’s judgment and in 
accordance with product labeling. 
 
Baseline Visit 
You will be asked to complete a Baseline Visit prior to entry into each phase of the study (i.e., 
Conversion Phase, Stabilization Phase, and Treatment Phase). During the Baseline Visit you will answer 
questions regarding your current antipsychotic therapy and any medications you are currently taking. 
Vital signs will be measured and body mass index (BMI) will be calculated. You will answer questions 
about your mood and feelings, and any adverse events or side effects you have experienced. 
 
After the first Baseline Visit, if you: 
 


Deborah Yurgelun-Todd, Ph.D. 
 
Page 3 of 15 
[A Randomized, Open-Label, Parallel-Group, Study of the Impact of Aripiprazole Once Monthly versus Standard of Care Oral Antipsychotic 
Medications on Changes in Brain Structure And Metabolism 
Version: June 2017, 4.0  
 
FOOTER FOR IRB USE ONLY 
Version: 102513 
 
 
University of Utah 
Institutional Review Board 
Approved 5/24/2017 
Expires 5/23/2018 11:59 PM 
IRB_00073657 
 
• 
Are in the aripiprazole once monthly group and are not currently receiving oral aripiprazole 
monotherapy which means that you take only aripiprazole and no other antipsychotic 
medications, you will be given a prescription for your oral SOC antipsychotic medication and 
move into the Conversion Phase (Phase A) to begin cross-titration. 
• 
Are in the aripiprazole once monthly group and are currently receiving oral aripiprazole 
monotherapy, you will move directly to the Stabilization Phase (Phase B). 
• 
Require a washout from any prohibited medications, you will enter Phase A. 
• 
Are in the SOC oral antipsychotic arm and do not require a washout from prohibited 
medications, you will move directly into the Stabilization Phase (Phase B).  
 
Conversion (Phase A) – 4 to 6 weeks 
In Phase A, if you are in the aripiprazole once monthly group and are not currently receiving aripiprazole 
monotherapy you will undergo cross-titration to receive oral aripiprazole monotherapy, 10 to 20 mg PO, 
daily. "Cross-titration" means that we will lower the dose of your current medication while 
simultaneously increasing the dose of another medication, in this case aripiprazole. In addition, if you 
are currently on a prohibited medication, you will require a washout from that medication. This means 
prohibited medications will be withdrawn on a schedule based on the investigator’s judgment.  
 
During Phase A, you will attend weekly visits until deemed eligible for Phase B by the investigator. The 
Baseline Visit for Phase B will occur during the last visit of Phase A. 
 
Stabilization Phase (Phase B) – 4 to 12 weeks 
In Phase B, you will be receiving SOC oral antipsychotic medication. All oral antipsychotic medications 
will be prescribed using doses consistent with their respective product labeling.  
 
During Phase B, you will attend biweekly visits until stability criteria are met for two consecutive visits. If 
stability is not met within 12 weeks, you will be discontinued from the study. The Baseline Visit for 
Phase C will occur during the last visit of Phase B. 
 
Treatment Period (Phase C) – 52 weeks 
The Treatment Period consists of 18 Treatment Visits. Weeks 1 – 4 occur weekly; weeks 5 – 8 occur 
biweekly; and weeks 9 – 18 occur every 4 weeks.  
 
• 
A total of 30 – 40 subjects with schizophrenia will receive aripiprazole once monthly. In addition, 
these subjects will continue to receive oral aripiprazole at the dose given prior to Phase C for 14 
days. 
• 
A total of 15 – 20 subjects will receive SOC oral antipsychotic medications, PO daily. 
• 
A total of 15 – 20 control subjects will not receive any study drug; however, they will undergo all 
other Phase C assessments.  
 
 


Deborah Yurgelun-Todd, Ph.D. 
 
Page 4 of 15 
[A Randomized, Open-Label, Parallel-Group, Study of the Impact of Aripiprazole Once Monthly versus Standard of Care Oral Antipsychotic 
Medications on Changes in Brain Structure And Metabolism 
Version: June 2017, 4.0  
 
FOOTER FOR IRB USE ONLY 
Version: 102513 
 
 
University of Utah 
Institutional Review Board 
Approved 5/24/2017 
Expires 5/23/2018 11:59 PM 
IRB_00073657 
 
During Phase C, your vital signs, waist circumference, weight and height will be recorded; adverse events 
and any medications you are taking will be reviewed; clinical assessments regarding your thoughts and 
feelings will be administered; and pregnancy testing will be performed (for women of childbearing age). 
 
After 6 and 12 months of treatment, you will receive a physical examination and ECG; provide blood and 
urine samples for routine laboratory tests and drug screening; and complete neuropsychological testing 
and an MRI protocol. The MRI protocol will last approximately an hour and thirty minutes, and the 
neuropsychological testing will last approximately an hour and fifteen minutes. 
 
Follow-Up Period 
If you receive at least one dose of study drug and are discontinued from the study for any reason, you 
will be followed for safety reasons for 30 days following the last dose of drug. 
 
RISKS 
During this study, you will be taking aripiprazole IM once monthly or SOC oral antipsychotic medications. 
Oral antipsychotic medications may include: Aripiprazole (Abilify®), Risperidone (Risperdal®), Lurasidone 
HCl (Latuda ®), Quetiapine Fumarate (Seroquel®), Olanzapine (Zyprexa®), and Ziprasidone HCl 
(Geodon®). The most common the side effects of antipsychotic medications are often mild such as 
drowsiness, rapid heartbeat, anxiety, an inner sense of restlessness, and dizziness. Other common side 
effects of antipsychotics may include: 
 
• 
A drop in blood pressure upon standing or stretching (Orthostatic hypotension) 
• 
Blurred vision 
• 
Changes in cholesterol and triglyceride levels (dyslipidemia) 
• 
Decreases in white blood cells 
• 
Diarrhea, constipation 
• 
Difficulty swallowing (Dysphagia) 
• 
Dry mouth (Salivary Hypersecretion)  
• 
Fatigue 
• 
Increased levels of prolactin in blood (Hyperprolactinemia) 
• 
Increased appetite, weight gain 
• 
Increased risk of suicidal thoughts or actions 
• 
Increases in blood sugar levels (Hyperglycemia) 
• 
Involuntary muscle contraction (Dystonia) 
• 
Nasal congestion, upper respiratory tract infection, Nasopharyngitis, and Pharyngolaryngeal 
pain 
• 
Nausea, vomiting 
• 
Neuroleptic Malignant Syndrome (NMS), a rare and serious condition that can lead to death 
• 
Potential for cognitive and motor impairment 
• 
Rash 
• 
Seizures (convulsions) 
• 
Tardive Dyskinesia (TD), symptoms include uncontrollable movements of face, tongue or other 
body parts. 


Deborah Yurgelun-Todd, Ph.D. 
 
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[A Randomized, Open-Label, Parallel-Group, Study of the Impact of Aripiprazole Once Monthly versus Standard of Care Oral Antipsychotic 
Medications on Changes in Brain Structure And Metabolism 
Version: June 2017, 4.0  
 
FOOTER FOR IRB USE ONLY 
Version: 102513 
 
 
University of Utah 
Institutional Review Board 
Approved 5/24/2017 
Expires 5/23/2018 11:59 PM 
IRB_00073657 
 
• 
Upper abdominal pain, stomach discomfort, dyspepsia 
• 
Weight gain 
 
Participants receiving long-acting IM aripiprazole may also experience pain, swelling, redness, and 
induration at the injection site. 
 
As part of this study, you may be asked to change your medications.  During the time in which your 
medications are being changed, you may also notice that your symptoms are different. We anticipate 
minimal risk during this time and we will work closely with you to evaluate and minimize any worsening 
of symptoms.  
 
During this study, you should not take any other medications without talking to the study doctor/staff. 
This includes over the counter medications, herbal or dietary preparations (tablets, capsules, etc.) or 
vitamins. 
 
Magnetic Resonance Imaging (MRI) 
There may be risks that are associated with MRI scans. 
Unlike X-rays or CAT scans, magnetic resonance (MR) technology does not use radiation. Instead, it uses 
strong magnetic fields and radio waves to collect the images and data. There are no known hazards or 
risks associated with MR techniques. Significant risks may exist for people with: 
• 
Cardiac pacemakers 
• 
Metal clips on blood vessels (also called stents) 
• 
Artificial heart valves 
• 
Artificial arms, hands, legs, etc. 
• 
Brain stimulator devices 
• 
Implanted drug pumps 
• 
Ear implants 
• 
Eye implants or known metal fragments in eyes 
• 
Exposure to shrapnel or metal filings 
• 
Other metallic surgical hardware in vital areas 
• 
Certain tattoos with metallic ink (please tell us if you have a tattoo) 
• 
Certain transdermal (skin) patches such as NicoDerm (nicotine for tobacco dependence), 
Transderm Scop (scopolamine for motion sickness), or Ortho Evra (birth control) 
 
Significant risks also can arise if certain materials (many types of metal objects) are brought into the 
scanning area, as they can be pulled into the magnet at great speed. Such items can cause serious injury 
if they hit anyone. Therefore, these types of items are not permitted in the scanning area. 
  
The MR exams are painless, and except for pulsating sounds, the subject will not be aware that scanning 
is taking place. The sounds that subjects hear inside the scanner are the normal operating sounds the 
scanner makes. While they may be annoying, their intensity is not harmful to the subject's hearing. 
However, they will be given a pair of earplugs to wear to muffle the sounds as well as a set of 
headphones, which further reduces the noise level and permits communication with the MR technician. 


Deborah Yurgelun-Todd, Ph.D. 
 
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[A Randomized, Open-Label, Parallel-Group, Study of the Impact of Aripiprazole Once Monthly versus Standard of Care Oral Antipsychotic 
Medications on Changes in Brain Structure And Metabolism 
Version: June 2017, 4.0  
 
FOOTER FOR IRB USE ONLY 
Version: 102513 
 
 
University of Utah 
Institutional Review Board 
Approved 5/24/2017 
Expires 5/23/2018 11:59 PM 
IRB_00073657 
 
  
The scans for this study take place on the 3.0T scanner, which is approved by the FDA for routine clinical 
studies in children and adults. Although there are no known risks from these scans, there could be 
adverse effects that are delayed or very mild, such that they have not yet been recognized. Most people 
experience no ill effects from these scans, but some people do report claustrophobia (fear of being in 
enclosed small spaces), dizziness, mild nausea, headaches, a metallic taste in their mouth, double vision, 
or sensation of flashing lights. These symptoms, if present, disappear shortly after leaving the scanner. 
  
In rare cases, a very slight, uncomfortable tingling of the back due is induced in some people undergoing 
certain types of scans. Subjects are asked that, if they experience this sensation, to report it immediately 
so the scan can be changed to avoid this. Although these precautions will avoid all known risks 
associated with MRI, this procedure may involve risks that are currently unforeseeable. 
 
Electrocardiograms (ECG) 
There is no pain or discomfort during an ECG; however the patches may cause a skin reaction such as 
redness or itching. Taking the pads off my cause localized irritation to the skin and/or hair loss, similar to 
having a Band-Aid taken off. 
 
Blood Draws 
During the collection of blood samples, participants may experience pain and/or bruising at the needle 
injection site.  Although rare, excess bleeding, clots, and infections at the injection site may 
occur.  Lightheadedness and/or fainting may also occur during or shortly after the blood draw. 
 
Confidentiality 
Although every effort to protect personal health information will be implemented, it is possible that if 
confidential information is inadvertently disclosed, there could be negative effects on the participant; 
such as, a negative effect to employment or ability to obtain insurance. 
 
REPRODUCTIVE RISKS 
Magnetic Resonance Imaging (MRI) 
If you are a female of childbearing age, a urine sample will be tested prior to MRI scanning, which will be 
tested to ensure that you are not pregnant. If you have a positive pregnancy result, we will inform you 
and you will not be allowed to participate in the study. It is important to be as sure as possible that you 
are not pregnant because the MRI technology being used may cause harm to an unborn child. 
 
Study Drugs 
It is unknown whether antipsychotic drugs can cause fetal harm when administered to a pregnant 
woman or can affect reproductive capacity. Neonates exposed to antipsychotic drugs during the third 
trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. 
There have been reports of agitation, hypertonia (increased tightness of muscle tone and reduced 
capacity of the muscle to stretch), hypotonia (decreased muscle tone and strength), tremor, somnolence 
(sleepiness), respiratory distress and feeding disorder in these neonates. These complications have 


Deborah Yurgelun-Todd, Ph.D. 
 
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[A Randomized, Open-Label, Parallel-Group, Study of the Impact of Aripiprazole Once Monthly versus Standard of Care Oral Antipsychotic 
Medications on Changes in Brain Structure And Metabolism 
Version: June 2017, 4.0  
 
FOOTER FOR IRB USE ONLY 
Version: 102513 
 
 
University of Utah 
Institutional Review Board 
Approved 5/24/2017 
Expires 5/23/2018 11:59 PM 
IRB_00073657 
 
varied in severity; while in some cases symptoms have been self-limited, in other cases, neonates have 
required intensive care unit support and prolonged hospitalization.  
 
 
Contraception 
To be in this study, you must agree to use an effective method of birth control during the course of the 
trial and for 30 days (female participants) and 90 days (male participants) after the last dose of oral 
antipsychotics, or 150 days (female participants) and 180 days (male participants) after the last dose of 
aripiprazole once monthly, in a manner such that risk of failure is minimized.  
 
Two of the following methods must be used: 
• 
Vasectomy 
• 
Tubal ligation 
• 
Vaginal diaphragm 
• 
IUD 
• 
Birth control pills 
• 
Birth control depot injection 
• 
Birth control implant 
• 
Condom 
• 
Sponge with spermicide 
 
If you and your partner(s) are sterile (i.e., women who have had an oophorectomy and/or hysterectomy 
or have been postmenopausal for at least 12 consecutive months; or men who have had orchiectomy) 
or remain abstinent, there are no contraceptive requirements for your participation in this study. 
 
Pregnancy  
In the event that you suspect pregnancy or become pregnant, it is very important for the investigator to 
be informed of the pregnancy immediately. If you become pregnant prior to receiving study drug, you 
will not receive study drug and will be dis-enrolled from the study. If you become pregnant while taking 
study drug, the drug will be permanently discontinued in an appropriate manner and you will be 
withdrawn from the study. OAPI will monitor the course of your pregnancy, including perinatal and 
neonatal outcome, and the infant will be followed for a minimum of 6 months. 
 
UNFORESEEABLE RISKS 
In addition to the risks listed above, the study drugs and procedures may have unknown risks. There is 
always the possibility that you will have a side effect that is currently unknown or not expected. It is 
important that you report any and all symptoms/health problems to the study doctor/staff. You will be 
monitored for side effects and the study doctor may decide that you should be withdrawn from the 
study for your safety. If any new information becomes available during the course of the study that may 
affect your willingness to participate, you will be informed.  
 
 


Deborah Yurgelun-Todd, Ph.D. 
 
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BENEFITS 
Participation in this study is purely for research purposes, and will not improve your health or treat any 
medical problem you may have. You may benefit by having physical examinations. The results of 
laboratory tests done at the screening visit will be made available to you upon request; however, if you 
are disqualified for study participation by other screening procedures, some laboratory tests may not be 
conducted. 
 
There may be no other direct benefits to you from this study. In the future, the information from this 
study may help others by providing important knowledge about the use of long acting IM aripiprazole 
versus oral antipsychotic medications for the treatment of schizophrenia. 
 
ALTERNATIVE PROCEDURES 
You may choose not to be in this study. If you choose not to participate, you may continue to receive 
treatment from your doctor.  Standard treatments include a range of medications, taken by mouth or by 
injection. If you currently do not have a doctor you may wish to contact one of the following mental 
health resources: 
 
• 
University Neuropsychiatric Institute (UNI)  
 
801-583-2500 
• 
UNI Adult Behavioral Clinic 
 
801-585-1212 
• 
Fourth Street Clinic 
 
801-364-0058 
• 
Valley Mental Health 
 
Phone: 801-270-6550 
 
www.vmh.com 
• 
Valley Mental Health 24-Hour Crisis Line 
 
Phone: 801-587-3000 
• 
National Alliance on Mental Illness 
 
www.nami.org 
• 
University of UT Counseling Center 
 
Phone: 801-581-6826 
• 
University of UT Center for Student Wellness 
 
Phone: 801-581-7776 
 
http://www.wellness.utah.edu/index.htm 
 
 
 
 
 
 


Deborah Yurgelun-Todd, Ph.D. 
 
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PERSON TO CONTACT 
If you have questions, complaints or concerns about this study, or if you feel that you have been harmed 
as a result of participation, please call the following people: 
 
 
 
Principal Investigator:  
Deborah Yurgelun-Todd, Ph.D. 
 
 
 
 
 
(801) 587-1471 (Monday-Friday 9AM-5PM) 
 
 
 
Co-Investigators: 
 
Melissa Lopez-Larson, M.D. 
 
 
 
 
 
(801) 587-1554 (Monday-Friday 9AM-5PM) 
 
 
 
 
 
 
Erin McGlade, Ph.D. 
 
 
 
 
 
(801) 587-1412 (Monday-Friday 9AM-5PM) 
 
 
 
Research Assistant: 
 
Jennifer DiMuzio 
 
 
 
 
 
(801) 587-1471 (Monday-Friday 9AM-5PM) 
 
Institutional Review Board: Contact the Institutional Review Board (IRB) if you have questions regarding 
your rights as a research participant. Also, contact the IRB if you have questions, complaints or concerns 
which you do not feel you can discuss with the investigator. The University of Utah IRB may be reached 
by phone at (801) 581-3655 or by e-mail at irb@hsc.utah.edu.   
 
Research Participant Advocate:  You may also contact the Research Participant Advocate (RPA) by 
phone at (801) 581-3803 or by email at participant.advocate@hsc.utah.edu.  
 
RESEARCH-RELATED INJURY 
If you are injured from being in this study, medical care is available to you at the University of Utah as it 
is to all sick or injured people. The University of Utah has not set aside any money to pay the costs for 
such care. The University will work with you to address costs from injuries. Costs would be charged to 
you or your insurance company (if you have insurance), to the study sponsor or other third party (if 
applicable), to the extent those parties are responsible for paying for medical care you receive. Since 
this is a research study, some health insurance plans may not pay for the costs. By signing this consent 
form you are not giving up your right to pursue legal action against any parties involved with this 
research. 
 
The University of Utah is a part of the government. If you are injured in this study, and want to sue the 
University or the doctors, nurses, students, or other people who work for the University, special laws 
may apply. The Governmental Immunity Act of Utah is a law that controls when a person needs to bring 
a claim against the government, and limits the amount of money a person may recover. See sections 
63G -7-101 to -904 of the Utah Code. 
 
VOLUNTARY PARTICIPATION 


Deborah Yurgelun-Todd, Ph.D. 
 
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It is up to you to decide whether or not to take part in this study. If you decide to take part you are still 
free to withdraw at any time and without giving a reason. Refusal to participate or the decision to 
withdraw from this study will involve no penalty or loss of benefits to which you are otherwise entitled. 
If you don’t take part, you can still receive all standard care that is available to you. This will not affect 
the relationship you have with your doctor or other staff, nor decrease the standard of care that you 
receive as a patient.  Should you choose to withdraw, you should notify Dr. Yurgelun-Todd or the 
research staff, and the study doctor. 
 
You may be asked return to the study doctor for a final examination.  During this final examination a 
physical examination, vital sign assessment, ECG, and clinical laboratory tests may be performed.  A 
review of your current medications and any side effects you may have experienced may be assessed. 
Also, you may be asked to complete a clinical assessment to determine your emotional state and mood. 
 
If your participation in the study is terminated for any reason, information related to your participation 
in the study that was collected prior to termination of your participation may continue to be used and 
disclosed by the study doctor for the purposes described in this consent form. 
 
RIGHT OF INVESTIGATOR TO WITHDRAW 
Dr. Yurgelun-Todd may make study withdrawal determinations, in coordination with participants, and 
their non-study treating clinician. Your study participation could be discontinued by the study doctor, 
without your consent, for any of the following reasons:   
a. the Sponsor cancels the study;  
b. the study doctor feels it is in your best interest;  
c. you need medication that would interfere with the study;  
d. your participation needs to be discontinued in order to comply with study requirements;  
e. at the request of the subject, investigator, OAPI or designee, or regulatory authority; 
f. you become pregnant;   
 
Your participation in the trial will also end if any of the following criteria are met: 
  
a. If any adverse event, intercurrent illness or abnormality in a laboratory assessment occurs that, 
in the opinion of the investigator, warrants your permanent withdrawal from the study 
b. If there is an increase in suicidal or homicidal ideation, study termination/withdrawal will be at 
the discretion of Dr. Yurgelun-Todd, in consultation with you and their treating clinician(s).  The 
investigators will work closely with the treating clinician(s) to maintain participant safety, and to 
arrange for inpatient hospitalization if it is necessary.  Participants whose clinical condition 
necessitates a move to a higher level of care (inpatient hospitalization) in order to maintain 
safety will be withdrawn from the study. 
c. If you are unable or unwilling to adhere to the study protocol, the Principal Investigator retains 
the right to withdraw them from the study without their permission. 
 


Deborah Yurgelun-Todd, Ph.D. 
 
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If Dr. Yurgelun-Todd determines that the investigational drug presents an unreasonable and significant 
risk to you she will discontinue the investigation immediately and notify the FDA, IRB, and the co-
investigators. You will be notified immediately if the study is discontinued for safety reasons.  
 
COSTS AND COMPENSATION TO PARTICIPANTS 
There is no cost to you for participation in this study, except costs of transportation to the study doctor’s 
office. The study visits, study-related procedures and tests, and study medication will be provided free 
of charge. 
 
You will be compensated up to $725.00 for your participation in this study. 
 
Since you will be paid for participating in this study, it is necessary for us to collect your Social Security 
Number. You will provide this information for a Federal W-9 Form that is filed with our Accounts Payable 
department. Accounts Payable will have limited access to the study information (e.g. the name of the 
study) for payment purposes. The amount you receive for taking part in this study will be turned into the 
Internal Revenue Service (IRS) as taxable income. You can choose not to provide us with your Social 
Security Number for this form and still participate in this study; however we will not be able to pay you 
as outlined in this consent form. 
 
NEW INFORMATION 
You will be told by Dr. Yurgelun-Todd or her staff of any significant new findings that develop during the 
course of this study that may affect your willingness to continue participating in this study. You may 
then use this information to make a decision about remaining in the study. 
 
NUMBER OF PARTICIPANTS 
We expect to enroll 80 participants at the University of Utah. 
 
AUTHORIZATION FOR USE OF YOUR PROTECTED HEALTH INFORMATION  
Signing this document means you allow us, the researchers in this study, and others working with us to 
use some information about your health for this research study. 
 
This is the information we will use and include in our research records:  
- 
Name 
- 
Address 
- 
Telephone number 
- 
Date of birth 
- 
Social security number 
- 
Medical and medication history 
- 
Information from physical examinations; such as, blood pressure reading, heart rate, 
breathing rate, and temperature 
- 
Information created or collected during the study 
 
How we will protect and share your information: 


Deborah Yurgelun-Todd, Ph.D. 
 
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• 
We will do everything we can to keep your information private but we cannot guarantee this. 
Study information will be kept in a secured manner and electronic records will be password 
protected. Study information may be stored with other information in your medical record. 
Other doctors, nurses, and third parties (like insurance companies) may be able to see this 
information as part of the regular treatment, payment, and health care operations of the 
hospital. We may also need to disclose information if required by law. 
 
• 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this website at any time. 
 
• 
In order to conduct this study and make sure it is conducted as described in this form, the 
research records may be used and reviewed by others who are working with us on this research: 
o Members of the research team and authorized members of the University of Utah who 
need the information to perform their duties (for example: to provide treatment, to 
ensure integrity of the research, and for accounting or billing matters); 
o The University of Utah Institutional Review Board (IRB), who reviews research involving 
people to make sure the study protects your rights; 
o Otsuka America Pharmaceuticals, Inc. (including its affiliates and partners), a 
pharmaceutical company that will make determinations regarding the disclosure of 
study information; 
o Food and Drug Administration, a federal agency that may inspect and/or copy the 
records that identify you, or health authority in other countries where this drug is being 
studied. 
 
• 
If we share your identifying information with groups outside of the University of Utah Health 
Science Center, they may not be required to follow the same federal privacy laws that we 
follow.  They may also share your information again with others not described in this form. 
 
• 
If you do not want us to use information about your health, you should not be part of this 
research.  If you choose not to participate, you can still receive health care services at the 
University of Utah Health Sciences Center.  
 
What if I decide to Not Participate after I sign the Consent and Authorization Form? 
You can tell us anytime that you do not want to be in this study and do not want us to use your health 
information.  You can also tell us in writing.  If you change your mind, we will not be able to collect new 
information about you, and you will be withdrawn from the research study. However, we can continue 
to use information we have already started to use in our research, as needed to maintain the integrity of 
the research.   
 
This authorization does not have an expiration date.   


Deborah Yurgelun-Todd, Ph.D. 
 
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You have a right to information used to make decisions about your health care. However, your 
information from this study will not be available during the study; it will be available after the study is 
finished. 
 
CONSENT 
I acknowledge I have been given an opportunity to ask questions regarding this research study and these 
questions have been answered to my satisfaction. I understand that if I have additional questions of in 
the event of a research-related illness or injury, I may contact Dr. Yurgelun-Todd at phone number 801-
587-1471. 
 
In the event I have any questions regarding my rights as a research subject, I may contact the University 
of Utah’s IRB or Ethics Committee at phone number 801-581-3655. 
 
In giving my consent, I acknowledge my participation in this research project is voluntary and I may 
refuse or withdraw from participation at any time without penalty or loss of benefits to which I am 
otherwise entitled. My signature below means I have read this consent form, understand its contents, 
and all my questions concerning this study have been answered by Dr. Yurgelun-Todd and her staff. It 
also means I agree that my personal health information may be used and transferred in the ways 
described in this informed consent form and that my personal health information may be added to 
research databases and used in the future by Sponsor, its affiliates, and licensing partners to develop a 
better understanding of safety and effectiveness of the study medication(s), study other therapies for 
patients, develop a better understanding of disease(s) included in the study, and to improve the 
efficiency, design and study methods of future clinical trials. I understand that I will not lose any of my 
legal rights as a research subject by signing this consent form.  
 
I agree to take part in this research study and authorize you to use and disclose health information 
about me for this study, as you have explained in this document. 
 
 
________________________ 
Participant’s Name 
 
________________________ 
 
 
 
 
____________ 
Participant’s Signature 
 
Date 
 
________________________ 
Name of Person Obtaining Authorization and Consent 
 
________________________ 
 
 
 
 
____________ 
Signature of Person Obtaining Authorization and Consent 
 
Date 
 
 


Deborah Yurgelun-Todd, Ph.D. 
 
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If the participant is unable to give consent and authorization, consent and authorization is given by 
the authorized personal representative of the individual: 
 
LEGALLY AUTHORIZED REPRESENTATIVE CONSENT STATEMENT: 
I confirm that I have read this consent and authorization document.  I have had the opportunity to ask 
questions and those questions have been answered to my satisfaction.  I am willing and authorized to 
serve as a surrogate decision maker for  
 
______________________________________. 
Participant’s Name 
 
I have been informed of my role and my obligation to protect the rights and welfare of the participant.  I 
understand that my obligation as a surrogate decision maker is to try to determine what the participant 
would decide if the participant were able to make such decisions or, if the participant’s wishes cannot 
be determined, what is in the participant’s best interests.  I will be given a signed copy of the consent 
and authorization form to keep. 
 
______________________________________ 
Name of Authorized Personal Representative 
 
_______________________________________  
_____________ 
Signature of Authorized Personal Representative 
 
Date 
 
Indicate the legal representative’s authority to act for the individual: 
 Spouse 


Deborah Yurgelun-Todd, Ph.D. 
 
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 Adult (18 years of age or over) for his or her parent  
 Individual with power of attorney 
 Guardian appointed to make medical decisions for individuals who are incapacitated