Clinical trial NCT02717130
Conditions: Schizophrenia
Sponsor: Florida Atlantic University
Start date: 2016-06-08; Completion date: 2017-05-25
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
An Open-label, Multi-center, Longitudinal, Within-subject Comparison Study to Evaluate the Effects of Aripiprazole Once Monthly in Subjects with Schizophrenia on 30-, 90-, and 180- day Re-hospitalization Rates Following Hospital Discharge Compared with Retrospective Re-hospitalization Rates while on Oral Antipsychotic Medication.

Detailed description:
This is an open-label, multi-center, longitudinal, within-subject comparison study of the effects of aripiprazole once monthly on 30-, 90-, and 180-day psychiatric re-hospitalization rates following hospital discharge in subjects with schizophrenia compared with prior psychiatric hospitalization rates while on oral antipsychotics.

Prospective subjects will undergo screening for eligibility for entry into the study while hospitalized for symptoms due to schizophrenia.

Prospective subjects will be hospitalized for the necessary length of time as determined by the assigned treatment provider as clinically indicated, per the current standard of care. To be eligible, the anticipated duration of hospitalization should be long enough to accommodate the screening procedures, the 3-day Oral Tolerability Phase (if applicable), and initiation of treatment with aripiprazole once monthly.

During the Screening Period, subjects can be treated with any oral antipsychotic medication of the clinician's choice, with the exception of clozapine and olanzapine. However, oral olanzapine is permitted during the Screening Period only for subjects who are eligible for Phase A. Following the Screening Period, subjects who have no history of aripiprazole use will be entered into Phase A, the Oral Tolerability Phase. Subjects from Phase A that demonstrate tolerability to aripiprazole will then be entered into Phase B (i.e., the Treatment Phase). Subjects who already have a history of tolerating at least three consecutive oral doses of aripiprazole will be entered directly into Phase B. All eligible subjects will eventually enter Phase B.

Subjects who meet the inclusion and exclusion criteria and have no history of oral aripiprazole use will enter Phase A after the Screening Period while still hospitalized. Subjects in Phase A will be administered oral aripiprazole, as indicated in the product labeling, to determine tolerability. Dosage will be based on symptoms and the judgment of the investigator. The dose of oral aripiprazole may be titrated as needed. Prior antipsychotic medications will be tapered off and discontinued during the Screening Period and Phase A as clinically appropriate.

During Phase A, tolerability to oral aripiprazole will be evaluated daily for a minimum of 3 days using safety and tolerability measures (i.e., AIMS, BARS, and SAS) in conjunction with clinical judgment. If the subject shows tolerability to the oral aripiprazole, the Phase B baseline/Day 1 should occur with the first aripiprazole once monthly injection given immediately after the Phase B baseline/Day1 assessments. If a subject is unable to tolerate oral aripiprazole during the tolerability assessment in Phase A, he or she will be withdrawn from the study.

During Phase B, the subject will receive the first aripiprazole once monthly intramuscular (IM) injection, in conjunction with the first of 14 doses of concomitant oral aripiprazole, as indicated in the product labeling, after the baseline data are collected.

All subjects must attend scheduled visits at the Baseline Visit and Weeks 2, 4, 8, 12, 16, 20, and 24, totaling 180 days. Aripiprazole once monthly injections will occur at the Baseline Visit and every 28 ( -2, +5) days at Weeks 4, 8, 12, 16, 20, and 24, totaling seven injections. After the initial injection of 400 mg, the monthly dosage can be decreased to 300 mg, based on the clinical judgment of the investigator. All aripiprazole once monthly injections will be administered based on the investigator's judgment and the prescribing information.

For subjects who are psychiatrically stabilized and discharged prior to the completion of the required 14-day course of oral aripiprazole, a pre-discharge assignment will be given to a community support worker (CSW). The CSW will maintain regular contact with the subject until the first outpatient visit in Phase B (Week 2), when oral aripiprazole will be discontinued. Regular contact is defined as no less than weekly, but can be more frequent depending on the clinical judgment of the CSW and outpatient treatment team. Following the Week 2 Visit, subjects will have contact with their assigned CSW based on routine clinical care. Contact with the CSW can be in person or by telephone, as clinically appropriate.

Note: All long-acting antipsychotics are excluded from use during the study; however, aripiprazole once monthly is allowed

Arms: arm 1: Aripiprazole once monthly (300-400 mg for entire study duration) plus 14 days oral antipsychotic medication (first injection only) (dosage according to package inserts). After the 14 day oral lead-in, after the first injection of aripiprazole once monthly, only oral aripiprazole will be allowed as a rescue medication.
Interventions: intervention 1: Aripiprazole
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Report: Collaborative Protocol 031-104-0014 
 
ClinicalTrials.gov Identifier: NCT02717130 
Page 1 of 80 
 
Final; 26 Feb 2018 
 
1 
TITLE PAGE 
ARIPIPRAZOLE, ABILIFY MAINTENA® 
CLINICAL STUDY REPORT 
An Open-label, Multi-center, Longitudinal, Within-subject Comparison Study to Evaluate the 
Effects of Aripiprazole Once Monthly in Subjects with Schizophrenia on 30-, 90- and 180-day 
Re-hospitalization Rates Following Hospital Discharge Compared with Retrospective 
Re-hospitalization Rates while on Oral Antipsychotic Medication 
 
Collaborative Protocol No.  031-104-0014 
 
 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
Principal Investigator: 
John W. Newcomer, MD 
Charles E. Schmidt College of Medicine 
Florida Atlantic University 
777 Glades Road, Boca Raton, FL  33431 
561-297-0252 
 
 
Immediately Reportable Event 
Julie Schweiger, CRCC 
314-362-3153 
 
 
Version: 
Final 
 
 
Issue Date: 
26 February 2018 
G-Port No.  1035 


Clinical Study Report: Collaborative Protocol 031-104-0014 
 
ClinicalTrials.gov Identifier: NCT02717130 
Page 2 of 80 
 
Final; 26 Feb 2018 
 
2 
SYNOPSIS 
Name of Sponsor:  JohnW. Newcomer, M.D. at Florida Atlantic University 
Name of Product:  Abilify Maintena®, aripiprazole 
Protocol Title: 
An Open-label, Multi-center, Longitudinal, Within-subject Comparison Study to Evaluate the 
Effects of Aripiprazole Once Monthly in Subjects with Schizophrenia on 30-, 90-, and 
180-day Re-hospitalization Rates Following Hospital Discharge Compared with 
Retrospective Re-hospitalization Rates while on Oral Antipsychotic Medication 
Treatment Indication:  
Schizophrenia 
Objective(s): 
The primary objective of the study was: 
• 
To evaluate the effect of aripiprazole once monthly on 30-, 90-, and 180-day 
psychiatric re-hospitalization rates following discharge due to symptoms associated 
with schizophrenia, compared with prior 30-, 90-, and 180-day psychiatric 
hospitalization rates in subjects previously treated with oral antipsychotic 
medication. 
The secondary objectives of the study were: 
Efficacy: 
• 
To evaluate the effect of aripiprazole once monthly on: 
o 
30-, 90-, and 180-day rates of unscheduled psychiatric emergency department 
(ED) visits compared with prior 30-, 90-, and 180-day unscheduled visits 
o 
Psychiatric ED visits plus hospitalizations compared with prior 30-, 90-, and 
180-day psychiatric visits plus hospitalizations 
o 
Total psychiatric hospitalization days over the 180-day study period compared 
with the total psychiatric hospitalization days over the prior 180-day period 
o 
Change from baseline in Clinical Global Impression–Severity (CGI-S) and 
Clinical Global Impression–Improvement (CGI-I) scores at 30-, 90-, and 
180- days 
• 
To evaluate changes from baseline for the following indicators for cardiometabolic 
risk (CMR): 
o 
Weight and body mass index (BMI) 
o 
Fasting glucose concentrations 
o 
Glycosylated hemoglobin (HbA1c) concentrations 
o 
Fasting plasma lipid concentrations (i.e., fasting triglycerides [primary 
analysis], total cholesterol, high-density lipoprotein [HDL], and low-density 
lipoprotein [LDL]) 
The exploratory objectives of the study are: 
Safety: 
• 
To evaluate changes from baseline to 180 days in: 
o 
Adverse events (AEs) 
o 
Clinical laboratory tests (i.e., hematology, fasting clinical chemistry, prolactin, 
and urinalysis) 
o 
Vital signs 


Clinical Study Report: Collaborative Protocol 031-104-0014 
 
ClinicalTrials.gov Identifier: NCT02717130 
Page 3 of 80 
 
Final; 26 Feb 2018 
 
Name of Sponsor:  JohnW. Newcomer, M.D. at Florida Atlantic University 
Name of Product:  Abilify Maintena®, aripiprazole 
Objectives continued: 
o 
Personal and Social Performance Scale (PSP) 
o 
Injection site reactions (i.e., localized pain, redness, swelling, and induration) 
o 
Extrapyramidal side effects (EPS): 
▪ 
Abnormal Involuntary Movement Scale (AIMS) 
▪ 
Simpson-Angus Scale (SAS) 
▪ 
Barnes Akathisia Rating Scale (BARS) 
o 
Columbia Suicide Severity Rating Scale (C-SSRS) for suicidality 
Study Design: 
This was an open-label, multi-center, longitudinal, within-subject comparison study of the 
effects of aripiprazole once monthly on 30-, 90-, and 180-day psychiatric re-hospitalization 
rates following hospital discharge in subjects with schizophrenia compared with prior 
psychiatric hospitalization rates while on oral antipsychotics. 
Prospective subjects underwent screening for eligibility for entry into the study during or 
immediately after hospitalization for symptoms due to schizophrenia. 
Prospective subjects were hospitalized for the necessary length of time as determined by the 
assigned treatment provider as clinically indicated, per the current standard of care.  To be 
eligible, the anticipated duration of hospitalization was to be long enough to accommodate 
the screening procedures, the 3-day Oral Tolerability Phase (if applicable), and initiation of 
treatment with aripiprazole once monthly. 
During the Screening Period, subjects could be treated with any oral antipsychotic medication 
of the clinician’s choice, with the exception of clozapine.  However, oral olanzapine was 
permitted, during the Screening Period only, for subjects who were eligible for Phase A.  
Following the Screening Period, subjects who had no history of aripiprazole use were entered 
into Phase A, the Oral Tolerability Phase.  Subjects from Phase A that demonstrated 
tolerability to aripiprazole were then entered into Phase B (i.e., the Treatment Phase, where 
all subjects were treated with long-acting injectable aripiprazole).  Subjects who already had 
a history of tolerating at least three consecutive oral doses of aripiprazole were entered 
directly into Phase B.  All eligible subjects would eventually enter Phase B.  Subjects may 
also have entered the study if they were clinically started on long-acting injectable 
aripiprazole during the hospitalization just prior to study entry. 
Subjects who met the inclusion and exclusion criteria and had no history of oral aripiprazole 
use entered Phase A after the Screening Period while still hospitalized.  Subjects in Phase A 
were administered oral aripiprazole, as indicated in the product labeling, to determine 
tolerability.  Dosage was based on symptoms and the judgment of the investigator.  The dose 
of oral aripiprazole could be titrated as needed.  Prior antipsychotic medications were tapered 
off and discontinued during the Screening Period and Phase A as clinically appropriate. 


Clinical Study Report: Collaborative Protocol 031-104-0014 
 
ClinicalTrials.gov Identifier: NCT02717130 
Page 4 of 80 
 
Final; 26 Feb 2018 
 
Name of Sponsor:  JohnW. Newcomer, M.D. at Florida Atlantic University 
Name of Product:  Abilify Maintena®, aripiprazole 
Study Design continued: 
During Phase A, tolerability to oral aripiprazole was evaluated daily (using clinical judgment) 
for a minimum of 3 days with baseline safety and tolerability measures (i.e., AIMS, BARS, 
and SAS) either during or closely following completion of oral treatment.  If the subject 
showed tolerability to the oral aripiprazole, the Phase B baseline/Day 1 was to occur with the 
first aripiprazole once monthly injection.  If a subject was unable to tolerate oral aripiprazole 
during the tolerability assessment in Phase A, he or she was withdrawn from the study.  
Subjects could have their baseline assessments performed any time during or immediately 
after treatment with oral antipsychotic aripiprazole (unless eligible to skip Phase A in which 
it is any oral antipsychotic), ideally prior to starting long-acting injectable aripiprazole. 
Participants were allowed, with Principal Investigator approval, to enter the study after 
starting treatment with long-acting injectable aripirazole in the hospital and baseline 
assessments were performed as soon as feasible. 
During Phase B, the subject received the first aripiprazole once monthly intramuscular (IM) 
injection, in conjunction with the first of 14 doses of concomitant oral aripiprazole, as 
indicated in the product labeling, after the baseline data were collected.  In cases where 
subjects were enrolled after starting long-acting injectable aripiprazole in the hospital, 
baseline data were collected no later than 48 hours after hospital discharge whenever possible 
and with Principal Investigator approval. 
All subjects were required to attend scheduled visits at the Baseline Visit and Weeks 2, 4, 8, 
12, 16, 20, and 24, totaling 180 days.  Aripiprazole once monthly injections occurred at the 
Baseline Visit and every 28 (-2, + 5) days at Weeks 4, 8, 12, 16, 20, and 24, totaling seven 
injections.  After the initial injection of 400 mg, the monthly dosage could be decreased to 
300 mg, based on the clinical judgment of the investigator.  All aripiprazole once monthly 
injections were administered based on the investigator’s judgment and the prescribing 
information. For subjects who entered the studies after starting the first dose of long-acting 
injectable aripiprazole in the hospital, if the initial injection was not 400 mg, the second 
injection should have been 400 mg, and thereafter, the monthly dose could be decreased to 
300 mg, based on clinical judgment of the investigator. 
For subjects who were psychiatrically stabilized and discharged prior to the completion of the 
required 14-day course of oral aripiprazole, a pre-discharge assignment was given to a 
community support worker (CSW) or Study Coordinator (SC).  The CSW/SC maintained 
regular contact with the subject until the first outpatient visit in Phase B (Week 2), when oral 
aripiprazole was discontinued.  Regular contact was defined as no less than weekly, but could 
be more frequent depending on the clinical judgment of the CSW/SC and outpatient 
treatment team.  Following the Week 2 Visit, subjects had contact with their assigned 
CSW/SC based on routine clinical care.  Contact with the CSW/SC could be in person or by 
telephone, as clinically appropriate. 
Note:  All long-acting antipsychotics were excluded from use during the study; however, 
aripiprazole once monthly was allowed (See Table 1 for more information about Prohibited 
and Restricted Medications). 


Clinical Study Report: Collaborative Protocol 031-104-0014 
 
ClinicalTrials.gov Identifier: NCT02717130 
Page 5 of 80 
 
Final; 26 Feb 2018 
 
Name of Sponsor:  JohnW. Newcomer, M.D. at Florida Atlantic University 
Name of Product:  Abilify Maintena®, aripiprazole 
Subject Population: 
Planned:  Approximately 177 subjects were planned to be enrolled competitively between 
each of four designated clinical sites across the state of Missouri to reach a total of 
90 completed subjects. 
This was to account for an expected 40% screen failure rate and an additional 40% drop-out 
rate.  Subjects served as their own controls. 
Prospective subjects were to be recruited from one of four established clinical sites at four 
inpatient hospitals associated with outpatient community mental health centers in Missouri:  
Washington University in St. Louis, University of Missouri, Columbia, MO; University of 
Missouri, Kansas City, MO; and Burrell Behavioral Health in Springfield, MO. 
Actual: A total of 9 subjects were recruited from a total of two of three active clinical sites. 
Burrell Behavioral Health in Springfield, MO never joined the study and did not screen or 
enroll any subjects. 
Subjects who did not meet all of the inclusion criteria or who met any of the exclusion 
criteria were not eligible to receive study drug. 
Study Drug, Dose, 
Formulation, Mode of 
Administration: 
• 
Aripiprazole, administered once monthly via gluteal or deltoid IM injection, as outlined 
in the product labeling 
• 
Oral aripiprazole 
o 
Subjects in Phase A were administered oral aripiprazole to determine tolerability, 
based on the prescribing information 
• 
Aripiprazole, both oral and once monthly was administered or prescribed as outlined in 
the product labeling 
Results: 
Efficacy: 
Due to low enrollment, no analysis of the primary or secondary outcome variables were 
possible.  
Safety:  
Due to low enrollment and subject discontinuations, no analysis of safety was performed. All 
available safety data are provided. 
Statistical Methods: 
Planned: For the primary outcome, 30-, 90-, and 180-day re-hospitalization rates following 
aripiprazole once monthly IM injections were to be compared with prior 30-, 90-, and 
180-day hospitalization rates in subjects previously treated with oral antipsychotic 
medication.  Descriptive statistics were to be provided for all efficacy variables and safety 
variables.  Continuous variables, including fasting laboratory values, were to be summarized 
by tabulations of mean, median, range, and standard deviation using change from baseline to 
30-, 90-, and 180-day values.  Tabulations of frequency distributions were provided for 
categorical variables.  The primary and secondary outcomes were to be analyzed using 
repeated measures analysis of covariance models. 
Actual: No statistical analyses were performed 
Study Duration: 
Planned: An approximate 6-month duration per subject was expected.  Subject recruitment 
was estimated at 18 months with a 180-day treatment period followed by a 30-day follow-up 
period.  Total study duration was expected to be approximately 2.5 years, allowing an 
additional 6 months for data analysis and manuscript preparation. 
Actual: First patient, first visit: June 2016; Last patient last visit May 2017. Study was 
terminated due to slow enrollment. 
 


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Page 6 of 80 
 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE ...................................................................................................................... 1 
2 
SYNOPSIS .......................................................................................................................... 2 
3 
TABLE OF CONTENTS .................................................................................................... 6 
LIST OF IN-TEXT TABLES ..............................................................................................9 
LIST OF IN-TEXT FIGURES.............................................................................................9 
LIST OF APPENDICES ......................................................................................................9 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 10 
5 
ETHICS............................................................................................................................. 12 
5.1 
Informed consent ...................................................................................................12 
6 
INVESTIGATORS AND STUDY PERSONNEL ........................................................... 13 
7 
INTRODUCTION ............................................................................................................ 14 
7.1 
ABILIFY (aripiprazole) .......................................................................................15 
7.2 
Relevant Nonclinical Studies .................................................................................15 
7.3 
Relevant Clinical Studies .......................................................................................16 
7.3.1 Schizophrenia Studies with Oral Aripiprazole ..........................................16 
7.3.2 Agitation Studies with Injectable Aripiprazole ..........................................17 
7.3.3 Clinical Studies in Schizophrenia with Aripiprazole Once Monthly.........17 
7.3.4 Known and Potential Risks and Benefits ...................................................18 
7.4 
Study Rationale ......................................................................................................20 
8 
STUDY OBJECTIVES ..................................................................................................... 21 
8.1 
Primary Objective(s) ..............................................................................................21 
8.2 
Secondary Objective(s) ..........................................................................................21 
8.3 
Exploratory Objectives ..........................................................................................21 
9 
INVESTIGATIONAL PLAN ........................................................................................... 23 
9.1 
Overall Study Design and Plan ..............................................................................23 
9.1.1 Pre-Screening Assessments .......................................................................25 
9.1.2 Screening Period ........................................................................................25 
9.1.3 Phase A – Oral Tolerability Phase .............................................................27 
9.1.4 Phase B (Treatment Phase) ........................................................................27 
9.1.4.1 
Baseline ....................................................................................27 
9.1.4.2 
Treatment Phase .......................................................................28 
9.1.4.3 
Early Termination ....................................................................30 
9.2 
Discussion of Study Design ...................................................................................30 
9.3 
Selection of Study Population ................................................................................30 
9.3.1 Inclusion Criteria .......................................................................................30 
9.3.2 Exclusion Criteria ......................................................................................31 
9.3.3 Removal of Subjects from Therapy or Assessment ...................................33 
9.3.3.1 
Entire Study .............................................................................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 


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9.4.2 Identity and Storage of Drug Under Study(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 ............................................................................................37 
9.5 
Study Assessments .................................................................................................37 
9.5.1 Assessments ...............................................................................................37 
9.5.1.1 
Pre-Screening Assessments .....................................................37 
9.5.1.2 
Demographics ..........................................................................38 
9.5.1.3 
Screening Assessments ............................................................38 
9.5.1.4 
Safety Assessments ..................................................................39 
9.5.1.4.1 Clinical Laboratory Tests .............................................39 
9.5.1.4.2 Vital Signs ....................................................................40 
9.5.1.5 
Adverse Events and Other Events of Interest ..........................40 
9.5.1.6 
Serious Adverse Events and Other Events of Interest .............42 
9.5.1.7 
Other Safety Assessments ........................................................43 
9.5.1.7.1 Injection Site Evaluation ..............................................43 
9.5.1.7.2 Body Weight, Height, Body Mass Index .....................43 
9.5.1.7.3 Suicidality ....................................................................44 
9.5.1.7.4 Pregnancy Test .............................................................44 
9.5.1.8 
Efficacy Assessments – Clinical Outcome ..............................45 
9.5.1.8.1 Clinical Global Impression–Improvement ...................45 
9.5.1.8.2 Clinical Global Impression–Severity ...........................45 
9.5.1.8.3 Personal and Social Performance Scale .......................45 
9.5.1.9 
Extrapyramidal Side Effects ....................................................46 
9.5.1.9.1 Abnormal Involuntary Movement Scale ......................46 
9.5.1.9.2 Barnes Akathisia Rating Scale .....................................46 
9.5.1.9.3 Simpson Angus Scale ..................................................46 
9.5.1.10 
Pharmacokinetic/Pharmacodynamic Assessments ..................46 
9.5.2 Schedule of Assessments ...........................................................................46 
9.5.3 Appropriateness of Measurements .............................................................50 
9.5.4 Reporting of Serious Adverse Events, Pregnancy, and Other 
Events of Interest .......................................................................................50 
9.5.4.1 
Reporting of Serious Adverse Events ......................................51 
9.5.5 Completion/Discontinuation of Subjects ...................................................51 
9.5.6 Confirmation of Medical Care by Another Physician ...............................51 
9.6 
Data Quality Assurance .........................................................................................52 
9.6.1 Monitoring .................................................................................................52 
9.6.2 Auditing .....................................................................................................52 
9.6.3 Data Collection ..........................................................................................52 
9.7 
Statistical Methods .................................................................................................52 
9.7.1 Statistical and Analytical Plans ..................................................................52 
9.7.1.1 
Primary Endpoint(s) .................................................................52 
9.7.1.2 
Secondary Endpoint(s) .............................................................53 
9.7.1.3 
Exploratory Endpoints .............................................................53 


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9.7.1.4 
Definitions of Analysis Sets.....................................................54 
9.7.1.5 
Subject Disposition ..................................................................54 
9.7.1.6 
Demographic and Other Baseline Characteristics ...................54 
9.7.1.7 
Prior and Concomitant Therapy ...............................................55 
9.7.1.8 
Safety Analyses ........................................................................55 
9.7.1.8.1 Adverse Events ............................................................55 
9.7.1.8.2 Laboratory Values ........................................................55 
9.7.1.8.3 Vital Signs ....................................................................56 
9.7.1.9 
Efficacy Analyses ....................................................................56 
9.7.1.10 
Other Analyses .........................................................................57 
9.7.2 Determination of Sample Size ...................................................................57 
9.7.3 Interim Analysis .........................................................................................57 
9.7.3.1 
Data Safety Monitoring Board .................................................57 
9.7.4 Other Statistical and Analytical Issues ......................................................57 
9.7.4.1 
Handling of Missing Data ........................................................57 
9.8 
Change to the Conduct of the Study or Analyses ..................................................58 
9.8.1 Protocol Amendments ................................................................................58 
9.8.1.1 
Amendment 1.0, 17 Dec 2015 .................................................58 
9.8.1.2 
Amendment 2.0, 26 Feb 2016 ..................................................58 
9.8.1.3 
Amendment 2.1, 24 Aug 2016 .................................................59 
10 
SUBJECT DISPOSITION ................................................................................................ 60 
11 
EFFICACY ....................................................................................................................... 61 
12 
SAFETY ........................................................................................................................... 62 
12.1 
Baseline Assessments and Screening.....................................................................62 
12.2 
Adverse events .......................................................................................................62 
12.3 
Deaths, Other Serious Adverse Events, and Adverse Events Leading to 
Discontinuation From the Study ............................................................................65 
12.3.1 Deaths ........................................................................................................65 
12.3.2 Other Serious Adverse Events ...................................................................65 
12.4 
Clinical Laboratory Results ...................................................................................66 
12.5 
Clinical Safety Variables .......................................................................................67 
13 
ADMINISTRATIVE PROCEDURES AND INSTRUCTIONS ...................................... 70 
13.1 
Changes to the Protocol .........................................................................................70 
13.2 
Adherence to the Protocol ......................................................................................70 
13.3 
Monitoring Procedures...........................................................................................70 
13.4 
Recording of Data ..................................................................................................71 
13.5 
Identification of Source Data .................................................................................71 
13.6 
Retention of Records..............................................................................................71 
13.7 
Reporting of Product Quality Complaints .............................................................72 
13.7.1 Information Required for Reporting Purposes ...........................................72 
13.7.2 Eliciting and Reporting Quality Complaints..............................................73 
13.7.3 Return Process ...........................................................................................73 
13.8 
Discontinuation of Study .......................................................................................73 
14 
REFERENCE LIST .......................................................................................................... 74 
15 
APPENDICES .................................................................................................................. 77 


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LIST OF IN-TEXT TABLES 
Table 1: 
Prohibited and Restricted Medications ..................................................................36 
Table 2: 
Safety Clinical Laboratory Tests ...........................................................................40 
Table 3: 
Schedule of Assessments .......................................................................................47 
Table 4: 
Reasons for Discontinuation ..................................................................................60 
Table 5: 
Baseline and Screening Assessments.....................................................................62 
Table 6: 
Adverse Events ......................................................................................................64 
Table 7: 
Blood Chemistry Safety Laboratory Results .........................................................67 
Table 8: Clinical Safety Variables .................................................................................................68 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Schematic.....................................................................................................24 
LIST OF APPENDICES 
Appendix 1 
Reference Ranges...................................................................................................78 
Appendix 2: 
Subject Data ...........................................................................................................79 
Appendix 3: 
Signature Page .......................................................................................................80 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANCOVA 
analysis of covariance 
AST 
aspartate transaminase 
BARS 
Barnes Akathisia Rating Scale 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
CFR 
Code of Federal Regulations 
CMR 
cardiometabolic risk 
CMS 
Centers for Medicare and Medicaid Services 
CNS 
central nervous system 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSW 
community support worker 
CV 
curriculum vitae 
CYP 
cytochrome P450 
DMH 
Missouri Department of Mental Health 
DSM-5 
Diagnostic and Statistical Manual, Fifth Edition 
ECG 
electrocardiogram 
ED 
emergency department 
EEG 
electroencephalogrsm 
EPS 
extrapyramidal side effects 
EU 
European Union 
FDA 
Food and Drug Administration 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
HDL 
high-density lipoprotein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IM 
intramuscular 
IRB 
institutional review board 
ITT 
intent-to-treat 
LAI 
long-acting injectable 


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LDL 
low-density lipoprotein 
MCHC 
mean corpuscular hemoglobin concentration 
LNH 
low/normal/high 
LOCF 
last observation carried forward 
MAOI 
monoamine oxidase inhibitor 
MCV 
mean corpuscular volume 
MIMH 
Missouri Institute of Mental Health 
MO 
Missouri 
OAPI 
Otsuka America Pharmaceutical, Inc. 
OC 
observed case 
OPC 
Otsuka Pharmaceutical Company, Ltd. 
OPDC 
Otsuka Pharmaceutical Development & Commercialization, Inc. 
PANSS 
Positive and Negative Syndrome Scale 
PK 
pharmacokinetic 
PQC 
product quality complaint 
PSP 
Personal and Social Performance Scale 
PT 
preferred term 
QT 
interval from beginning of the QRS complex to end of the T wave in the 
frontal plane 
QTc 
corrected QT interval 
RBC 
red blood cell 
REALM-SF 
Rapid Estimate of Adult Literacy in Medicine-Short Form 
SAE 
serious adverse event 
SC 
Study Coordinator 
RSRR 
risk-standardized readmission rate 
SAS 
Simpson Angus Scale 
SD 
standard deviation 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
UBACC 
University of California, San Diego Brief Assessment of Capacity to 
Consent 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
 


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5 
ETHICS 
This study was conducted in compliance with the protocol, United States (US) Food and Drug 
Administration (FDA) regulations, the International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) Guidelines, and all other applicable local laws and regulatory 
requirements.  Each study sought approval by an institutional review board (IRB) according to 
regional requirements.  The IRB evaluated the ethical, scientific, and medical appropriateness of 
the study.  Further, in preparing and handling case report forms (CRFs), the investigator, 
sub-investigator and their staff took measures to ensure adequate care in protecting subject privacy.  
To this end, a subject number and subject identification code was used to identify each subject. 
5.1 
INFORMED CONSENT 
All subjects had the purpose of the study, study interventions and evaluations, and the potential 
risks and benefits of participation explained to them and any questions were answered.  If a subject 
agreed to participate in the study, the subject reviewed and signed the informed consent form 
(ICF). 
Written informed consent was obtained from all subjects (or their guardian or legal representative, 
as applicable for local laws).  Consent was documented on a written ICF.  The ICF was approved 
by the same IRB that approved the protocol.  Each ICF complied with the FDA regulations in 
Title 21 Code of Federal Regulations (CFR) Part 50 ICH, GCP, and local regulatory requirements.  
The investigator agreed to obtain approval from the sponsor for any written ICF used in the study, 
prior to submission to the IRB. 
Investigators could discuss study availability and the possibility for entry with a potential subject 
without first obtaining consent.  However, informed consent must have been obtained and 
documented prior to initiation of any procedures that were performed solely for the purpose of 
determining eligibility for this study, including withdrawal from current medication(s). 
Once appropriate essential information was provided and fully explained in layman’s language to 
the subject by the investigator, or a qualified designee, the IRB-approved written ICF was signed 
and dated by both the subject and the person obtaining consent (i.e., investigator or designee), as 
well as by any other parties required by the IRB.  The subject received a copy of the signed 
informed consent form; the original was kept on file by the investigator. 


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6 
INVESTIGATORS AND STUDY PERSONNEL 
This was a collaboratively designed, investigator-sponsored study that was conducted at four 
centers in the US. 
Co-investigators: 
Consultants: 
Ginger Nicol, MD 
Assistant Professor of Psychiatry 
Washington University School of Medicine 
Department of Psychiatry, Box 8134 
660 Euclid Avenue  
Campus Box 8134 
St. Louis, MO  63110 
314-362-2461 or 314-362-5154 
nicolg@wustl.edu 
 
Roger W. Sommi, PharmD, BCCP, FCCP 
Associate Dean 
UMKC School of Pharmacy at MU 
2464 Charlotte 
Kansas City, MO  64108 
816-512-7475 
 
John Lauriello, MD 
Professor and Chair of Psychiatry 
University of Missouri-Columbia 
Department of Psychiatry 
1 Hospital Drive 
Columbia, MO  65212 
573-882-8913 
laurielloj@health.missouri.edu 
 
Planned not Actual: 
Paul Thomlinson, PhD 
Vice President of Research & Quality 
Assurance 
Research & Quality Assurance - 
Administration  
Burrell Behavioral Health 
1300 E. Bradford Parkway 
Springfield, MO  65804  
417-761-5015 
417-761-5011 (fax) 
Paul.Thomlinson@burrellcenter.com 
Joe Parks, MD 
Director 
MO HealthNet Division 
615 Howerton Court 
Jefferson City, MO  65109 
573-751-6884 
Joe.parks@dss.mo.gov 
 
Matthew G. Hile, PhD 
Director, Behavioral Informatics 
Research Associate Professor 
Missouri Institute of Mental Health 
5400 Arsenal  
St. Louis, MO  63139-1403 USA 
314-516-8459  
314-516-8477 (fax) 
Matthew.Hile@mimh.edu 
Otsuka Contact: 
Current: 
Timothy M. Wilt, PMP 
Sr. Manager, Medical Affairs Operations & 
Research 
OTSUKA Pharmaceutical Development & 
Commercialization 
timothy.wilt@otsuka-us.com 
 
Original: 
Susan N. Legacy MD, MSc 
Associate Director-CNS Medical Affairs 
Otsuka America Pharmaceutical, Inc. 
1 University Square Drive, Suite 500 
Princeton, NJ  08540 
609-249-6597 or 802-734-0502 
609-249-0597 (fax) 
Email: susan.legacy@otsuka-us.com 
www.otsuka-us.com 
 


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7 
INTRODUCTION 
The prevalence of long-acting injectable (LAI) antipsychotic agent use for the treatment of 
schizophrenia, especially for early-onset or first-episode patients, remains at or below 30% in most 
developed countries1-3.  Remarkably, even when identified as treatment non-adherent, less than a 
third of schizophrenia patients are prescribed LAI antipsychotics in the US4.  In general, 
antipsychotic treatment non-adherence is common in patients with schizophrenia5,6, and is 
associated with costly acute psychiatric care including emergency room visits and inpatient 
hospitalization7.  Non-pharmacologic efforts to improve treatment adherence include 
patient-provider agreements8 and enhanced outpatient case management services, including 
compulsory care9.  However, these approaches tend to be only modestly effective at improving 
treatment adherence.  The use of LAIs in this patient population is associated with decreased rates 
of symptomatic relapse, better long-term symptom management and improvement in functional 
outcomes10.  These clinical advantages lead to potential advantages in cost-effectiveness over oral 
antipsychotic treatment11. 
Efforts to promote the use of evidence-based treatments that improve clinical outcomes and 
contain healthcare costs, especially in chronic medical and psychiatric illnesses, have been a major 
focus of health care quality improvement initiatives.  The Centers for Medicare and Medicaid 
Services (CMS) has focused interest on 30-day hospital readmission rates as an indicator of 
cost-effective health care delivery.  In October 2012, CMS established the Accountable Care 
Organization12 with a plan to assess the risk-standardized readmission rate (RSRR) of all 
conditions, with a specific goal of lowering RSRR scores in hospitals by increasing quality of 
health care and decreasing need for rehospitalization13.  For repeated hospital readmissions within 
30 days, hospitals can incur adjustment in Medicare readmission payments of up to 1% reduction 
in payment in 201314.  The Federal Register (May 2012) estimated that the Hospital Readmissions 
Reduction Program will result in a 0.3% decrease, or approximately $300 million reduction, in 
payments to hospitals in 201315.  Nationally, it is estimated that hospitals may lose approximately 
a minimum of $150,000 to a maximum of $3.9 million in 201316.  Medicare 2013 readmission 
reports for 76 hospitals in Missouri to date indicate that 72% of hospitals were required to forfeit 
an average of 0.47% of their total Medicare reimbursements, while only 28% of hospitals had no 
reported readmission penalties17. 
In patients with severe illnesses such as schizophrenia, the risk for relapse and re-hospitalization 
is substantially increased following hospitalizations for acute exacerbation, in part due to limited 
access to outpatient mental health services to assist with adherence to oral antipsychotic 
medication.  Non-adherence to antipsychotic medication is a well-established risk factor for 
symptomatic relapse.  LAI antipsychotics can improve treatment adherence, but there has been no 
study to our knowledge of the effect of LAI antipsychotics on the policy- and cost-relevant 
endpoint of 30-day hospital readmission rates. 
Abilify Maintena®, approved by FDA for the treatment of schizophrenia on 28 February 2013, is 
now available to prescribers.  Given high interest from clinicians, policy-makers, and healthcare 
administrators on the effect of new medications on cost-effective health care delivery, we proposed 
to study the impact of this new LAI on hospital readmission rates in the high-cost population of 
patients with schizophrenia who use hospital services. 


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7.1 
ABILIFY (ARIPIPRAZOLE) 
Aripiprazole (ABILIFY®) is a dopamine partial agonist discovered by Otsuka Pharmaceutical 
Company, Ltd. (OPC) and co-developed by Bristol-Myers Squibb and OPC.  OPC and 
H. Lundbeck A/S are jointly developing the intramuscular (IM) injection formulation of 
aripiprazole.  Aripiprazole oral tablets are approved in the US for the treatment of adults and 
adolescents with acute schizophrenia, maintenance of stability in adults with schizophrenia, 
treatment of acute manic episodes associated with bipolar I disorder in adults and pediatric 
patients, maintenance of efficacy in adults with bipolar I disorder, and as adjunctive treatment of 
major depressive disorder.  Aripiprazole is also approved for the treatment of schizophrenia in the 
European Union (EU), Australia, and a number of countries in Asia, Europe, and Latin America.  
The aripiprazole immediate-release IM injection formulation is approved for agitation in 
schizophrenia and bipolar mania in the US and EU.  In addition, an oral solution formulation and 
orally disintegrating (i.e., dispersible) tablets have been approved and marketed in the US and EU.  
The favorable side effect profile of oral aripiprazole, including its low incidence of extrapyramidal 
side effects (EPS), low risk of prolactin elevation, decreased adrenergic and anticholinergic side 
effects, and minimal weight gain, makes it an excellent candidate for a long-acting injection 
formulation.  The aripiprazole once monthly formulation was recently approved for treatment of 
schizophrenia in the US. 
A brief summary of nonclinical and clinical data is included below. 
7.2 
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 animal models 
of dopaminergic hyperactivity.  Aripiprazole exhibits high affinity for dopamine D2 and D3 and 
serotonin 5-HT1A and 5-HT2A receptors, and moderate affinity for dopamine D4, serotonin 5-HT2C 
and 5-HT7, alpha1-adrenergic, and histamine H1 receptors, and the serotonin reuptake site.  
Aripiprazole also displays 5-HT1A partial agonist and 5-HT2A antagonist activity in nonclinical 
studies.  The emerging literature for other antipsychotics indicates that 5-HT1A and 5-HT2A activity 
may be correlated with the clinical observation of effectiveness against negative symptoms in 
subjects with schizophrenia.  It seems likely that the favorable safety and tolerability profile of 
aripiprazole, including its low incidence of EPS, lack of prolactin elevation, decreased adrenergic 
and anticholinergic side effects, and decreased weight gain, is also mediated by its unique profile 
of interaction with central neuroreceptors.  Please refer to the Investigator’s Brochure (IB)18 for 
information regarding nonclinical toxicity and pharmacokinetic (PK) studies conducted using 
aripiprazole in animals. 


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7.3 
RELEVANT CLINICAL STUDIES 
7.3.1 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 (31-97-201 and 31-97-202)19,20 each included two 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)21 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 CN13804722,23 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 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)24,25 of aripiprazole 30 mg versus haloperidol 10 mg were conducted 
in acutely relapsing schizophrenic subjects with the intention of pooling the data for analysis.  On 
the primary efficacy measure (i.e., time to failure to maintain response in responders) no difference 
was seen between aripiprazole and haloperidol.  However, analysis of secondary efficacy measures 
showed that aripiprazole 30 mg was superior to haloperidol for negative symptoms, depressive 
symptoms, and discontinuation for any reason. 
The subject-rated and investigator-rated acceptability of aripiprazole treatment was examined in 
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)26.  A separate open-label study (CN138152)27,28 
compared aripiprazole 10 to 30 mg daily with standard of care (SOC) treatment with 


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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 tolerability29. 
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 IB18. 
7.3.2 Agitation Studies with Injectable Aripiprazole 
The efficacy of immediate-release IM aripiprazole for the treatment of agitation was established 
in three short-term (i.e., 24-hour) placebo-controlled studies30.  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. 
7.3.3 Clinical Studies in Schizophrenia with Aripiprazole Once Monthly 
Protocol CN138020, a clinical study conducted by Bristol-Myers Squibb, assessed the safety, 
tolerability, and PK of single doses of the aripiprazole once monthly formulation.  This was an 
open-label, two-phase, nonrandomized, ascending dose, sequential panel study in subjects with a 
confirmed diagnosis of chronic schizophrenia or schizoaffective disorder.  Subjects received a 
single 5 mg dose of the standard IM formulation followed by safety and PK monitoring.  After a 
minimum 28-day washout, subjects who qualified based on no significant adverse events (AEs) or 
clinical laboratory abnormalities received a single dose of 15, 50, 100, 200, 300, or 400 mg of 
aripiprazole once monthly formulation, followed by safety and PK monitoring.  The IM 
formulation appeared to be well tolerated.  Peak plasma concentrations in most subjects were 
observed after approximately 100 hours.  Most AEs were mild (43%) to moderate (33%) in 
severity.  The most commonly reported treatment emergent 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. (OPDC) conducted a Phase 1B 
study (i.e., Protocol 31-05-244) to assess the safety, tolerability, and PK of multiple doses of the 
aripiprazole once monthly formulation in subjects with schizophrenia.  The results showed that 
once monthly administration of the 400-mg and 300-mg IM injections resulted in mean 


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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 three doses of aripiprazole once monthly (i.e., 200, 300, and 400 mg) demonstrated acceptable 
safety, tolerability, and potential effectiveness31. 
A Phase 3 study (i.e., Protocol 31-07-246) was conducted to evaluate the efficacy and safety of 
aripiprazole once monthly compared with placebo in schizophrenic subjects who had maintained 
stability on aripiprazole once monthly for at least 12 weeks.  Aripiprazole once monthly 400- or 
300-mg administered as monthly gluteal injections was effective for the maintenance treatment of 
schizophrenia in adults as demonstrated by a statistically significant difference, compared with 
placebo, in the primary efficacy endpoint of time to impending relapse.  The percentage of subjects 
who met the criteria for impending relapse was significantly lower in the aripiprazole once 
monthly group than in the placebo group.  The maintenance of stability was also demonstrated by 
statistically significant differences favoring aripiprazole once monthly in PANSS and CGI scores 
that remained significant throughout the double-blind, placebo-controlled phase.  In addition, the 
Personal and Social Performance (PSP) Scale total score, cognitive function assessments, and 
Investigator’s Assessment Questionnaire score were supportive of the efficacy of aripiprazole once 
monthly treatment.  Aripiprazole once monthly was well tolerated by adult subjects with 
schizophrenia as demonstrated by an AE profile similar to placebo.  Most treatment-emergent 
adverse events (TEAEs) were either mild or moderate in severity.  The only TEAE reported by 
≥ 5% of subjects receiving aripiprazole 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. 
7.3.4 Known and Potential Risks and Benefits 
As of 10 Jun 2010, 15,088 adult subjects were treated with aripiprazole oral tablet formulation in 
Phase 2, 3, and 4 studies, representing 8,577 subject-exposure years.  Of these, 3,901 (25.9%) 
subjects were treated with aripiprazole for 180 days or longer; 2,259 (15.0%) subjects received 
aripiprazole for at least 360 days, with 933 (6.2%) subjects 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.  Akathisia was the only commonly observed AE that 
occurred in  5% of aripiprazole-treated subjects and at an incidence more than twice that of 
placebo (8% vs. 4%, respectively).  Aripiprazole was well-tolerated in the long-term studies.  
Changes in body weight, fasting glucose, lipid profile, and serum prolactin levels were similar 
between aripiprazole- and placebo-treated subjects.  No clinically relevant changes in QTc were 
observed in either group23. 


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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 (ULN) compared with the haloperidol group (61%)25. 
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 elevation32. 
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 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 


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were no reported observations indicating clinically important adverse changes in vital signs, 
laboratory assessments, or ECGs.  Additional information can be obtained from the ABILIFY US 
package insert. 
7.4 
STUDY RATIONALE 
Non-adherence to antipsychotic medication is a well-established risk factor for symptomatic 
relapse.  LAI antipsychotics can improve treatment adherence, but at the time of this study there 
were, to our knowledge, no study on the effect of LAI antipsychotics on the policy- and 
cost-relevant endpoint of 30-day hospital readmission rates. 
The primary hypothesis was that treatment with aripiprazole once monthly would result in lower 
hospitalization rates for psychiatric symptom recurrence than patients experienced prior to 
treatment with aripiprazole once monthly. 
The secondary hypotheses were that treatment with aripiprazole once monthly would result in 
fewer unscheduled psychiatric emergency department (ED) visits, ED visits associated with 
psychiatric hospitalization, and fewer total psychiatric hospitalization days than patients 
experienced prior to treatment with aripiprazole once monthly.  In addition, we hypothesize that 
clinical functioning, measured by CGI-S and CGI-I scores, and change from baseline in measures 
of cardiometabolic risk (CMR) such as weight, body mass index (BMI), fasting glucose, and 
glycosylated hemoglobin (HbA1c) would improve from baseline in patients treated with 
aripiprazole once monthly that were previously treated with oral antipsychotics.  
The study design, following well-characterized subjects for 180 days after starting aripiprazole 
once monthly treatment, and retrospectively reviewing data regarding prior hospitalizations, 
psychiatric ED visits, and prior total psychiatric hospitalization days, will allow the proposed 
hypotheses to be tested. 


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8 
STUDY OBJECTIVES 
8.1 
PRIMARY OBJECTIVE(S) 
The primary objective of the study was: 
• To evaluate the effect of aripiprazole once monthly on 30-, 90-, and 180-day psychiatric 
re-hospitalization rates following discharge due to symptoms associated with 
schizophrenia, compared with prior 30-, 90-, and 180-day psychiatric hospitalization rates 
in subjects previously treated with oral antipsychotic medication. 
8.2 
SECONDARY OBJECTIVE(S) 
The secondary objectives of the study were: 
Efficacy: 
• To evaluate the effect of aripiprazole once monthly on: 
o 30-, 90-, and 180-day rates of unscheduled psychiatric ED visits compared with prior 
30-, 90-, and 180-day unscheduled visits 
o Psychiatric ED visits plus hospitalizations compared with prior 30-, 90-, and 180-day 
psychiatric visits plus hospitalizations 
o Total psychiatric hospitalization days over the 180-day study period compared with 
the total psychiatric hospitalization days over the prior 180-day period 
o Change from baseline in CGI-S and CGI-I scores at 30-, 90-, and 180-days 
• To evaluate changes from baseline for the following indicators for CMR: 
o Weight and BMI 
o Fasting glucose concentrations 
o HbA1c concentrations 
o Fasting plasma lipid concentrations (i.e., fasting triglyceride [primary analysis], total 
cholesterol, high-density lipoprotein [HDL], and low-density lipoprotein [LDL]) 
8.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of the study were: 
Safety: 
• To evaluate changes from baseline to 180 days in: 
o AEs 
o Clinical laboratory tests (i.e., hematology, fasting clinical chemistry, prolactin, and 
urinalysis) 


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o Vital signs 
o PSP 
o Injection site reactions (i.e., localized pain, redness, swelling, and induration) 
o EPS: 
▪ Abnormal Involuntary Movement Scale (AIMS) 
▪ Simpson-Angus Scale (SAS) 
▪ Barnes Akathisia Rating Scale (BARS) 
o Columbia Suicide Severity Rating Scale (C-SSRS) for suicidality 


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9 
INVESTIGATIONAL PLAN 
9.1 
OVERALL STUDY DESIGN AND PLAN 
This was an open-label, multi-center, longitudinal, within-subject comparison study of the effects 
of aripiprazole once monthly on 30-, 90-, and 180-day psychiatric re-hospitalization rates 
following hospital discharge in subjects with schizophrenia compared with prior psychiatric 
hospitalization rates while on oral antipsychotics. 
Prospective subjects underwent screening for eligibility for entry into the study during or 
immediately after hospitalization for symptoms due to schizophrenia. 
An overview of the planned study design is provided in Figure 1. 
. 
 


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Figure 1 
Study Schematic 
AE = adverse event, AIMS = Abnormal Involuntary Movement Scale, BARS = Barnes Akathisia Rating Scale, BMI = body mass index, CGI-I = Clinical Global Impression–
Improvement, CGI-S = Clinical Global Impression–Severity, C-SSRS = Columbia Suicide Severity Rating Scale, HbA1c = glycosylated hemoglobin, PSP = Personal and Social 
Performance Scale, REALM-SF = Rapid Estimate of Adult Literacy in Medicine–Short Form, SAS = Simpson Angus Scale, UBACC = University of California, San Diego Brief 
Assessment of Capacity to Consent 
Screening 
Phase A 
Oral Tolerability 
Phase B 
Maintenance Treatment 
Follow-up 
Total:  
177 eligible 
subjects with 
schizophrenia 
1 day 
3-day tolerability to 
oral aripiprazole 
Minimum of 
3 days 
Subjects with 
history of 
tolerating ≥ 3 
doses of oral 
aripiprazole 
Aripiprazole once monthly plus 
14 days of oral antipsychotic 
medication (first injection only) 
After the 14-day oral lead-in, after 
the first injection of aripiprazole 
once monthly, only oral aripiprazole 
will be allowed as a rescue 
medication 
Vital signs; height; weight; BMI; 
clinical laboratory tests including 
fasting glucose, lipids, HbA1c, and 
prolactin; urine pregnancy test, 
CGI-S, CGI-I, AIMS, BARS, SAS, 
C-SSRS, PSP, AE reporting, 
injection site assessments, and 
concomitant medications 
Safety follow-up:  
AEs, SAS, 
AIMS, BARS, 
concomitant 
medications 
180 days/ 
8 visits
30 (± 5 days) 
Subjects with 
no history of 
oral 
aripiprazole 
use 
Pre-Screening 
All subjects 
prior to study 
enrollment: 
REALM-SF 
and UBACC 


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9.1.1 Pre-Screening Assessments 
Pre-Screening assessments were conducted to help investigators identify any subjects with literacy 
or capacity to consent issues prior to study enrollment. 
These assessments occurred before the subject entered the Screening Period and gave their written 
consent via the ICF.  Pre-Screening assessments were conducted via the following: 
• Rapid Estimate of Adult Literacy in Medicine–Short Form (REALM-SF) 
• University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) 
9.1.2 Screening Period 
All recruitment methods conformed to the guidelines of the IRB at the clinical site.  The subjects 
participating in this study had to be capable of understanding the nature of the study.  The ICF 
contained a full description of the procedures and their associated risks.  Subjects were 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 were given the opportunity to ask questions.  Subjects were asked to 
paraphrase the ICF.  When ready, subjects were asked to give written consent to participate in the 
study.  After the ICF was signed by both the subject and the investigator, each subject was given 
a copy of the signed ICF.  The investigator had full responsibility for all issues pertaining to assent 
and informed consent.  Procedures to be followed when obtaining informed consent are detailed 
in Section 5.1. 
During the Screening Period, subjects could be treated with any oral antipsychotic medication of 
the clinician’s choice, with the exception of clozapine.  However, oral olanzapine was permitted 
during the Screening Period only for subjects who were eligible for Phase A. 
Eligibility for the study was determined during the screening period, which could occur at any 
time, beginning with the first day of hospitalization.  Eligibility for the study was assessed via the 
following: 
• Confirmation of a current diagnosis of schizophrenia according to Diagnostic and 
Statistical Manual, Fifth Edition (DSM-5) criteria 
• Review of inclusion and exclusion criteria 
• Complete medical history, including demographics, complete psychiatric history including 
all psychiatric and non-psychiatric hospitalizations and medical interventions occurring 
within the 6 months prior to the date of signing the ICF: 
o Data regarding psychiatric and non-psychiatric hospitalizations, including treatment 
records relevant to determination of study eligibility and identified outcome variables 
related to ED, outpatient and inpatient treatment episodes as described in the inclusion 
and exclusion criteria (Section 9.3.1 and Section 9.3.2, respectively) occurring within 
the 6 months prior to the date of signing the ICF were obtained by searching MO 


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HealthNet (Medicaid) and Missouri Department of Mental Health (DMH) data via 
collaboration with the Missouri Institute of Mental Health (MIMH) or confirmed 
through all available medical records and reliable data from caregivers.  Availability of 
Medicaid data or documentation of at least one inpatient hospitalization, ED visit, or 
equivalent (i.e., urgent care center) visit within the previous 6 months of screening was 
required for eligibility (see inclusion and exclusion criteria, Section 9.3). 
• Admission vital signs (e.g., blood pressure, heart rate, respiratory rate, and temperature) 
• Admission height, weight, and calculation of BMI 
• Admission ECG 
• Admission HbA1c, if available 
• Admission safety clinical laboratory tests (Section 9.5.1.4.1) 
• Admission clinical laboratory results were assessed to rule out exclusionary values 
(Section 9.3) 
• Urine pregnancy test for women of childbearing age 
• Previous medications taken within 30 days prior to starting study drug were recorded.  
Concomitant medications including details (e.g., drug name, dose, and frequency) of all 
current medication(s) and any antipsychotic medications taken within 6 months of 
screening were recorded. 
• The nature of acute hospitalization in this population could indicate prior discontinuation 
of antipsychotic medications due to noncompliance.  Appropriate review of all medications 
for psychiatric illness, including newly prescribed antipsychotic medication was conducted 
during screening.  Discontinuation or tapering of any psychotropic medication, if deemed 
clinically appropriate or necessary for those subjects entering Phase A (i.e., Oral 
Tolerability Phase), started at screening and continued during Phase A. 
• Additional clinical laboratory tests (fasting or non-fasting as needed) which were not 
obtained at admission, were deemed necessary by the PI and/or were required to verify 
inclusion and exclusion criteria  
Fasting or non-fasting clinical laboratory tests that were required to establish eligibility could be 
performed at any time during the Screening Period.  Study specific clinical laboratory tests that 
required fasting (i.e., fasting lipid profile and fasting glucose) were performed during the Baseline 
Visit. 
Prospective subjects were hospitalized for the necessary length of time as determined by the 
assigned treatment provider as clinically indicated, per the current SOC.  To be eligible, the 
anticipated duration of hospitalization was to be long enough to accommodate the screening 
procedures, the 3-day Oral Tolerability Phase (if applicable), and initiation of treatment with 


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aripiprazole once monthly. However, some subjects could also enter the study if they were 
clinically started on long-acting injectable aripiprazole during the hospitalization just prior to study 
entry. 
Following the Screening Period, subjects who had no history of aripiprazole use were entered into 
Phase A, the Oral Tolerability Phase.  Subjects from Phase A that demonstrated tolerability to 
aripiprazole were then entered into Phase B, the Treatment Phase, where all subjects were treated 
with long-acting injectable aripiprazole.  Subjects who already had a history of tolerating at least 
three consecutive oral doses of aripiprazole were entered directly into Phase B.  All eligible 
subjects eventually entered Phase B. 
9.1.3 Phase A – Oral Tolerability Phase 
The Oral Tolerability Phase lasted for a minimum of 3 days.  Subjects with a history of tolerating 
aripiprazole (e.g., a history of at least 3 days of oral exposure) were not entered into Phase A; these 
subjects were entered directly into Phase B following the Screening Phase. 
Subjects who met the inclusion and exclusion criteria and had no history of oral aripiprazole use 
entered Phase A after the Screening Period while still hospitalized.  Subjects in Phase A were 
administered oral aripiprazole, as indicated in the product labeling, to determine tolerability.  
Dosage was based on symptoms and the judgment of the investigator.  The dose of oral aripiprazole 
could be titrated as needed.  Prior antipsychotic medications were tapered off and discontinued 
during the Screening Period and Phase A as clinically appropriate. 
During Phase A, tolerability to oral aripiprazole was evaluated daily for a minimum of 3 days 
using baseline safety and tolerability measures (i.e., AIMS, BARS, and SAS) either during or 
closely following completion of oral treatment, in conjunction with clinical judgment.  If a subject 
was unable to tolerate oral aripiprazole, he or she was withdrawn from the study.  If the subject 
showed tolerability to the oral aripiprazole, Phase B baseline/Day 1 occurred with the first 
aripiprazole once monthly injection given immediately after the Phase B baseline/Day 1 
assessments. 
Prior antipsychotic medications could be continued or tapered to discontinuation at the 
investigators discretion based on his or her clinical judgment.  Reporting and recording of AEs 
was completed. 
9.1.4 Phase B (Treatment Phase) 
9.1.4.1 Baseline 
Baseline was considered Day 1, or first day of long-acting injectable treatment, of Phase B.  
However, some subjects could have had their baseline assessments (including any remaining 
clinical laboratory tests required for screening) performed any time during or immediately after 
treatment with oral antipsychotic aripiprazole (unless eligible to skip Phase A in which it is any 
oral antipsychotic), ideally prior to starting long-acting injectable aripiprazole. Participants were 
allowed, with Principal Investigator approval, to enter the study after starting treatment with long-
acting injectable aripiprazole in the hospital and baseline assessments were performed as soon as 
feasible within 48 hours of hospital discharge. 


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Subjects who completed the baseline assessments and met the criteria for inclusion and not for 
exclusion (Section 9.3.1 and Section 9.3.2) began the Treatment Phase (Phase B). 
Baseline assessments were: 
• Contact from the community support worker (CSW) or study coordinator (SC) via 
telephone or in-person 
• Routine vital signs (e.g., blood pressure, heart rate, respiratory rate, and temperature) 
• Height, weight, and calculation of BMI 
• Fasting lipid profile (e.g., fasting triglycerides, cholesterol [total, HDL, LDL]) 
• HbA1c 
• Prolactin concentration 
• CGI-I 
• C-SSRS (Since Last Visit) for suicidality 
• AIMS, BARS, and SAS to assess EPS 
• PSP 
• Injection site reaction assessment (i.e., localized pain, redness, swelling, and induration), 
if applicable 
• AEs and concomitant medications 
• Aripiprazole once monthly IM injection plus Day 1 of 14 days of oral aripiprazole, (last 
baseline procedure), unless subject received injection while hospitalized prior to study 
entry. 
9.1.4.2 Treatment Phase 
Eligible subjects who had a history of tolerating oral aripiprazole or were currently taking oral 
aripiprazole entered Phase B directly from the Screening Period.  All other subjects entered Phase 
B following successful completion of Phase A.  After the baseline assessments were completed, 
the subject received the first aripiprazole once monthly IM injection, in conjunction with the first 
of 14 doses of concomitant oral antipsychotic medication (see Figure 1).  Use of concomitant oral 
aripiprazole during this lead-in was per the investigator’s judgment based on the prescribing 
instructions. 
All subjects must have attended scheduled visits at the Baseline Visit and Weeks 2, 4, 8, 12, 16, 
20, and 24, totaling 180 days.  Aripiprazole once monthly injections occurred at the Baseline Visit 
and every 28 (-2, +5) days at Weeks 4, 8, 12, 16, 20, and 24, totaling seven injections.  After the 


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initial injection of 400 mg, the monthly dosage could be decreased to 300 mg, based on the clinical 
judgment of the investigator.  All aripiprazole once monthly injections were administered based 
on the investigator’s judgment and the prescribing information.  For subjects who entered the 
studies after starting the first dose of long-acting injectable aripiprazole in the hospital, if the initial 
injection was not 400 mg, the second injection should have been 400 mg, and thereafter, the 
monthly dose could be decreased to 300 mg, based on clinical judgment of the investigator. 
For subjects who were psychiatrically stabilized and discharged prior to the completion of the 
required 14-day course of oral antipsychotic medication, a pre-discharge assignment was given to 
a CSW/SC.  The CSW/SC maintained regular contact with the subject until the first outpatient 
visit in Phase B (Week 2), when oral aripiprazole was discontinued.  Regular contact was defined 
as no less than weekly, but could have been more frequent depending on the clinical judgment of 
the CSW/SC and outpatient treatment team.  Following the Week 2 Visit, subjects were to have 
contact with their assigned CSW/SC based on routine clinical care.  Contact with the CSW/SC 
could be in person or by telephone, as clinically appropriate. 
The treating clinician performed a clinical interview and mental status examination based on 
current clinical standards of care at all outpatient visits, whether scheduled or unscheduled.  All 
episodes of clinical care (i.e., psychiatric and non-psychiatric) were recorded in the source 
documentation.  In addition, the following clinical evaluations were performed as outlined in 
Table 3: 
• Routine vital signs (e.g., blood pressure, heart rate, respiratory rate, and temperature) at 
each visit 
• Height, weight and calculation of BMI at each visit 
• Fasting lipid tests [e.g., fasting triglycerides, cholesterol (total, HDL, LDL)] 
• HbA1c 
• Additional clinical laboratory testing (e.g., hematology, fasting clinical chemistry, 
prolactin, urinalysis and urine pregnancy test) as described in Table 3 and clinically 
indicated and determined by treatment team 
• AEs and concomitant medications 
• CGI-I 
• PSP 
• C-SSRS (Since Last Visit) for suicidality 
• AIMS, BARS, and SAS to assess EPS 
• Injection site reaction (i.e., localized pain, redness, swelling, and induration) 


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9.1.4.3 Early Termination 
All subjects who completed or withdrew from the study received a telephone call for safety follow-
up at 30 (± 5) days after the last study visit unless they withdrew their consent for participation in 
the study.  This telephone contact was made to assess if there were any AEs experienced since the 
last visit.  In addition, the subject was asked about any new medications or changes in existing 
medications and the information was documented in the source documentation.  The study site 
registered the contact in the interactive voice response system or interactive web response system. 
The end of the study was the date of the last study visit for the last subject. 
9.2 
DISCUSSION OF STUDY DESIGN 
The study design, following well-characterized patients for 180 days after starting aripiprazole 
once monthly treatment, and retrospectively reviewing data regarding prior hospitalizations, 
psychiatric ED visits, and prior total psychiatric hospitalization days, was planned to allow the 
proposed hypotheses to be tested adequately. 
By utilizing retrospective review of hospitalizations, each subject served as his or her own control.  
The 30-, 90-, and 180-day analyses allowed for relatively equivalent comparison of the previous 
6-month data. 
This was an open-label study with one treatment arm, therefore, no active or placebo control or 
randomization was used.  Treatment bias was eliminated via the objective assessments employed. 
9.3 
SELECTION OF STUDY POPULATION 
Approximately 177 subjects were planned to be enrolled competitively between each of four 
designated clinical sites across the state of Missouri to reach a total of 90 completed subjects.  This 
was to account for an expected 40% screen failure rate and an additional 40% drop-out rate.  
Subjects served as their own controls. 
Prospective subjects were planned to be recruited from two of three established clinical sites at 
inpatient hospitals associated with outpatient community mental health centers in Missouri:  
Washington University in St. Louis, University of Missouri, Columbia, MO; and University of 
Missouri, Kansas City, MO. 
Subjects who did not meet all of the inclusion criteria or who met any of the exclusion criteria 
were not eligible to receive study drug. 
9.3.1 Inclusion Criteria 
Subjects must have met all of the following criteria to be included in this study: 
1. Were able to provide written informed consent. 
2. Were male and female subjects 18 to 65 years of age, inclusive, at time of informed consent 


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3. Had a current and confirmed diagnosis of schizophrenia as defined by DSM-5 criteria and 
a history of the illness for at least 6 months prior to screening from a reliable source (e.g., 
subject, family member, friend, caregiver, healthcare provider, or medical records) 
4. Present at one of the selected inpatient units with acute psychotic symptoms for 
hospitalization at study entry 
5. Had a clinically indicated need for a change in current antipsychotic therapy 
6. Were on Medicaid with searchable claims data or were Medicaid-eligible 
7. Had at least one inpatient psychiatric hospitalization or psychiatric ED visit within the 
6 months prior to screening as confirmed through Medicaid or all available medical records 
and reliable data from caregivers 
8. Had been previously prescribed oral antipsychotic treatment for at least a substantial 
portion of the 6 consecutive months prior to screening, with estimated duration of 
prescribed treatment within the 6 months prior to screening as determined by Principal 
Investigator discretion and confirmed through Medicaid or all available medical records 
and reliable data from caregivers 
9. Had a history of response to antipsychotic treatment, with no history of clozapine treatment 
10. Were able to understand the nature of the study and follow protocol requirements, 
including the prescribed dosage regimens, tablet ingestion, aripiprazole once monthly 
injection, and discontinuation of prohibited concomitant medications 
11. Were able to read and understand the written word with a passing score of 4 to 6 (i.e., 
equivalent to seventh to eighth grade reading level for REALM-SF literacy assessment) in 
order to complete subject-reported outcomes measures  
12. Were willing to accept a monthly injection 
13. Were male and female subjects who were surgically sterile (i.e., have undergone 
orchiectomy or hysterectomy, respectively); female subjects who were postmenopausal for 
at least 12 consecutive months; or male and female subjects who agreed to use an approved 
form of birth control during study participation 
9.3.2 Exclusion Criteria 
Subjects who met any of the following criteria were excluded from this study: 
1. Had current psychotic symptoms that could be explained by a diagnosis other than 
schizophrenia, including schizophreniform disorder, schizoaffective disorder, major 
depressive disorder, bipolar disorder, delirium, dementia, amnestic or other cognitive 
disorders.  Also excluded were subjects with borderline, paranoid, histrionic, schizotypal, 
schizoid, or antisocial personality disorder. 


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2. Prisoners or subjects who were involuntarily incarcerated, or were incarcerated in the past 
7 months for any reason 
3. Required potent cytochrome P450 (CYP)2D or CYP3A4 inhibitors or CYP3A4 inducers 
4. Were allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other 
quinolinones or had a history of hypersensitivity to antipsychotic agents 
5. Had received electroconvulsive therapy within the 6 months prior to screening 
6. Had a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia 
as assessed by the investigator 
7. Had a current diagnosis of diabetes or known fasting triglyceride levels consistent with risk 
for pancreatitis 
8. Met DSM-5 criteria for a current substance use disorder within 3 months prior to screening: 
a. Ingestion of an identified substance alone may not have met the criteria for 
substance use diagnosis and therefore might not exclude the patient. Exceptions to 
this included the use of intravenous drugs within 3 months prior to screening. 
b. Patients with a diagnosis of a substance use disorder greater than 3 months prior to 
screening may or may not have been still in remission even if they have had some 
sporadic use. They must have met DSM-5 criteria identified for the specific 
substance to be out of remission. 
9. Received treatment with long-acting injectable antipsychotics (e.g., haloperidol decanoate, 
fluphenazine decanoate, risperidone long acting injection [Risperdal Consta®], 
paliperidone palmitate extended release injectable suspension [Invega® Sustenna®], 
olanzapine for extended release injectable suspension [Zyprexa® Relprevv™]), in which the 
last dose was within 7 months prior to screening.  Prior use of aripiprazole was allowed, 
but must have been discontinued prior to the current hospitalization. 
10. Had a significant risk of committing suicide based on history, routine psychiatric status 
examination, investigator's judgment, or who had an answer of "yes" on Question 4 or 
Question 5 within the last 30 days on the baseline version of the C-SSRS 
11. Had a history or evidence of a medical condition that would expose them to an undue risk 
of a significant AE or interfere with assessments of safety or efficacy during the course of 
the study, including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine, 
neurologic, hematologic, or immunologic disease as determined by the clinical judgment 
of the investigator 
12. Had results from one or more of the following laboratory tests, vital signs, and ECG tests 
at screening that were exclusionary (laboratory testing and ECGs were performed locally): 
a. Platelets ≤ 75,000/mm3 


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b. Hemoglobin ≤ 9 g/dL 
c. HbA1c > 7.0% or fasting blood glucose > 126 mg/dL 
d. Neutrophils, absolute ≤ 1000/mm3 
e. Aspartate transaminase (AST) > 3x ULN 
f. Alanine transaminase (ALT) > 3x ULN 
g. Creatinine ≥ 2 mg/dL 
h. Diastolic blood pressure > 105 mmHg 
i. QTc > 475 msec on either the QTcB (Bazett) or QTcF (Fridericia) corrections on 
ECG, confirmed by a second tracing 
j. Any other abnormal laboratory tests, vital sign results, or ECG findings that, in the 
judgment of the investigator, were medically significant and would affect the safety 
of the subject or the interpretation of the study results.  Abnormal results for 
laboratory parameters or vital signs were to be repeated to ensure reproducibility of 
the abnormality before excluding a subject based on the criteria noted above. 
13. Had been previously enrolled in an aripiprazole once monthly clinical study 
14. Had participated in any clinical study with an investigational agent within the past 30 days 
15. Were pregnant or lactating 
9.3.3 Removal of Subjects from Therapy or Assessment 
9.3.3.1 Entire Study 
If the sponsor terminated or suspended the study for safety or unanticipated other reasons, prompt 
notification was to be given to Otsuka America Pharmaceutical, Inc. (OAPI), IRBs, and regulatory 
authorities in accordance with regulatory requirements. 
9.3.3.2 Individual Center 
The sponsor was to notify OAPI promptly if the study is terminated by the sponsor or the IRB at 
the site. 
9.3.3.3 Individual Subject 
If a subject discontinued from the study prematurely, the reason must have been fully evaluated 
and recorded appropriately in source documents and the CRF.  If the subject was being withdrawn 
because of an AE, that AE should have been indicated as the reason for withdrawal. 


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An increase in suicidal ideation or homicidal ideation would result in withdrawal from the study, 
based on the investigators discretion. 
All subjects had the right to withdraw at any point during treatment without prejudice.  The 
investigator could discontinue a subject’s participation in the study at any time if medically 
necessary.  In addition, subjects meeting the following criteria were to be withdrawn from the 
study: 
1. Occurrence of any AE, intercurrent illness or abnormality in a laboratory assessment 
which, in the opinion of the investigator, warranted 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 became pregnant 
6. Subject was lost to follow-up 
The sponsor notified OAPI promptly when a subject was withdrawn. 
9.4 
TREATMENTS 
9.4.1 Treatments Administered 
All active study drugs were provided by the manufacturer at no cost. 
Aripiprazole once monthly and oral aripiprazole were prescribed and administered according to 
recommendations contained in their respective product labeling. 
The following treatments were administered to subjects in this study: 
• Aripiprazole, administered once monthly via gluteal or deltoid IM injection, as outlined 
in the product labeling 
• Oral aripiprazole: 
o Subjects in Phase A were administered oral aripiprazole to determine tolerability, based 
on the prescribing information 
DOSAGE ADJUSTMENTS FOR MISSED DOSES OF ARIPIPRAZOLE ONCE MONTHLY 
If the second or third doses were missed: 


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• If > 4 weeks and < 5 weeks elapsed since the last injection, the injection as administered 
soon as possible 
• If > 5 weeks elapsed since the last injection, concomitant oral aripiprazole was restarted 
and given for 14 days with the next administered injection 
If the fourth or subsequent doses were missed: 
• If > 4 weeks and < 6 weeks elapsed since the last injection, the injection was administered 
as soon as possible 
• If > 6 weeks elapsed since the last injection, concomitant oral aripiprazole was restarted 
and given for 14 days with the next administered injection 
9.4.2 Identity and Storage of Drug Under Study(s) 
All study drug was securely locked in a cabinet or enclosure according to the storage instructions 
on the product labeling.  Access was limited to the investigators and their designees.  Neither 
investigators nor any designees were allowed to provide study drugs to any subject not 
participating in this protocol. 
9.4.3 Method of Assigning Subjects to Treatment Groups 
A total of 177 subjects were planned to be enrolled in the study.  Subjects were assigned a subject 
ID number chronologically based on the order of enrollment into the study.  The study was a 
single-arm, nonrandomized study.  
9.4.4 Blinding 
The study was not blinded. 
9.4.5 Prohibited Medication 
During the Screening Period, subjects could be treated with any oral antipsychotic of the clinician’s 
choice, with the exception of clozapine and olanzapine.  However, oral olanzapine was permitted 
during the Screening Period only for subjects who are eligible for Phase A. 
Following the concomitant 14-day oral lead-in in Phase B after the first injection of aripiprazole 
once monthly, oral aripiprazole was the only allowed rescue medication.  Subjects requiring any 
other antipsychotic medications except for oral aripiprazole for rescue during Phase B of the study 
after the first 14 days were discontinued. 
A summary of medications that are prohibited or restricted prior to screening or during the study 
is provided in Table 1. 


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Table 1: 
Prohibited and Restricted Medications 
Medication 
Prohibition or Restriction 
Antipsychotics 
No more than one SOC antipsychotic allowed 
Antidepressants including MAOIs 
No new starts allowed; could continue if already 
taking for ≥ 2 months on a stable dose 
Benzodiazepine 
The use of one benzodiazepine was allowed.  
Mood stabilizers 
No new starts allowed – could continue if already 
taking for ≥ 2 months on a stable dose 
Non-benzodiazepine sleep aidsa 
Allowed 
Anticholinergics 
≤ 4 mg/day benztropine or equivalent; not within 
12 hours of any rating scales 
Propranolol for akathisia or tremor 
Maximum 60 mg/day; not within 8 hours of any 
rating scales.  Subjects receiving propranolol for 
heart disease could remain on stable, pre-study 
doses, as needed as long as the dose did 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 were allowed, 
however, the investigator could adjust the dose of 
study drug per the prescribing instructions. 
CYP3A4 inducers were not allowed 
Oral olanzapineb and clozapine 
During Screening Period 
All long-acting antipsychotics, except 
for aripiprazole once monthlyc 
Not allowed 
CNS = central nervous system, CYP = cytochrome P450, EPS = extrapyramidal side effects, 
GABA = gamma-aminobutyric acid, MAOI = monoamine oxidase inhibitor, SOC = standard of care 
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 was permitted, but not in addition to a benzodiazepine for 
insomnia. 
b:  Oral olanzapine was allowed during the Screening Period only if the subject was eligible for Phase A. 
c:  Prior use of aripiprazole was allowed, but must have been discontinued prior to the current 
hospitalization. 
9.4.6 Treatment Compliance 
Most of the study drugs were administered during the subject’s hospitalization or at pre-specified 
visits and were recorded in the source documentation.  Oral aripiprazole usage continuing after 


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discharge was monitored by self-report to the CSW/SC and by pill counts, when possible, at the 
next visit after completion of the 14-day oral aripiprazole period. 
9.4.7 Accountability 
Study drug was not prescribed or administered until the following documentation was provided by 
the sponsor to OAPI: 
• A signed and dated confidentiality agreement 
• 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 was to be conducted 
• A copy of the IRB-approved ICF and any other documentation provided to the subjects to 
be used in this study 
• A signed and dated curriculum vitae (CV) of the sponsor including a copy of the sponsor’s 
current medical license or medical registration number on the CV 
• A signed and dated clinical studies agreement 
The sponsor, site investigators, and the study staff were responsible for the accountability of all 
study drugs (dispensing, inventory, and record keeping) adherence to GCP guidelines and any 
local or regional requirements. 
Under no circumstances was the sponsor or site investigators to allow the study drugs to be used 
other than as directed by the protocol.  Study drugs were not dispensed to any individual who was 
not enrolled in the study unless that person was a parent or legal guardian for the subject and signed 
the ICF as such. 
The sponsor, or designee, maintained an inventory record of study drugs received, dispensed, 
administered, disposed of, and returned.  The study drugs and inventory records were to 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 were returned to the site 
investigator by the subject. 
9.5 
STUDY ASSESSMENTS 
9.5.1 Assessments 
9.5.1.1 Pre-Screening Assessments 
RAPID ESTIMATE OF ADULT LITERACY IN MEDICINE-SHORT FORM 
The REALM-SF is a 7-item word recognition test to provide investigators with a fast and valid 
assessment of subject health literacy.  The interviewer asked the subject to read each of the words 


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aloud and reply “blank” if unable to read a particular word.  If the subject took more than 5 seconds 
on a word, the interviewer would say "blank" and point to the next word, if necessary, to move the 
patient along.  If the subject began to miss every word, the interviewer would ask the subject to 
pronounce the known words only. 
The score and grade equivalents for the REALM-SF were:  0 = third grade and below; will not be 
able to read most low-literacy materials; will need repeated oral instructions, materials composed 
primarily of illustrations, or audio or video tapes; 1 to 3 = fourth to sixth grade; will need 
low-literacy materials, may not be able to read prescription labels; 4 to 6 = seventh to eighth grade; 
will struggle with most patient education materials; will not be offended by low-literacy materials; 
and 7 = high school; will be able to read most patient education materials. 
UNIVERSITY OF CALIFORNIA, SAN DIEGO BRIEF ASSESSMENT OF CAPACITY TO CONSENT 
The UBACC is a 10-item scale designed to help investigators identify any subjects with 
questionable capacity to consent to study participation prior to enrollment in a study.  Questions 
focus on the ability of the subject to understand, appreciate, reason, and express a choice about 
participating in a particular clinical study. 
After explaining the details of the study and the ICF, the interviewer asked each question and rated 
the subject’s responses on a scale of 0 to 2, with “0” being the lowest (i.e., little to no understanding 
of this aspect of the study) and “2” being the highest (i.e., clear understanding of this aspect of the 
study).  If a subject had trouble understanding one of the questions on the UBACC, the question 
could be rephrased. 
Subjects were allowed to refer to the ICF when answering these questions, but were encouraged 
to respond in their own words. 
9.5.1.2 Demographics 
Subject demographic information was collected at the Screening Visit.  Demographic information 
included date of birth or age, sex, race or ethnicity, and previous hospitalizations or ED visits. 
9.5.1.3 Screening Assessments 
MEDICAL HISTORY 
Medical and surgical history and current medical conditions were recorded at the Screening Visit.  
All relevant medical and surgical history within 1 year was noted in the CRF. 
PSYCHIATRIC HISTORY 
A review of the subject’s psychiatric history was performed including all antipsychotic 
medications used within the 6 months prior to screening.  Confirmation of a current diagnosis of 
schizophrenia, as defined by DSM-5 criteria was obtained.  The complete psychiatric history 
included a clinical interview documented in the medical record and completion of a consensus 
diagnosis form, where the diagnosis for other records, the study team interview, and the consensus 
diagnosis were recorded. 


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ELECTROCARDIOGRAM 
A 12-lead ECG was performed while the subject was in a supine position and after having rested 
for 5 minutes. 
DOCUMENTATION OF PREVIOUS HOSPITALIZATIONS 
Data regarding psychiatric and non-psychiatric hospitalizations and medical interventions 
occurring within the 6 months prior to the date of the signing the ICF were obtained by searching 
MO HealthNet (Medicaid) and the DMH database or confirmed through all available medical 
records and reliable data from caregivers. 
EXCLUSIONARY LABORATORY MEASUREMENTS 
At screening, laboratory testing including triglycerides (screening only) were assessed to rule out 
exclusionary values (see Section 9.3.2).  Subjects who had any of the excluded laboratory values 
were dropped from the study.  All other clinical laboratory measurements are described in 
Section 9.5.1.4.1). 
9.5.1.4 Safety Assessments 
Safety was assessed by AE reporting, clinical laboratory tests (i.e., hematology, fasting clinical 
chemistry, and lipid profile), urinalysis, urine pregnancy testing and vital signs measurements.  In 
addition, body weight, BMI, and serum prolactin concentrations were monitored. 
The following scales were used to assess for EPS: 
• AIMS 
• SAS 
• BARS 
For subjects receiving an injection, the investigator, or qualified designee, assessed the injection 
site for localized pain, redness, swelling, and induration. 
9.5.1.4.1 Clinical Laboratory Tests 
The local laboratory was used for all laboratory testing required during the study.  Reports from 
the laboratory were filed with the source documents for each subject.  Samples were obtained at 
the visits designated in Table 3, and as far as possible, samples were drawn at the same time of 
day at each visit.  Additional samples could be collected for further evaluation of safety as 
warranted by the investigator’s discretion.  Subjects were to be fasting for a minimum of 10 hours 
prior to blood draws for assessment of safety, including screening.  If non-fasting blood samples 
were obtained initially for determining eligibility for the study, a fasting blood sample was to be 
drawn prior to enrollment.  The clinical laboratory tests performed during the study are provided 
in Table 2. 


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Table 2: 
Safety Clinical Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count with differential 
Serum Chemistry: 
Alanine transaminase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate transaminase (AST) 
Bilirubin, total 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine  
Glucose 
Potassium 
Protein, total 
Sodium 
Urinalysis: 
Appearance 
Color 
Dipstick  
Microscopic Analysis of RBC and WBC (i.e., per 
high powered field)] 
pH 
Specific gravity 
Additional Tests: 
Fasting glucose 
HbA1c 
Lipid profile (cholesterol [total, HDL, LDL]) 
Serum prolactin 
Triglyceridesa 
Urine β-hCGb for women of child-bearing potential 
β-hCG = beta-human chorionic gonadotropin, HbA1c = glycosylated hemoglobin, HDL = high-density lipoprotein, 
LDL = low-density lipoprotein 
a:  Triglycerides were measured at screening only, to rule out exclusionary values 
b:  Serum β-hCG was performed if the subject or investigator suspected that the subject may be pregnant 
9.5.1.4.2 Vital Signs 
Vital sign measurements (i.e., systolic and diastolic blood pressure [BP] [mmHg], heart rate [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) were 
obtained at the visits designated on the Schedule of Assessments (Table 3) by a validated method.  
Blood pressure and heart rate were measured after the subject was supine for 5 minutes and again 
standing for ≥ 1 minute. 
9.5.1.5 Adverse Events and Other Events of Interest 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a drug under study.  An AE does not necessarily have a causal relationship with the 
study drug.  For this study, the study drug was aripiprazole once monthly and oral aripiprazole. 
The criteria for identifying AEs were: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug under study, whether or 
not considered related to the drug under study 
• Any new disease or exacerbation of an existing disease 


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• 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 
(i.e., baseline) 
• An abnormal laboratory test result was considered an AE if the identified laboratory 
abnormality led to any type of intervention, whether prescribed in the protocol or not. 
A laboratory result was to be considered by the investigator to be an AE if it: 
• Resulted in the withdrawal of study drug 
• Resulted in withholding of study drug pending some investigational outcome 
• Resulted in an intervention, based on medical evaluation (e.g., potassium supplement for 
hypokalemia) 
• Resulted 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 were reported on the CRF.  All AEs, regardless of relationship 
to study drug or procedure, were collected beginning from the time the subject signed the study 
ICF through the last visit.  Serious AEs were collected for 30 days after the last dose or at the 
Follow-up Visit, whichever came later. 
Abnormal laboratory values were not listed as separate AEs if they were considered to be part of 
the clinical syndrome that is being reported as an AE.  Any laboratory abnormality considered to 
constitute an AE was reported as an AE on the CRF. 
It was the responsibility of the investigator to review all laboratory findings in all subjects and 
determine if they constitute an AE.  Medical and scientific judgment was to be exercised in 
deciding whether an isolated laboratory abnormality was classified as an AE. 
It was the responsibility of the investigator to review the results of the C-SSRS in all subjects and 
determine if any result constituted an AE.  Medical and scientific judgment was to be exercised in 
deciding whether an isolated suicidality rating scale response was to be classified as an AE (see 
Other Safety Assessments [Section 9.5.1.7.3] for a description of the C-SSRS). 
Every effort was to be made by the investigator to categorize each AE according to its severity and 
its relationship to the study treatment. 
Assessing Severity of Adverse Events 
AEs were graded on a 3-point scale (i.e., mild, moderate, and severe) and reported in the detail 
indicated on the CRF.  The definitions were as follows: 
Mild: 
Discomfort noticed, but no disruption of normal daily activity 


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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 9.5.1.6] for the definition of an SAE). 
The causal relationship of the study drug to an AE was assessed as related or unrelated, as follows: 
Related: 
Definite: 
There was a reasonable causal relationship between the study drug and the AE, 
when the event responded to withdrawal of the study drug (i.e., dechallenge), 
and recurred with rechallenge by administration of the study drug. 
Probable: 
There was a reasonable causal relationship between the study drug and the AE.  
The event responded to dechallenge.  Rechallenge was not required. 
Possible: 
There was a reasonable causal relationship between the study drug and the AE.  
Dechallenge was lacking or unclear. 
Unrelated: 
Not Likely: 
There was a temporal relationship to study drug administration, but there 
was not a reasonable causal relationship between the study drug and the 
event. 
Not Related: 
There was not a temporal or causal relationship to the study drug 
administration. 
9.5.1.6 Serious Adverse Events and Other Events of Interest 
An SAE was any untoward medical occurrence that at any dose: 
• Resulted in death 
• Was life-threatening (i.e., the subject was at immediate risk of death from the adverse event 
as it occurred; this did not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death) 
• Required inpatient hospitalization or prolongation of existing hospitalization 
• Resulted in persistent or significant disability or incapacity 
• Was a congenital anomaly or birth defect in the child of a subject who was exposed to the 
study drug 
Other important medical events that may not have been immediately life-threatening or resulted in 
death or hospitalization but, when based on appropriate medical judgment, may have jeopardized 
the subject or may have required intervention to prevent one of the outcomes in the definition of 


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SAE listed above should also have been considered SAEs.  Medical and scientific judgment was 
to be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, other events of interest included 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 
were to be captured using the SAE procedures but were to be considered SAEs only if they met 
one of the above criteria.  All AEs associated with events of interest were to be reported on the 
CRF whether or not they met the criteria for SAEs. 
The following hospitalizations were 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 had 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 
9.5.1.7 Other Safety Assessments 
9.5.1.7.1 Injection Site Evaluation 
For subjects receiving an injection, the investigator, or qualified designee, assessed the injection 
site for localized pain, redness, swelling, and induration. 
This assessment was completed on the same day the injection was administered. 
9.5.1.7.2 Body Weight, Height, Body Mass Index 
An assessment for potential of prolactin-related effects was performed via measurement of body 
weight (kg) and determination of BMI. 
The calculation for BMI was: 
weight (kg) 
[height (m)]2 
 


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9.5.1.7.3 Suicidality 
Columbia Suicide Severity Rating Scale 
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 or “Since Last Visit” 
evaluation that focuses on suicidality since the last study visit.  The baseline C-SSRS form was 
completed at baseline of Phase 1.  The “Since Last Visit” C-SSRS form was completed at all 
subsequent visits. 
Four constructs were measured: 
1. The severity of ideation (i.e., the "severity subscale"), which is rated on a 5-point ordinal 
scale with 1 = wish to be dead, 2 = nonspecific active suicidal thoughts, 3 = suicidal 
thoughts with methods, 4 = suicidal intent, and 5 = suicidal intent with plan. 
2. The intensity of ideation subscale (i.e., the "intensity subscale"), which is comprised of five 
items, each rated on a 5-point ordinal scale:  frequency, duration, controllability, deterrents, 
and reason for ideation. 
3. The behavior subscale, which is rated on a nominal scale that includes actual, aborted, and 
interrupted attempts; preparatory behavior; and non-suicidal 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 zero, potential lethality of attempts is rated on a 
3-point ordinal scale. 
9.5.1.7.4 Pregnancy Test 
Women of childbearing potential and men who are sexually active must have used an effective 
method of birth control during the course of the study 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 or 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 have been used:  vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device, birth control pills, birth control injection, birth control 
implant, condom with spermicide, or sponge with spermicide.  Any single method of birth control, 
including vasectomy and tubal ligation, could fail, leading to pregnancy. 
Before enrolling women of child-bearing potential in this clinical study, investigators reviewed 
guidelines about study participation for women of childbearing potential.  The topics generally 
included: 


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• 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 were advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy.  The subject signed an ICF stating that the above-mentioned risk factors and the 
consequences were discussed with her. 
9.5.1.8 Efficacy Assessments – Clinical Outcome 
9.5.1.8.1 Clinical Global Impression–Improvement 
The efficacy of study medication was rated for each subject using the CGI-I scale.  The rater or 
investigator rated the subject’s total improvement whether or not it was due entirely to drug 
treatment.  All responses were to be compared to the subject’s condition at baseline of the 
appropriate phase.  The CGI-I during Phase B would have been assessed relative to the subject’s 
condition at the Phase B baseline visit.  Response choices included:  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. 
9.5.1.8.2 Clinical Global Impression–Severity 
The severity of illness for each subject was rated using the CGI-S scale.  To assess CGI-S, the rater 
or investigator answered the following question:  “Considering your total clinical experience with 
this particular population, how mentally ill is the patient at this time?”  Response choices included: 
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. 
9.5.1.8.3 Personal and Social Performance Scale 
The PSP is a 100-point scale divided into 10 subcategories that assesses function using four 
domains.  The domains are:  a) socially useful activities including work and study, b) personal and 
social relationships, c) self-care, and d) disturbing and aggressive behaviors.  Each domain is 
graded using a 6-point scale:  absent, mild, manifest, marked, severe, and very severe. 
The clinician selects the 10-point category based on a combination of severity in each of the four 
domains.  Higher scores indicate improved functioning.  The PSP takes approximately 10 minutes 
of the clinician’s time. 


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9.5.1.9 Extrapyramidal Side Effects 
9.5.1.9.1 Abnormal Involuntary Movement Scale 
The AIMS assessment consists of 10 items describing symptoms of dyskinesia.  Facial and oral 
movements (i.e., Items 1 through 4), extremity movements (i.e., Items 5 and 6), and trunk 
movements (i.e., Item 7) were observed unobtrusively while the subject was at rest (e.g., in the 
waiting room), and the investigator also made global judgments on the subject’s dyskinesias 
(i.e., Items 8 through 10).  Each item was rated on a 5-point scale, with a score of zero representing 
an absence of symptoms (i.e., for Item 10, no awareness), and a score of four indicating a severe 
condition (i.e., for Item 10, awareness/severe distress). 
9.5.1.9.2 Barnes Akathisia Rating Scale 
The BARS assessment consists of four 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 three items were rated on a 4-point scale, 
with a score of zero representing absence of symptoms and a score of three representing a severe 
condition.  The global clinical evaluation was made on a 6-point scale, with zero representing 
absence of symptoms and a score of five representing severe akathisia. 
9.5.1.9.3 Simpson Angus Scale 
The SAS assessment consists of a list of 10 symptoms of parkinsonism (i.e., gait, arm dropping, 
shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and 
akathisia).  Each item was rated on a 5-point scale, with a score of one representing absence of 
symptoms, and a score of five representing a severe condition.  The SAS Total Score was the sum 
of the scores for all 10 items. 
9.5.1.10 Pharmacokinetic/Pharmacodynamic Assessments 
Not applicable. 
9.5.2 Schedule of Assessments 
The Schedule of Assessments for the study is provided in Table 3. 


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Table 3: 
Schedule of Assessments 
Visit 
1 
2 
3 
4 
5 
6 
7 
8q 
Study Period 
Screening/ 
Assessment 
Phase A 
(Oral 
Tolerability 
Phasea) 
Phase B (Treatment Phase) 
Day 
Variable 
-3 to -1 
Baseline 
Day 1b,g 
15g 
30 
60 
90 
120 
150 
180 
Week 
 
 
 
2e 
4 
8 
12 
16 
20 
24 
Procedure 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Confirmation of diagnosis of 
schizophrenia (DSM-5) 
X 
 
 
 
 
 
 
 
 
 
Review inclusion/and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
 
 
Complete psychiatric historyc 
X 
 
 
 
 
 
 
 
 
 
Antipsychotic therapy – current use 
and historyd 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy teste 
X 
 
 
 
 
 
 
 
 
X 
Documentation of psychiatric and 
non-psychiatric hospitalizations and 
interventionsf 
X 
 
 
 
 
 
 
 
 
 
Contact from the CSW/SC via 
telephone or in-persong 
 
 
Xg 
Xg 
 
 
 
 
 
 
Clinical interview and mental status 
examinationh 
 
 
 
 
X 
X 
X 
X 
X 
X 
Vital signsi 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight, BMIj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Screening or safety clinical laboratory 
testing as neededk,l,m  
Xm 
 
Xr 
Xr 
Xr 
Xr 
Xr 
Xr 
Xr 
Xr 
Fasting lipid profilen 
X 
 
X 
 
X 
 
X 
 
 
X 
HbA1cl 
X 
 
X 
 
X 
 
X 
 
 
X 
Prolactink 
 
 
X 
 
X 
 
 
 
 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 3: 
Schedule of Assessments 
Visit 
1 
2 
3 
4 
5 
6 
7 
8q 
Study Period 
Screening/ 
Assessment 
Phase A 
(Oral 
Tolerability 
Phasea) 
Phase B (Treatment Phase) 
Day 
Variable 
-3 to -1 
Baseline 
Day 1b,g 
15g 
30 
60 
90 
120 
150 
180 
Week 
 
 
 
2e 
4 
8 
12 
16 
20 
24 
Procedure 
CGI-S 
X 
 
 
 
 
 
 
 
 
 
AIMS, BARS, SAS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
PSP 
 
 
X 
 
 
 
 
 
 
X 
C-SSRSo 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Oral aripiprazole treatmenta,p 
 
X 
X 
 
 
 
 
 
 
 
Administer aripiprazole once monthly 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Injection site assessment 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Reporting of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse events, AIMS = Abnormal Involuntary Movement Scale, ALP = alkaline phosphatase, ALT = alanine transaminase, AST = aspartate transaminase, BARS = Barnes 
Akathisia Rating Scale, BMI = body mass index, BUN = blood urea nitrogen, CBC = complete blood count, CGI-I = Clinical Global Impression–Improvement, CGI-S = Clinical 
Global Impression–Severity, C‑SSRS = Columbia Suicide Severity Rating Scale, CSW = community support worker, DSM-5 = Diagnostic and Statistical Manual, Fifth Edition, 
ECG = electrocardiogram, ED = emergency department,  HbA1c = glycosylated hemoglobin, HDL = high-density lipoprotein, Hgb = hemoglobin, ICF = Informed Consent Form, LDL 
= low-density lipoprotein, MO = Missouri, PSP = Personal and Social Performance Scale, SAS = Simpson Angus Scale, SC = Study Coordinator, ULN = upper limit of normal 
Note:  Baseline was considered Day 1, or first day of long-acting injectable treatment in the hospital, of Phase B.  However, some subjects may have had their baseline assessments 
(including clinical laboratory tests) performed any time during or immediately after treatment with oral antipsychotic aripiprazole (unless eligible to skip Phase A in which it was any 
oral antipsychotic), ideally prior to starting long-acting injectable aripiprazole. Participants were allowed, with Principal Investigator approval, to enter the study after starting treatment 
with long-acting injectable aripiprazole in the hospital and baseline assessments were performed as soon as feasible within 48 hours of hospital discharge. 
a The Oral Tolerability Phase lasted for a minimum of 3 days.  Subjects who had history of tolerability (e.g., taking at least 3 consecutive doses) with oral aripiprazole and no history of 
intolerance could receive their aripiprazole once monthly injection immediately upon completion of the screening procedures.  All subjects received the first injection of aripiprazole 
once monthly at Baseline, Day 1. 
b:  Discharge could occur at any time after the first injection of aripiprazole once monthly. 
c:  The complete psychiatric history included a diagnosis reconciliation form on which information from medical records and a clinical interview by a study clinician were recorded. 
d:  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 
were recorded.  All antipsychotic medications used within 6 months of screening were recorded. 
e:  A urine pregnancy test was performed for women of childbearing potential only at screening, Visit 10, and at the Follow-up visit; subsequent testing was done as is clinically 
indicated.  If a subject or investigator suspected that the subject may be pregnant, a serum pregnancy test would then be performed. 


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Table 3: 
Schedule of Assessments 
Visit 
1 
2 
3 
4 
5 
6 
7 
8q 
Study Period 
Screening/ 
Assessment 
Phase A 
(Oral 
Tolerability 
Phasea) 
Phase B (Treatment Phase) 
Day 
Variable 
-3 to -1 
Baseline 
Day 1b,g 
15g 
30 
60 
90 
120 
150 
180 
Week 
 
 
 
2e 
4 
8 
12 
16 
20 
24 
Procedure 
f:  Data regarding psychiatric and non-psychiatric hospitalizations and medical interventions occurring within the 6 months prior to the date of the signing the ICF were obtained by 
searching MO HealthNet (Medicaid) and MO Department of Mental Health (DMH) data via collaboration with the Missouri Institute of Mental Health (MIMH); availability of 
Medicaid data and documentation of at least one inpatient hospitalization or ED visit within the previous 6 months was required for eligibility. 
g:  For subjects who were psychiatrically stabilized and discharged prior to the completion of the required 14-day course of oral aripiprazole, a pre-discharge assignment was given to a 
CSW or SC.  The CSW/SC maintained regular contact with the subject until the Week 2 visit.  Following the Week 2 visit, subjects had contact with their assigned CSW/SC based on 
routine clinical care. 
h:  At all outpatient visits, scheduled or unscheduled. 
i:  Vital signs were recorded daily while hospitalized. 
j:  BMI was calculated as:  mass (kg)/height (m2). 
k:  Subjects should have been fasting for a minimum of 10 hours prior to blood draws for all laboratory assessments.  Every effort was made to obtain the clinical laboratory samples at 
the same time of day at each visit.  All laboratory testing was performed at local laboratories at the clinical sites. 
l:  Safety clinical laboratory testing was conducted at screening, and as deemed clinically necessary thereafter.  Standard clinical safety laboratory testing included:  hematology (CBC 
with differential, and platelet count), chemistry (ALT, albumin, ALP, AST, total bilirubin, BUN, calcium, chloride, creatinine, glucose, potassium, serum prolactin, total protein, and 
sodium).  Urinalysis was a dipstick with microscopic as clinically indicated. 
m:  Exclusionary tests at screening were: platelets ≤ 75,000 mm3, Hgb ≤ 9 g/dL, fasting glucose > 126 mg/dL, HbA1c > 7.0%, absolute neutrophils ≤ 1,000/mm3, ALT > 3x ULN, 
AST > 3 x ULN, creatinine ≥ 2 mg/dL, diastolic blood pressure > 105 mm Hg, QTc > 475 msec on either the Bazett or Fridericia corrections on ECG, any other abnormal findings that 
would affect the safety of the subject or interpretation of the study results (Section 9.3.2). 
n:  Lipid profile included:  total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. 
o:  At screening the baseline C-SSRS was completed, at subsequent visits, the “since last visit” version was completed. 
p:  All subjects received 14 days of oral aripiprazole beginning with the first dose of aripiprazole once monthly. 
q:  All subjects who completed or withdrew from the study received a telephone call for safety follow-up at 30 (± 5) days after the last study visit unless they withdrew their consent for 
participation in the study to assess for any AEs experienced since the last visit (Section 9.1.4.3). 
r: Clinical laboratory testing only as needed for safety purposes, as determined by the Principal Investigator. 
 
 


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9.5.3 Appropriateness of Measurements 
All clinical assessments were standard measurements commonly used in studies of schizophrenia. 
The safety assessments performed in the study, including hematology analyses, blood chemistry 
tests, urinalysis, and assessment of AEs, were standard evaluations to ensure subject safety. 
9.5.4 Reporting of Serious Adverse Events, Pregnancy, and Other Events of Interest 
Collection of safety information was completed from the first administration of the study drug 
until 28 days after discontinuation, unless otherwise specified in the protocol.  The longer of the 
two timeframes was employed if there was a conflict. 
Safety information was defined as any information from any source containing information such 
as: 
• AE or suspicion thereof 
• Lack of efficacy 
• Overdose/incorrect dosage (i.e., accidental or intentional) 
• Abuse/misuse (e.g., patients sharing medication); even without resulting adverse reaction 
• Accidental exposure (e.g., child takes parent’s medication) 
• Medication error 
• Withdrawal reactions 
• Disease progression/exacerbation of existing disease 
• Drug-drug/drug-food interactions 
• Exposure to drug during pregnancy, 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 
• Exposure to drug during lactation, including uneventful 
• Suspected counterfeit product 
• Suspected transfer of infectious disease/agent by the medicinal product concerned 
• Product Quality Complaint (PQC) with safety related/medically important information  
• Pediatric use, if not an approved use 


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• Occupational exposure 
• Off-label use 
9.5.4.1 Reporting of Serious Adverse Events 
All SAEs, regardless of their relationship to study treatment, were reported to the following 
according to the agreement between the investigator and the sponsor, John W. Newcomer, MD, at 
Florida Atlantic University. 
Report all Immediately Reportable Events (i.e., SAEs, potential Hy’s Law cases, pregnancies 
and AEs requiring discontinuation of study drug) to: 
Contact:  Julie Schweiger (back-up contact Karen Flavin) 
Address:  660 South Euclid Avenue, Campus Box 8134, St. Louis, MO  63110 
For Medical Emergencies:  Tel:  314-362-3153; Fax:  314-747-1160 
 
9.5.5 Completion/Discontinuation of Subjects 
A subject could elect to discontinue the study at any time for any reason without prejudice.  All 
subjects who discontinued the study were to complete the study’s early discontinuation procedures 
indicated in the Schedule of Assessments (Table 3) whenever possible. 
The investigator promptly explained to the subject involved that the study would be discontinued 
for that subject and provided appropriate medical treatment and other necessary measures for the 
subject.  A subject who ceased to return for visits was 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 
was recorded in the CRF. 
Subjects who discontinued early from the study were discontinued for one of these primary 
reasons:  AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, withdrawal of 
consent, pregnancy, study termination, or other (to be specified).  In addition to the primary reason, 
the subject could indicate one or more secondary reasons for discontinuation. 
A subject removed from the study for any reason could not be replaced. 
9.5.6 Confirmation of Medical Care by Another Physician 
The investigator instructed subjects to inform site personnel when they were planning to receive 
medical care by another physician.  At each visit, the investigator asked the subject whether he or 
she had received medical care by another physician since the last visit or was planning to do so in 
the future.  When the subject was going to receive medical care by another physician, the 
investigator, with the consent of the subject, informed the other physician that the subject was 
participating in the clinical study. 


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9.6 
DATA QUALITY ASSURANCE 
9.6.1 Monitoring 
The sponsor had ethical, legal, and scientific obligations to follow the study in a detailed and 
orderly manner in accordance with established research principles, the ICH GCP Guideline, FDA 
regulations and applicable regulatory requirements and local laws.  As part of a concerted effort 
to fulfill these obligations (i.e., maintain current personal knowledge of the progress of the study), 
an independent group of the sponsor's monitors contracted from Washington University School of 
Medicine (WUSM), separate from the clinical site staff at WUSM, could visit the site during the 
study, as well as communicate frequently via telephone and written communications. 
9.6.2 Auditing 
The OAPI Quality Management Unit (or representative) could conduct study site audits.  Audits 
would include, but were not be limited to, drug supply, presence of required documents, the 
informed consent process, and comparison of CRFs with source documents.  The sponsor agreed 
to participate with audits. 
Regulatory authorities could inspect the sites during or after the study.  The sponsor agreed to 
cooperate with such inspections and to contact the sponsor and OAPI immediately if such an 
inspection occurs. 
9.6.3 Data Collection 
The study was expected to start in the spring of 2016 and be completed on or about 
01 December 2018.  Data collection began when the first subject signed the ICF, on 08 June 2016 
and would have been completed on the date at which the last subject’s data has been entered into 
the database and no data queries are outstanding, approximately 01 November 2018. 
9.7 
STATISTICAL METHODS 
The plan analyses are described below. No actual formal statistical analyses were performed. 
9.7.1 Statistical and Analytical Plans 
9.7.1.1 Primary Endpoint(s) 
The primary efficacy endpoint was: 
• Comparison of rates of psychiatric re hospitalization for symptoms associated with 
schizophrenia after receiving aripiprazole once monthly for 30, 90, and 180 days following 
hospital discharge for acute psychiatric stabilization, compared with retrospective 30-, 90-
, and 180-day hospitalization rates, respectively, in subjects previously treated with oral 
antipsychotic medication. 


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9.7.1.2 Secondary Endpoint(s) 
The secondary endpoints were: 
Efficacy: 
• Comparison of: 
o 30-, 90-, and 180-day rates of unscheduled psychiatric ED visits compared with prior 
30-, 90-, and 180-day unscheduled visits 
o Psychiatric ED visits plus hospitalizations compared with prior 30-, 90-, and 180-day 
psychiatric visits plus hospitalizations 
o Total psychiatric hospitalization days over the 30-, 90- and 180-day study period 
compared with the total psychiatric hospitalization days over the prior 30-, 90- and 
180-day period 
o Change from baseline in CGI-I, based on the initial CGI-S, and CGI-I scores at 30-, 
90-, and 180-days 
• Changes from baseline on the following indicators for CMR after receiving aripiprazole 
once monthly: 
o Weight and BMI 
o Fasting glucose concentrations, HbA1c concentrations, and fasting lipids 
concentrations (i.e., fasting triglyceride, total cholesterol, HDL, and LDL) 
9.7.1.3 Exploratory Endpoints 
Safety: 
• AEs 
• Clinical laboratory tests (i.e., hematology, fasting clinical chemistry, prolactin and 
urinalysis) 
• Vital signs 
• PSP 
• Injection site reaction (i.e., localized pain, redness, swelling, and induration) 
• C-SSRS for suicidality 
• EPS assessments, including: 
o AIMS 


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o SAS 
o BARS 
9.7.1.4 Definitions of Analysis Sets 
Enrolled Sample:  All subjects who signed an informed consent form for the study. 
Phase A Safety Sample:  All subjects who took at least one dose of oral aripiprazole in Phase A 
and had at least one post-dose safety assessment. 
Phase B Safety Sample:  All subjects who received at least one dose of aripiprazole once monthly 
in Phase B. 
Phase B Efficacy Sample:  The core dataset for all outcome or efficacy analyses was to be the 
intent-to-treat (ITT) dataset that was to consist of data from all subjects entering Phase B.  
However, as described in Section 9.7.4.1, in order to handle missing data and restrictions imposed 
by different types of analyses (e.g., change from baseline), other datasets derived from the ITT 
dataset could be used for the efficacy analyses. 
9.7.1.5 Subject Disposition 
The method for summarizing the number (i.e., percentage) of subjects who were screened for the 
study (i.e., enrolled subjects, or those who signed informed consent) and reasons for screen failure 
were documented in full using the dedicated Washington University REDCap file for this study, 
with data fields for Enrollment Tracking, Screen Visits, Screen Failures, and Subject Visit 
Tracking.  These REDCap data fields provided a clear accounting of all subjects who entered the 
study, the number of subjects screened for inclusion, and a breakdown of the reasons for excluding 
subjects during screening.  In addition, pre-enrollment general pre-screening failures were tracked. 
Non-identifying or random numbers were used to identify subjects on the Screening Log and 
Screen Failure logs.  Consented Subjects who met inclusion and exclusion criteria were entered 
on the Enrollment log with an assigned study number.  Completion of each study visit for enrolled 
subjects through completion of study was documented on the Subject Visit Tracking Log.  Subjects 
not completing the study with a description of the reason for discontinuation were documented on 
the Subject Visit Tracking Log. 
The Excel format of these forms allowed data to be analyzed by investigators at any time during 
the study and to report progress to the sponsor and regulatory agencies. 
9.7.1.6 Demographic and Other Baseline Characteristics 
Baseline demographic characteristics including age, race, ethnicity, gender, weight, height and 
BMI were to be summarized by descriptive statistics (i.e., frequency, mean, median, standard 
deviation [SD], maximum, minimum, and percentage when applicable). 
Baseline disease severity and psychiatric history was also summarized by descriptive statistics. 


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9.7.1.7 Prior and Concomitant Therapy 
The Phase B Efficacy set was used. 
9.7.1.8 Safety Analyses 
All safety analyses were to be performed on the Safety Analysis Sets.  Safety data were 
summarized on an “as treated” basis using descriptive statistics (e.g., n, mean, standard deviation, 
median, minimum, maximum for continuous variables; and n [%] for categorical variables).  
Safety variables included TEAEs, clinical laboratory parameters, vital signs, and 12-lead ECG 
results.  Study Day 1 for all safety analyses was defined as the date of the first dose of study drug. 
In general, baseline measurements of safety variables were defined as the last measurements prior 
to the first dosing of study drug for each phase of the study.  Safety analyses were conducted based 
on the safety populations (Section 9.7.1.4). 
9.7.1.8.1 Adverse Events 
The AE verbatim descriptions (i.e., investigator terms from the CRF) were to be recorded and 
entered into the database. 
A TEAE was defined as an AE that emerged during treatment, having been absent at pretreatment 
(i.e., baseline) or 
• Reemerged during treatment, having been present at pretreatment (i.e., baseline) but 
stopped before treatment 
• Worsened in severity during treatment relative to the pretreatment state, when the AE was 
continuous. 
Only those AEs that were treatment emergent were to be included in summary tables.  All AEs, 
treatment emergent or otherwise, were presented in subject data listings. 
Treatment-emergent AEs were summarized.  The incidence of TEAEs was reported as the number 
(i.e., percentage) of subjects with TEAEs by system organ class and preferred term (PT).  A subject 
was counted only once within a system organ class and PT, even if the subject experienced more 
than one TEAE within a specific system organ class and PT.  The number (i.e., percentage) of 
subjects with TEAEs was also summarized by maximum severity (i.e., mild, moderate, or severe). 
The number (i.e., percentage) of subjects with TEAEs were also summarized by relationship to 
study drug (i.e., possibly related, probably related, and not related). 
9.7.1.8.2 Laboratory Values 
Laboratory results were to be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.4 Safety Assessments, the actual value and the 
change from baseline to each post-baseline visit and to the end of treatment (i.e., defined as the 
last on-treatment value) was summarized using descriptive statistics.  Qualitative parameters listed 


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in Section 9.5.1.4 were summarized using frequencies (i.e., number and percentage of subjects), 
and changes from baseline to each post-baseline visit and to end of treatment were reported.  
Percentages were based on the number of subjects with both nonmissing baseline and relevant 
post-baseline results. 
Laboratory test results were assigned a low/normal/high (LNH) classification according to whether 
the value was below (L), within (N), or above (H) the laboratory parameter’s reference range. 
9.7.1.8.3 Vital Signs 
Descriptive statistics for vital signs parameters (i.e., diastolic and systolic BP, heart rate, 
respiration rate, temperature, and weight) and changes from baseline were to be presented by visit. 
9.7.1.9 Efficacy Analyses 
The primary objective of the study was to evaluate the effect of aripiprazole once monthly on 30-, 
90-, and 180-day psychiatric re-hospitalization rates following discharge due to symptoms 
associated with schizophrenia, compared with retrospective 30-, 90-, and 180-day psychiatric 
hospitalization rates in subjects previously treated with oral antipsychotic medication. 
Because all primary and secondary outcome measures described in the specific aims were 
continuous and a reflection of a single design configuration involving longitudinal measures, in 
some cases including retrospective as well as prospective time points, the basic structure of the 
data analytic strategies was the same for all objectives. 
The primary and secondary outcomes were to be analyzed using repeated measures analysis of 
covariance (ANCOVA) models.  For example, in the three primary outcome models, testing for a 
main effect of time on 30-, 90-, or 180-day pre-hospitalization (i.e., oral antipsychotic) versus 30-, 
90-, or 180-day post-hospitalization (i.e., aripiprazole once monthly) rates, respectively.  
Covariates would have included psychiatric symptoms severity at baseline, measured by CGI-S 
scores. 
Some secondary outcome measures such as BMI, fasting lipid parameters, and glucose that were 
measured at time points post-hospitalization only (i.e., at baseline, 30-, 90-, and 180-days) were to 
be evaluated using mixed model repeated measures analysis of variance to determine whether there 
are changes over time.  Other covariates could include race, gender, age, family history of diabetes, 
and BMI. 
Only one primary specific objective was defined, with three time-point comparisons (i.e., 30, 90, 
and 180 days) with the primary comparison being hospitalization rate for the period of 30 days 
pre-hospitalization (i.e., at least one, based on the index hospitalization) to 30 days 
post-hospitalization both because of the importance of that objective and to minimize multiple 
comparisons concerns.  Because of the multiple comparisons issue, p-values associated with the 
secondary and exploratory analyses performed were to be interpreted cautiously as 
hypothesis-generating rather than as hypothesis-confirming. 


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9.7.1.10 Other Analyses 
In general, continuous variables were to be summarized by descriptive statistics (i.e., n, mean, 
median, SD, standard error, maximum, and minimum).  The repeated measures ANCOVA was 
used based on the Phase B sample.  The variables relating to hospitalization data were to be 
comparing retrospective versus prospective data.  The number of hospital stays per subject, 
cumulative duration of hospitalization, mean duration of hospitalization, and the number and mean 
duration of all other (i.e., non-inpatient) hospitalization programs were to be compared between 
the SOC and aripiprazole once monthly by ANCOVA and summarized using descriptive statistics.  
The Kaplan-Meier estimate of the median discontinuous time and the overall Kaplan-Meier curve 
for the Phase B efficacy sample were to be provided for the time-to-discontinuation due to all 
causes.  In addition, discontinuation rate due to all reasons, change from baseline in CGI-S and 
CGI-I scores were to be summarized using descriptive statistics for the Phase B efficacy sample. 
9.7.2 Determination of Sample Size 
The primary endpoints of this study were comparisons of the rate of hospitalization for specified 
pre-hospitalization (i.e., pre-aripiprazole once monthly) timeframes (i.e., 30-, 90-, and 180-days) 
to corresponding post-hospitalization timeframes.  Based on published results of other studies, it 
was generally reasonable to assume 30% of subjects would be hospitalized pre-medication switch 
and 15% would be hospitalized post-switch to aripiprazole once monthly.  In this study, 100% of 
the pre-aripiprazole once monthly subjects would have had at least one hospitalization (i.e., index 
inpatient hospitalization at least).  The estimated sample size of 90 completed subjects would have 
provided approximately 80% power (alpha = 0.05 two-sided) to detect a clinically relevant 
difference between pre-switch and post-switch hospitalization rates.  The recent Otsuka Mirror 
study had 121 completers with only a 28% pre-switch hospitalization rate, compared to the present 
design with a 100% pre-switch hospitalization rate, with highly significant reductions in total 
psychiatric hospitalization rates in the Mirror study.  A medium effect size = 0.5 with a sample 
size of N = 90 provided approximately 80% power to detect significance at the 5% level 
(two-tailed test). 
9.7.3 Interim Analysis 
No interim analysis was planned. 
9.7.3.1 Data Safety Monitoring Board 
No Data Safety Monitoring Board was planned for this non-randomized, unblinded study. 
9.7.4 Other Statistical and Analytical Issues 
9.7.4.1 Handling of Missing Data 
In order to assess sensitivity of results due to missing data, two types of analyses were to be 
performed:  last observation carried forward (LOCF) and observed case (OC).  The primary data 
set for efficacy analyses by visit was to be the LOCF data set derived from the Phase B efficacy 
sample.  The LOCF data set would have included data recorded at a scheduled Phase B visit or, if 
no observation was recorded at that visit, data carried forward from the previous scheduled Phase 


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B time point.  Baseline data (i.e., Day 0 in Phase B) were not to be carried forward to impute 
missing values for the LOCF data set.  Analyses based on the OC data set were to be performed.  
The OC data set would have consisted of the actual observations or hospitalization/ED data 
recorded at each relevant time point. 
9.8 
CHANGE TO THE CONDUCT OF THE STUDY OR ANALYSES 
9.8.1 Protocol Amendments 
There were three amendments to the protocol; major changes are described below. 
9.8.1.1 Amendment 1.0, 17 Dec 2015 
• Study population recruitment procedures and locations were clarified. 
• Updated text to reflect the change in the product labeling that allows for deltoid injections and 
the reason for administration of oral aripiprazole was added for consistency.  
• Pre-Screening assessments to help investigators identify any subjects with literacy or capacity 
to consent issues prior to study enrollment were added.  
• The Follow up Period was eliminated from the study duration. 
• Study population recruitment procedures and locations were clarified. 
• The IRB requirement regarding consent by a legal representative in addition to the subject as 
part of the inclusion criteria was eliminated. 
• Corrected text to clarify the accountability documentation to OAPI, including the elimination 
of the need for FDA Form 1572.  
• Removed waiting time requirement after IM injection during injection site evaluation. 
• Study duration was changed, resulting in elimination of Visit 9. 
• Added text regarding the time period for the collection of safety information and the definition 
of safety information. 
• Moved text regarding safety endpoints into a new section as they are considered exploratory 
endpoints. 
 
9.8.1.2 Amendment 2.0, 26 Feb 2016 
• Added text to clarify use of olanzapine and aripiprazole during study duration; text added to 
clarify the type of antipsychotic allowed during Screening Period; added text to describe 
decision procedures for aripiprazole once monthly injection administration; added text 
regarding long-acting antipsychotics as exclusionary medications with the exception of 
aripiprazole once monthly. 
• Added text regarding how data regarding psychiatric and non-psychiatric hospitalizations will 
be confirmed; text regarding timing of hospitalization and types of documentation to determine 
eligibility was added for clarification; added text to clarify that DSM-5 diagnosis of 
schizophrenia must be current. 
• Added text regarding aripiprazole dosage decrease. 
• Updated inclusion and exclusion criteria. 
• Score cap for the UBACC was removed.to allow for greater flexibility for inclusion on the 
study. 


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• Updated text to clarify that the diagnosis of schizophrenia according to DSM-5 criteria had to 
be current; added text describing methods for confirmation of data regarding psychiatric and 
non-psychiatric hospitalizations and medical interventions. 
• The primary efficacy endpoint was reworded for clarity and consistency with other sections 
(administrative change). 
 
9.8.1.3 Amendment 2.1, 24 Aug 2016 
• 
Added text to clarify when screening for eligibility for entry into the study will occur. 
• 
Added text to clarify that olanzapine is no longer considered an exclusionary medication 
during the Screening Period, except for those who are eligible for Phase A. 
• 
Added text to clarify the use of long-acting injectable aripiprazole during Phase B for all 
subjects and eligibility of subjects who were clinically started on long-acting injectable 
aripiprazole during hospitalization just prior to study entry. 
• 
Updated text to clarify timing and use of baseline assessments for determining tolerability to 
oral aripiprazole during Phase A of the study; removed text to clarify timing of Phase B 
baseline/Day 1. 
• 
Added text regarding timing of the collection of baseline data during Phase B for subjects that 
are enrolled after starting long-acting injectable aripiprazole in the hospital. 
• 
Added text stating that the Study Coordinator can receive a pre-discharge assignment, in 
addition to a community support worker, for subjects who are psychiatrically stabilized and 
discharged prior to the completion of the required 14-day course of oral aripiprazole. 
• 
Added text to clarify which clinical laboratory tests require fasting according to when they 
are performed (i.e., Screening Period versus Baseline Visit) 
• 
Added text regarding the eligibility of subjects already clinically started on long-acting 
injectable aripiprazole during the hospitalization just prior to study entry. 
• 
Added text regarding the timing of the Baseline Visit and how baseline assessments are to be 
conducted. 
• 
Updated text regarding how and which baseline assessments will be conducted. 
• 
Updated exclusion criteria. 
 
 


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10 SUBJECT DISPOSITION 
A total of nine subjects were enrolled in the study from two of three active sites. 
Site 
Total 
Enrolled 
Washington University in St. Louis 
(600-100x) 
2 
University of Missouri, Columbia 
N/A 
University of Missouri, Kansas City 
(600400x) 
6 
All Sites 
9 
N/A = not applicable 
Of the nine enrolled subjects, eight received study drug and their demographic characteristics and 
study data are provided in Table 4 through Table 7.  
Of the nine enrolled subjects, one subject completed the trial (600-1001). Eight subjects 
discontinued the study prior to completion, with one of those eight discontinuing prior to receiving 
any study drug. Discontinuations are provided in Table 4: 
Table 4: 
Reasons for Discontinuation 
Reason for Discontinuation 
Subject ID 
Withdrew consent prior to study drug administration 
Subject 604001 
Withdrew consent (reason not specified) 
Subject 600-1002 
Terminated early due to study closure 
Subject 600-1003 
Subject 604003 
Subject 604005 
Subject 604006 
Terminated early by the site investigator in relation to persistent 
psychotic symptoms, psychiatric hospitalization and clinical decision 
to use risperidone 
Subject 604002 
Withdrawn from study due to a TESAE of seizure resulting in 
hospitalization. 
Subject 604004 
ID = identification, TESAE = treatment-emergent serious adverse event 
 


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11 EFFICACY 
This study was terminated due to lack of enrollment. An insufficient number of subjects were 
enrolled to analyze the data for efficacy. Efficacy data collected are provided in Appendix 
2Appendix 1.  


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12 SAFETY  
12.1 BASELINE ASSESSMENTS AND SCREENING 
Baseline and screening data collected are provided in Table 5 and Appendix 2. 
Table 5: 
Baseline and Screening Assessments 
Baseline Data Category 
Result 
N = 8 
Age, mean (SD) 
32.84 (8.69) 
Gender, n (%) 
8 (100.0) 
Male 
3 (37.50) 
Female 
5 (62.50) 
Race, n (%) 
8 (100.0) 
Caucasian 
2 (25.00) 
Black 
6 (75.00) 
Ethnicity, n (%) 
8 (100.0) 
Hispanic 
0 (0.00) 
Not Hispanic 
8 (100.00) 
CGI, Severity of Illness, n (%) 
8 (100.0) 
Moderately Ill 
1 (12.50) 
Markedly Ill 
5 (62.50) 
Severely Ill 
2 (25.00) 
BMI (kg/m2), mean (SD) 
29.08 (7.88) 
Height (cm), mean (SD) 
167.48 (13.40) 
Weight (kg), mean (SD) 
80.02 (16.36) 
Fasting Lipids (mg/dL), mean (SD) 
 
Total Cholesterol 
169.75 (32.38) 
Triglycerides 
97.63 (58.34) 
HDL cholesterol 
66.25 (33.97) 
LDL choloesterol 
84.13 (28.38) 
HbA1c (%), mean (SD) 
5.11 (0.28) 
BMI = body mass index, CGI = Clinical Global Impression, HbA1c = glycosylated hemoglobin, HDL = high-density 
lipoprotein, LDL = low-density lipoprotein, SD = standard deviation 
 
12.2 ADVERSE EVENTS 
Four subjects experienced a total of 10 TEAEs, 4 of which were SAEs.  Subject 604002 
experienced two psychiatric hospitalizations that were not unexpected in this study population; 
one during study participation leading to discontinuation and one during the immediate post-study 
follow-up period.  Of note, Subject 604002 also experienced two psychiatric ED visits during study 
participation, not unexpected for this population and coded in the study as a primary outcome 
rather than as an SAE.  Subject 604004 experienced one TESAE during the study, seizure, leading 
to discontinuation and one AE of generalized weakness during the immediate post-study follow-up 


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period.  The narrative is provided in Section 12.3.2. Adverse event data collected is provided in 
Table 6 and Appendix 2. 
 


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Table 6: 
Adverse Events 
Subject ID 
Adverse Event 
SAE? Intensity 
Action Taken 
Relationship to 
Study Drug 
Onset Date/ 
End Datea 
Outcomea 
604002 
Psychiatric 
hospitalization 
Y 
Moderate 
Aripiprazole stopped, 
subject discontinued 
from study, 
risperidone started 
Not related 
02 Nov 2016/ 
14 Nov 2016 
Resolved 
Psychiatric 
hospitalization 
Y 
Moderate 
None, subject no 
longer in study 
Not related 
28 Nov 2016/ 
02 Dec 2016 
Resolvecd 
604004 
Seizure 
Y 
Severe 
Aripiprazole stopped, 
subject discontinued 
from study 
Not likely 
11 Jan 2017/ 
17 Janu 2017 
Resolved 
Generalized weakness 
Y 
Moderate 
None, no longer in 
study 
Not likely 
29 Jan 2017/ 
3 Feb 2017 
Resolved 
Prolonged QTc 
interval 
N 
Mild 
None, subject 
discontinued from 
study 
Not likely 
13 Jan 2017/ 
15 Jan 2017 
Resolved 
Insomnia 
N 
Moderate 
None 
Not related 
10 Jan 2017/ 
1 Feb 2017 
Resolved 
Cellulitis 
N 
Moderate 
None, no longer in 
study 
Not related 
25 Jan 2017/ 
29 Jan 2017 
Resolved 
604003 
Sialorrhea 
N 
Mild  
None 
Possibly related 
18 Jan 2017/ 
Ongoing 
Lost to Follow-up 
Injection site pain 
N 
Mild  
None 
Definitely related 
30 Jan 2017/ 
31 Jan 2017 
Resolved 
604005 
Akthesia 
N 
Mild 
None 
Possibly related 
13 Mar 2017/ 
Ongoing 
Lost to Follow-up 
ID = identification, QTc = corrected QT interval, SAE = serious adverse event 
a: at the time of last follow-up 
 
 
 


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12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND ADVERSE EVENTS LEADING TO 
DISCONTINUATION FROM THE STUDY 
One subject (604002) experienced a TESAE of psychiatric symptom increase leading to 
psychiatric hospitalization, a primary study endpoint and not an unexpected SAE in this 
population.  Another subject (604004) experienced an unexpected TESAE, seizures, during the 
study, which resulted in discontinuation from the study as described in Section 12.3.2. 
12.3.1 Deaths 
There were no deaths during the study. 
12.3.2 Other Serious Adverse Events 
An unexpected TESAE was experienced by only one subject (604004).  However, this subject 
experienced two SAEs, one during the study leading to that subject’s study discontinuation and 
one during the immediate follow up period.  This subject was a 40-year-old woman diagnosed 
with schizophrenia in 2005.  Her medical history included a historical diagnosis of Dandy-Walker 
syndrome, benign occipital lobe cyst, childhood seizures reported to not extend into adulthood, 
and increased BMI. Concomitant medications were quetiapine, haloperidol and zolpidem for sleep 
during her initial admission prior to study entry. 
The subject was admitted to the behavioral health unit on 05 Jan 2017 with increasing auditory 
hallucinations and insomnia impairing her functioning.  She had trouble with adherence to 
medication and daytime sedation and a clinical decision was made to transition from quetiapine to 
oral aripiprazole, 5 mg, per oral every morning. She was enrolled in the study on 10 Jan 2017 
entering into Phase B of the study at a dose of 10 mg oral aripiprazole, and received her first 
injection of long-acting aripiprazole on that day. 
The subject had reported not sleeping for 7 days and experienced a fall on 11 Jan 2017 while 
walking backwards.  On that day she experienced a generalized tonic clonic seizure, was cyanotic, 
and lost consciousness.  Oxygen and lorazepam were administered and she was transported to the 
ED and subsequently admitted to the medical floor.  The subject was withdrawn from the study 
due to the seizure, which resulted in medical hospitalizations.  On 13 Jan 2017, she experienced 
two seizures approximately 6 hours apart; the second immediately following an 
electroencephalogram (EEG).  The seizures were treated with levetiracetam and lorazepam.  In 
addition, lorazepam was given for anxiety.  The subjects EEG showed multiple sub-clinical 
seizures lasting from 10 to 26 seconds.  The subject was discontinued from the study on 13 Jan 
2017. 
She was discharged on 17 Jan 2017 without oral antipsychotic medication and was prescribed 
levetiracetam, temazepam for insomnia, and hydroxyzine for anxiety.  The seizures were 
considered resolved on 17 Jan 2017. 
During the follow-up period, the subject was taking cephalexin from 25 Jan 2017 for cellulitis.  
She presented to the ED on 29 Jan 2017 with a complaint of generalized weakness which was 
moderate in severity, resulting in hospital admission during the 30-day period following 
discontinuation from the study on 13 Jan 2017.  Laboratory tests were unremarkable.  On 30 Jan 


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Final; 26 Feb 2018 
 
2017, after discharge from the hospital, she received benztropine (indication unknown), 
hydroxyzine for anxiety and temazepam for insomnia.  The subject was restarted on quetiapine on 
01 Feb 2017.  On 03 Feb 2017 the subject had made a full recovery from the generalized weakness 
and was ambulating without assistance.  The benztropine was discontinued on 14 Feb 2017. 
The site investigator assessed the seizures and generalized weakness to be unlikely related to study 
drug. 
12.4 CLINICAL LABORATORY RESULTS 
There were no treatment-emergent clinically significant laboratory results reported during the 
study.  There were a number of subjects with elevated laboratory results at screening.  Reference 
ranges and results for out of range screening laboratory values are provided in Appendix 1.   
Subject 604002 had a creatinine concentration of 0.68 at screening and returned to within normal 
range [0.82] on Day 30 (reference range: 0.76 to 1.27 mg/dL; KC LabCorp [Male]). Subject 
604002 also had a total bilirubin of 0.2 on Day 30 (reference range: 0.3 to 1.2 mg/dL KC Truman 
Medical Center EMR; however, this value is defined as normal in the KC Truman Medicla Center 
Laboratory where the test was completed). 
Subject 600-1003 had a low glucose concentration on Day 30 (67 mg/dL; reference range: 70 to 
110 mg/dL, KC Truman Medical Center Laboratory). This subjects screening glucose was within 
the normal range.  
None of these reported laboratory results were considered clinically significant.  The means and 
standard deviations for the chemistry safety laboratory data are provided in Table 7; the small 
sample sizes preclude analyses or any conclusions regarding trends. 


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Final; 26 Feb 2018 
 
Table 7: 
Blood Chemistry Safety Laboratory Results 
Blood 
Chemistry 
Unit 
Timepoints 
 
Screening 
(n = 8) 
Phase B 
Day 30 
(n = 2) 
Day 120 
(n =3) 
Day 180 
(n = 1) 
Mean (SDa) 
Albumin 
g/dL 
4.19 (0.43) 
4.30 (0.42) 
4.70 (0.26) 
4.50 
Calcium 
mg/dL 
9.01 (0.71) 
9.25 (0.64) 
9.70 (0.20) 
9.50 
BUN 
mg/dL 
10.88 (3.04) 
12.50 (0.71) 
12.33 (1.15) 
13.00 
Total bilirubin 
mg/dL 
0.44 (0.16) 
0.50 (0.42) 
0.43 (0.21) 
0.60 
ALP 
U/L 
68.88 (17.40) 
68.00 (1.41) 
80.33 (18.34) 
68.00 
AST 
U/L 
17.50 (5.24) 
16.50 (2.12) 
16.33 (0.58) 
22.00 
ALT 
U/L 
16.25 (4.17) 
15.50 (0.71) 
18.33 (5.86) 
23.00 
Creatinine 
mg/dL 
0.76 (0.25) 
0.87 (0.07) 
0.99 (0.08) 
0.86 
Sodium 
mmol/L 
139.88 (3.52) 
140.50 (2.12) 
141.00 (1.73) 
141.00 
Potassium 
mmol/L 
4.08 (0.29) 
4.05 (0.35) 
4.27 (0.06) 
4.00 
Chloride 
mmol/L 
102.25 (3.81) 
104.00 (1.41) 
103.00 (1.73) 
104.00 
Carbon dioxide 
mmol/L 
25.38 (3.62) 
25.00 (4.24) 
23.67 (2.52) 
26.00 
Fasting glucose 
mg/dL 
88.63 (10.36) 
90.00 (9.90) 
86.00 (16.46) 
ND 
Total protein 
g/dL 
7.04 (0.82) 
7.30 (0.71) 
7.53 (0.50) 
7.10 
ALP = alkaline phosphatase, ALT = alanine transaminase, AST = aspartate transaminase, BUN = blood urea nitrogen, ND = 
not done, SD = standard deviation 
a:  Standard deviations were not calculated for Day 180, these data were for an n of 1 
 
12.5 CLINICAL SAFETY VARIABLES 
Clinical safety variables are provided in Table 8. 
 


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Table 8: Clinical Safety Variables 
Clinical Variable 
Timepoints 
Screening 
Phase A 
Phase B 
Day 1 
Day 15 
Day 30 
Day 60 
Day 90 
Day 120 
Day 150 
Day 180 
LOCF 
Mean (SD) 
Total # of psychiatric ER 
visits per subject 
N/A 
N/A 
N/A 
N/A 
N/A 
3d 
N/A 
N/A 
N/A 
N/A 
3d 
Total # of psychiatric 
hospitalizations per subject 
N/A 
N/A 
N/A 
N/A 
N/A 
1d A 
N/A 
N/A 
N/A 
N/A 
1d 
BMI (kg/m2) 
29.08 
(7.88) 
N/A 
30.134 
(8.52) 
27.46 
(8.47) 
27.92 
(8.58) 
28.57 
(9.11) 
28.94 
(9.72) 
29.25 
(9.75) 
33.71 
(ND) 
34.37 
(ND) 
29.18 
(8.14) 
Height (cm) 
167.48 
(13.40) 
N/A 
168.06 
(11.19) 
167.03 
(15.77) 
166.76 
(16.15) 
166.96 
(16.01) 
171.82 
(13.82) 
171.82 
(13.82) 
161.29 
(N/A) 
161.20 
(N/A) 
168.36 
(14.11) 
Weight (kg) 
80.02 
(16.36) 
N/A 
83.07 
(14.84) 
74.89 
(16.76) 
75.93 
(17.11) 
77.73 
(18.45) 
82.50 
(15.36) 
83.43 
(15.40) 
87.70 
(N/A) 
89.30 
(N/A) 
81.00 
(16.50) 
HBA1c (%) 
5.11 (0.28) 
N/A 
N/A 
N/A 
5.03 
(0.50) 
5.00 (N/A) 
5.13 
(0.46) 
5.27 
(0.51) 
N/A 
5.10 
(N/A) 
5.18 
(0.38) 
Total cholesterol (mg/dL) 
169.75 
(32.38) 
N/A 
N/A 
N/A 
186.00 
(47.27) 
N/A 
186.75 
(15.97) 
175.67 
(26.76) 
N/A 
214 
(N/A) 
177.80 
(30.19) 
Triglycerides (mg/dL) 
97.63 
(58.34) 
N/A 
N/A 
N/A 
68.50 
(24.09) 
N/A 
84.75 
(22.57) 
75.33 
(14.84) 
N/A 
89 (N/A) 
70.80 
(21.48) 
HDL cholesterol (mg/dL) 
66.25 
(33.97) 
N/A 
N/A 
N/A 
63.00 
(23.31) 
N/A 
58.75 
(12.84) 
55.00 
(10.82) 
N/A 
90 (N/A) 
64.40 
(17.04) 
LDL cholesterol (mg/dL) 
84.13 
(28.38) 
N/A 
N/A 
N/A 
109.50 
(29.37) 
N/A 
111.00 
(4.97) 
105.33 
(15.04) 
N/A 
106 
(N/A) 
99.00 
(18.01) 
Prolactin (ng/mL) 
24.15 
(12.82) 
N/A 
21.29 
(30.80) 
N/A 
7.50 
(3.63) 
5.80 (N/A) 
6.30 
(5.15) 
6.63 
(5.65) 
N/A 
2.70 
(ND) 
15.93 
(25.40) 
CGIa Severity of illness 
5.13 (0.64) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
CGIb Improvement 
N/A 
N/A 
3.40 
(0.55) 
3.20 
(0.84) 
2.80 
(1.30) 
3.20 (1.64) 
2.75 
(0.96) 
2.75 
(0.96) 
2.00 
(ND) 
2.00 
(N/A 
3.43 
(1.40) 
AIMS Severity of 
Abnormal Movementsc 
0.13 (0.35) 
0.25 
(0.50) 
0.00 
(0.00) 
0.20 
(0.45) 
0.20 
(0.45) 
0.20 (0.45) 
0.25 
(0.50) 
0.25 
(0.50) 
0.00  
0.00 
0.14 
(0.38) 
BARS Total score 
0.88 (2.47) 
0.00 
(0.00) 
0.60 
(1.34) 
0.40 
(0.55) 
0.00 
(0.00) 
1.00 (2.24) 
0.50 
(1.00) 
0.50 
(1.00) 
0.00 
0.00 
0.29 
(0.76) 
SARS Total score 
2.13 (3.09) 
1.50 
(3.00) 
1.40 
(2.61) 
1.20 
(1.30) 
2.00 
(2.92) 
1.60 (1.95) 
1.75 
(2.2) 
2.50 
(2.89) 
0.00 
0,00 
2.83 
(2.79) 


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AIMS = abnormal involuntary movement scale, BARS = Barnes Akathisia Rating Scale, BMI = body mass index, CGI = Clinical Global Impression, ER = emergency room, 
HbA1c = glycosylated hemoglobin, HDL = high-density lipoprotein, LDL = low-density lipoprotein, N/A = not applicable, SARS = Simpson-Angus Rating Scale, SD = standard 
deviation 
Note: Standard deviations not provided for Day 150 and Day 180 data due to n = 1 subject 
a:  Scale = normal, not all ill (1), borderline mentally ill (2), mildly ill (3), moderately ill (4), markedly ill (5), severely ill (6), among the most extremely ill patients (7) 
b:  Scale = very much improved (1), much improved (2), minimally improved (3), no change (4), minimally worse (5), much worse (6), very much worse (7) 
c: Scale = none (0), minimal, maybe extreme normal (1), mild (2), moderate (3). Severe (4) 
d:  Only 1 subject had ER visits (n = 3) and psychiatric hospitalizations (n = 1) 
 
 
 
 
 
 
 


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


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• Pain, quality of life, or medical history questionnaires completed by subjects 
• Records of telephone contacts 
• Diaries or evaluation checklists 
• Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• Laboratory results and other laboratory test outputs (e.g., urine pregnancy test result 
documentation and urine dip-sticks) 
• Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs 
• CRF components (e.g., questionnaires) that are completed directly by subjects and serve 
as their own source 
13.4 RECORDING OF DATA 
CRFs linked to REDCap were required and completed for each subject by qualified and authorized 
personnel.  All data on the CRF reflected the corresponding source document, except when a 
section of the CRF itself was used as the source document.  Any corrections to entries made on 
the CRF were documented in a valid audit trail where the correction was dated, the individual 
making the correction was identified, the reason for the change was stated, and the original data 
were not obscured.  Only data required by the protocol for the purposes of the study were collected. 
The investigator signed each CRF. 
13.5 IDENTIFICATION OF SOURCE DATA 
All data to be recorded on the CRF reflected the corresponding source documents. 
13.6 RETENTION OF RECORDS 
The circumstances of completion or termination of the study notwithstanding, the investigator was 
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 retains study documents for the length of 
time agreed upon in the study contract. 
It was requested that at the completion of the required retention period, or should the investigator 
retire or relocate, the sponsor contact OAPI, allowing OAPI the option of permanently retaining 
the study records. 


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


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13.7.2 Eliciting and Reporting Quality Complaints 
The sponsor or designee was required to record all PQCs identified through any means from the 
receipt of study drug through and including reconciliation and up to destruction, including subject 
dosing.  Identification of a PQC by a subject would be reported to the site investigator, who would 
report the PQC. 
The sponsor or designee was required to notify OAPI within 24 hours of becoming aware of the 
PQC by e-mail or telephone: 
• Online:  send the required information to OAPI-EQCProductComplaints@otsuka-us.com 
• Telephone:  Rocky Mountain Call Center at 1-800-438-6055 
13.7.3 Return Process 
During the PQC reporting process, it would be indicated if the sample under complaint was 
available for return.  If the sample was available for return, OAPI-EQC would provide a product 
retrieval package to return the sample in the product retrieval package. 
Documentation in the site source documents that a complaint sample for a dispensed product 
would have been forwarded to OAPI-EQC for complaint investigation. 
Assessment and evaluation of PQCs would be handled by the OAPI-EQC Quality Management 
Group. 
13.8 DISCONTINUATION OF STUDY 
OAPI reserved the right to discontinue the study for medical reasons or any other reason at any 
time.  If a study was prematurely terminated or suspended, OAPI promptly informed the sponsors 
or institutions and the sponsor and investigators informed the regulatory authorities of the 
termination or suspension and the reason(s) for the termination or suspension.  The IRB would 
also be informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor, investigators, or institution, as specified by the applicable regulatory requirement(s). 
The sponsor reserved the right to discontinue the study should his/her judgment so dictate.  If the 
sponsor terminated or suspended a study without prior agreement of OAPI, the sponsor would 
inform the institution where applicable, and the sponsor or institution would promptly inform all 
investigators, OAPI, and the relevant IRB and provide OAPI and the IRB with a detailed written 
explanation of the termination or suspension.  Study records were retained as noted above. 


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14 REFERENCE LIST 
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5. Coldham EL, Addington J, Addington D. Medication adherence of individuals with a 
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adherence in psychosis: predictors and impact on outcome. A 2-year follow-up of first-
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http://www.cms.gov/Medicare/Medicare-Fee-for-Service-
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25. 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. 
26. Marcus R.  A Prospective, Multicenter, Open-Label Study of Aripiprazole in the 
Management of Patients with Schizophrenia in General Psychiatric Practices (Broad 
Effectiveness Trial with Aripiprazole - BETA).  Bristol-Myers Squibb Company Study 
No. CN138100, 2005 
27. 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. 
28. Kerwin R, Millet B, Herman E, Banki CM, Lublin H, Pans M, et al.  A multicentre, 
randomized, naturalistic, open-label study between aripiprazole and standard of care in 
the management of community-treated schizophrenic patients Schizophrenia Trial of 
Aripiprazole:  (STAR) study. . Eur Psychiatry, 2007. 22(433-43). 
29. Tandon R, Devellis RF, Han J, Li H, Frangou S, Dursun S for the IAQ Validation Study 
Group.  Validation of the Investigator's Assessment Questionnaire, a new clinical tool for 
relative assessment of response to antipsychotics in patients with schizophrenia and 
schizoaffective disorder.  Psychiatry Research, 2005.  136(211-21). 
30. 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. 
31. 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 
32. Vieta E, Bourin M, Sanchez R, Marcus R, Stock E, McQuade R.  Effectiveness of 
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Final; 26 Feb 2018 
 
15 APPENDICES 
 
 


Collaborative Protocol 031-104-0014 
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Final; 26 Feb 2018 
 
Appendix 1 
Reference Ranges 
 
Blood 
Chemistry 
Unit 
KC LabCorp 
KC Truman 
Medical Center 
Washington 
University CLCS 
Albumin 
g/dL 
3.5 – 5.5 
3.4 – 5.0 
3.5 – 5.2 
Calcium 
mg/dL 
8.7 – 10.2 
8.5 – 10.1 
8.6 – 10.3 
BUN 
mg/dL 
6 - 20 
7 - 20 
7 - 23 
Total bilirubin 
mg/dL 
0.0 – 1.2 
0.0 – 1.0 
0.2 – 1.4 
ALP 
U/L 
39 - 117 
50 - 136 
35 - 129 
AST 
U/L 
0 - 40 
15 - 37 
11 - 47 
ALT 
U/L 
0 - 32 
30 - 65 
6 - 53 
Creatinine 
mg/dL 
0.76 – 1.27 (Male) 
0.57 – 1.00 (Female) 
0.6 – 1.3 
0.7 - 1.3 (Male) 
0.6 – 1.1 (Female) 
Sodium 
mmol/L 
134 - 144 
136 - 145 
135 – 145 
Potassium 
mmol/L 
3.5 – 5.2 
3.6 – 5.2 
3.3 – 5.1 
Chloride 
mmol/L 
97 - 106 
98 - 107 
95 - 107 
Carbon dioxide 
mmol/L 
18 - 29 
21 - 32 
21 - 29 
Fasting glucose 
mg/dL 
65 - 99 
70 - 110 
64 - 99 
Total protein 
g/dL 
6.0 – 8.5 
6.4 – 8.2 
6.1 – 8.4 
 
 
 
 


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Final; 26 Feb 2018 
 
Appendix 2: Subject Data 
 
 
 
 
 
 
 


Collaborative Protocol 031-104-0014 
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Final; 26 Feb 2018 
 
Appendix 3: Signature Page 
SIGNATURE PAGE 
Study Protocol Number: 
031-104-0014 
Study Protocol Title: 
An 
Open-label, 
Multi-center, 
Longitudinal, 
Within-subject 
Comparison Study to Evaluate the Effects of Aripiprazole Once 
Monthly in Subjects with Schizophrenia on 30-, 90-, and 180-day 
Re-hospitalization Rates Following Hospital Discharge Compared 
with Retrospective Re-hospitalization Rates while on Oral 
Antipsychotic Medication 
Drug Under Study: 
Abilify Maintena®, aripiprazole 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
 
John W. Newcomer, MD 
  
  
Investigator 
 Signature 
 Date