Conditions: Schizophrenia Schizoaffective Disorder, Depressive Type Schizophreniform Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
This 12-month study will evaluate the efficacy of aripiprazole lauroxil compared to oral aripiprazole in preventing the re-emergence of psychotic symptoms in patients with a recent onset of schizophrenia.

Detailed description:
This is a single-site 12-month open-label randomized study comparing the efficacy of the FDA-approved long-acting formulation of aripiprazole lauroxil to the efficacy of oral aripiprazole among patients with a recent onset of schizophrenia, schizophreniform, or schizoaffective (depressed) disorder. All assessments and treatment will take place at the UCLA Aftercare Research Program (300 UCLA Medical Plaza, Los Angeles, CA 90095), which is a program that specializes in the treatment and study of individuals with a recent onset of schizophrenia. The primary goal is to evaluate the efficacy of aripiprazole lauroxil compared to oral aripiprazole in preventing the re-emergence of psychotic symptoms in patients with a recent onset of schizophrenia. All patients on oral medications will, at least initially, be treated with oral aripiprazole.

Arms:
arm 1: Patients successfully completing the Stabilization period will be randomized to one of the two medications groups: For patients assigned to the AL-LAI (aripiprazole lauroxil- long-acting injections), initiation of AL-LAI will begin with a one-day initiation regimen (using AL-NCD IM (aripiprazole lauroxil NanoCrystal Dispersion)). Subsequent dosing of AL-LAI will be flexible based on clinician judgment. Treatment with AL-LAI can be initiated at a dose of 441mg or 661mg (administered monthly), 882mg (administered monthly or every 6 weeks), or 1064mg (administered every 2 months). Note: These dosages are not assigned levels of the intervention and dosage levels may be changed at any time throughout the 12-month intervention based on clinical need and clinician judgement. Starting dosages do not indicate separate treatment conditions. arm 2: Patients successfully completing the Stabilization period will be randomized to one of the two medications groups: Patients assigned to the oral medication condition will continue with ARI-ORAL. ARI-ORAL dosage will be flexible and dosage will be at the discretion of the treating psychiatrist. Patients discontinuing ARI-ORAL study drug after Randomization to oral antipsychotic medication, can remain in active treatment and follow-up within the study, and may be prescribed any of a number of first-line oral antipsychotics.

Interventions: intervention 1: Aripiprazole Lauroxil intervention 2: ARI-ORAL intervention 3: AL-NCD
Intervention descriptions: intervention 1: 12 month longitudinal aripiprazole lauroxil treatment and assessment follow-through intervention 2: oral aripiprazole intervention 3: Aripiprazole Lauroxil 675 MG/2.4 ML Intramuscular Suspension, Extended Release

Protocol document:
Prot_SAP_001.pdf: 
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1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
 
Aripiprazole lauroxil for Preventing Psychotic Relapse After an Initial 
Schizophrenia Episode (APPRAISE) 
Document Status: 
Final 
Document Date: 
07 Feb 2019 
 
 
 
 
 
 
 
 
 
 
 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Telephone Number 
To contact the treating psychiatrists during 
regular business hours, call the main line for the 
Aftercare Research Program. Case managers may 
also be contacted through this main number. 
Laurie Casaus, M.D. or  
Margaret Distler, M.D. 
+1 (310) 206-3142 
To contact the treating psychiatrists outside of 
business hours, call the 24-Hour Emergency Live 
Answering Service/ Page Operator.  One of the 
two treating psychiatrists is always on call.  Call 
schedule rotates and is provided to the answering 
service.  Case managers also have a rotating after 
hours call and may be contacted through this 
same answering service. 
Laurie Casaus, M.D. or  
Margaret Distler, M.D. 
+1 (310) 825-6301 


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2. 
SYNOPSIS 
Sponsor:  University of California, Los Angeles (UCLA) 
Investigational Products:   
• 
aripiprazole lauroxil long-acting injectable (AL-LAI; ARISTADA®)  
• 
aripiprazole lauroxil NanoCrystal® Dispersion (AL-NCD; ARISTADA INITIO®) 
Active Ingredient: aripiprazole lauroxil 
Study Title: Aripiprazole lauroxil for Preventing Psychotic Relapse After an Initial Schizophrenia 
Episode (APPRAISE) 
Study Center: UCLA 
Investigator: Kenneth Subotnik, Ph.D. 
Study Period (years):  
Estimated date first patient’s consent: TBD 
Estimated date last patient’s visit: TBD + 48 months 
Phase of development: Phase 4 
 
Objectives:  
Primary:  
The primary objective is to assess whether schizophrenia patients who recently experienced their first 
psychotic episode that are randomized to AL-LAI are less likely to experience a  re-emergence of 
positive psychotic symptoms compared to those randomized to oral aripiprazole (ARI-ORAL).  
Secondary: 
The secondary objectives are to: 
1. Examine differences in functional outcome between the two treatment groups. We anticipate 
that role functioning will improve more in the group randomized to AL-LAI than those 
assigned to the ARI-ORAL group.  
2. Evaluate and compare the cognitive changes of the AL-LAI vs. ARI-ORAL group over the 
12-month Treatment period. It is hypothesized that patients assigned to AL-LAI will 
demonstrate relatively better performance on a standardized measure of cognition than those 
assigned to ARI-ORAL.  
Exploratory: 
Additional exploratory objectives are to determine whether the two medication groups differ in other 
symptoms domains, adherence, and tolerability (eg, negative symptoms, suicidality, self-reported 
awareness of having a mental disorder, service engagement, sexual/prolactin-related side effects, 
treatment engagement, and quality of life). 
Study Design/Methods:  
This is a single-site study with all assessments and treatment to take place at the UCLA Aftercare 
Research Program (300 UCLA Medical Plaza, Los Angeles, CA 90095), which is a program that 
specializes in the treatment and study of individuals with a recent onset of schizophrenia. Patients 
entering the program will have extensive diagnostic and treatment evaluations, and eligible patients 
meeting diagnostic criteria will be invited to participate in a 12-month open-label randomized study 
comparing AL-LAI with ARI-ORAL. The flow for each patient after initial enrollment and evaluation 
will involve a Stabilization period of up to 90 days with at least the final 2 weeks on oral aripiprazole 


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as the sole antipsychotic medication, after which the patients will be randomly assigned to treatment 
with either ARI-ORAL or AL-LAI for a 12-month Treatment period.  
Overview of the Randomized Treatment Groups:  
Patients successfully completing the Stabilization period will be randomized to one of two 
medications groups: converting from oral antipsychotic to AL-LAI vs continuing on (ARI-ORAL). 
Randomization will be automated by UCLA. Patients successfully completing the Stabilization period 
will be randomized to one of two medications groups: converting from oral antipsychotic to AL-LAI 
vs continuing on (ARI ORAL). Each treatment group will be further randomized to computerized 
cognitive training with or without aerobic exercise. 
Randomization to AL-LAI: Initiation of AL-LAI will begin with a one-day initiation regimen (one 
intramuscular injection of 675 mg AL-NCD and one single-dose of 30 mg oral aripiprazole). 
Subsequent dosing of AL-LAI will be flexible based on clinician judgment. The first AL-LAI 
injection may be administered on the same day as the one-day initiation regimen or up to 10 days 
thereafter. Treatment with AL-LAI can be initiated at a dose of 441 mg, 662 mg or 882 mg; 441 mg 
administered monthly, 882 mg administered every 6 weeks or 1064 mg administered every two 
months. 
Randomization to ARI-ORAL: Patients will continue with ARI-ORAL doses within the recommended 
oral dosage range for the treatment of schizophrenia (10-30mg/day) with the usual starting dosage of 
10 mg/day. ARI-ORAL dosage will be flexible and dosage will be at the discretion of the treating 
psychiatrist. Patients assigned to this treatment arm will receive a written prescription for a 30-day 
supply along with a medication coupon so there will be no medication cost to the patient.  
Discontinuation of Assigned Treatment 
Both groups will remain on their assigned treatment for 12 months or discontinue their assigned 
medication early. The reason(s) for early discontinuation of initial antipsychotic will be recorded, 
including whether it is initiated by the clinician or patient, and whether it is efficacy or tolerability 
related. Patients will be assessed for the reason for discontinuation using a version of the All-Cause 
Discontinuation (ACD) measure that was the primary outcome of the CATIE schizophrenia study. If a 
switch to another antipsychotic medication is warranted, the new therapy will be determined by the 
prescribing psychiatrist’s judgment using the medication selection recommendation adapted from 
NAVIGATE pharmacologic treatment manual developed as part of the Recovery After an Initial 
Schizophrenia Episode (RAISE) study intervention groups. Patients discontinuing study drug after 
Randomization, but remaining in active treatment and follow-up, may be prescribed any first-line oral 
antipsychotic within the prescribing information dosage for schizophrenia. Patients will be 
encouraged to stay in the study for the remainder of the 12-month Treatment period and will be 
administered all of the scheduled assessments even if the initial randomly assigned antipsychotic 
medication is discontinued by the treating psychiatrist.  
Symptom assessments will occur every two weeks, functional endpoint will occur every three months, 
and the cognitive endpoint will occur at baseline and at the 6- and 12-month points. All patients 
participating in the protocol will be invited to concurrently participate in a separate NIMH-funded 
psychosocial intervention protocol comparing the effectiveness of computerized cognitive training 
with and without aerobic exercise training. 
Number of Patients Planned: Approximately 128 patients enrolled into the Stabilization period for 
final randomized sample of 90 (45 in each group) with a target of 14 relapses 


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Main Criteria for Inclusion:  
Men and women aged 18 to 45 years, inclusive, with current diagnosis of schizophreniform disorder, 
schizophrenia, or schizoaffective depressed subtype disorder as defined by DSM-5 with the first 
psychotic episode having occurred within the last 24 months prior to Screening.  
Reference Therapy, Dosage, Duration, and Mode of Administration:  
ARI-ORAL treatment will be initiated for all patients during the Stabilization period per the label 
recommended range for the treatment of schizophrenia ARI-ORAL will continue to be prescribed for 
patients randomly assigned to the ARI-ORAL group during the Treatment period.  
AL-LAI treatment will be initiated with the one-day initiation regimen (675 mg AL-NCD and 30 mg 
oral aripiprazole), but may alternatively be initiated with 21 consecutive days of supplementation with 
ARI-ORAL if clinically appropriate or preferable. The first AL-LAI injection may be administered on 
the same day as AL-NCD or up to 10 days thereafter as per clinical judgment. AL-LAI will be 
flexibly dosed for 12 months per label and can be initiated at a dose of 441 mg, 662 mg or 882 mg 
administered monthly, 882 mg administered every 6 weeks or 1064 mg administered every two 
months.  
Duration of Study: ~15 months (3 months Stabilization period and 12 month Treatment period)  
Criteria for Efficacy Evaluation:  
Primary Endpoint 
The primary endpoint will be time to first positive symptom exacerbation and/or relapse following a 
period of absence or relatively low levels of psychotic symptoms based on the expanded 24-item 
version Brief Psychiatric Rating Scale.  
Secondary Endpoints 
Functional assessment: The Role ratings on the Global Functioning Scale (GFS: Role) will serve as 
the measure of functional outcome. The GFS: ROLE will be administered every three months 
throughout the 12-month Treatment period.  
Cognitive assessment: The Overall Composite T-score from the MATRICS Consensus Cognitive 
Battery (MCCB) will be the overall index of cognitive performance. The MCCB will be administered 
every six months throughout the 12-month Treatment period. 
Exploratory Endpoints 
Endpoints include Quality of Life, negative symptoms, self-reported awareness of having a mental 
disorder, service engagement, prolactin-related side effects, treatment satisfaction, and 
family/caregiver medication administration burden.  
Safety Assessments 
Extrapyramidal symptoms will be assessed on three scales (Abnormal Involuntary Movement Scale, 
Barnes Akathisia Rating Scale, and the Extrapyramidal Symptom Rating Scale). Adverse events 
(including serious and AEs of special interest), and suicidality will be monitored. 
Statistical methods: 
Sample Size Considerations: 
Ninety first-episode patients will be randomized (1:1) fashion to either AL-LAI or ARI-ORAL, and 
based on our previous RCT, assume a 20% attrition rate over 12 months. 45 randomized patients (36 
completers) in each group provides at least 80% power. Statistical power considerations are based on 
the effect sizes observed when comparing long-acting injectable risperidone vs oral risperidone 
(survival analysis for psychotic relapse: 5% relapse in the risperidone long-acting injectable group and 
33% relapse in the oral risperidone group). On the basis of hazard function rates of 5.0% (AL-LAI) 


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and 33% (ARI-ORAL), the study has 87% power (α=0.05). On a more conservative basis of hazard 
function rates of 7.5% (AL-LAI) and 33% (ARI-ORAL), the study has 78% power (α=0.05). 
For the secondary hypothesis for the relative changes in the MCCB Composite score and the GFS: 
Role, we will use a two-sided significance level of α=0.025 to account for type 1 error inflation. For 
the MCCB Composite score, assuming a within-patient correlation between repeated measurements of 
r=0.89 (based on a prior study), the proposed design provides us sufficient power (>=0.80) for Group 
X Time interaction effects as small as Cohen’s f=0.09. Based on our previous work, we anticipate a 
medium effect size (Cohen’s f=0.25 or d=0.50), and this design provides a power of >0.99 for an 
effect of this size. For the GFS rating, if we assume a within-patient correlation of r=0.5, with 
α=0.025, our GLMM will have 80% power to detect an interaction corresponding to an effect size of 
f=0.20. Based on a prior study, we anticipate an effect size of f=0.32 or d=0.63 for the GFS: Role 
ratings, for which we would have >99% power.  
Thus, for both primary and secondary outcome measures we will be able to detect differential 
treatment effects based on our proposed design and expected sample size. 
Analysis of Efficacy:  
The primary hypothesis is that the hazard function (i.e. the risk of an event per unit of time) of the two 
medication groups differs between AL-LAI and the ARI-ORAL group. The hypothesis will be 
examined in a Cox regression model on the time to first relapse. We will include medication group 
membership, participation status in the NIMH exercise study, and length of stabilization period as 
predictors in the model. 
The secondary hypotheses of the MCCB composite score and the GFS (Role) rating will be examined 
in general linear mixed models (GLMMs). We will include participation status in the NIMH exercise 
study, medication group as a between-patient variable and time as a within-patient variable in the 
model, and time*group as a within-between interaction term. Additionally, we will include length of 
stabilization period as a person level time invariant covariate. The primary effect of interest is the 
difference in the pattern of change over time of the dependent variable between the medication groups 
(i.e. the time*group interaction term). GLMMs properly account for correlations induced by repeated 
measurements within patients and automatically handle missing data, producing unbiased estimates as 
long as observations are missing at random. The GLMM will use Satterthwaite’s approximation to 
estimate degrees of freedom for the tests of the fixed and random effects, and model the variance-
covariance matrix as a Toeplitz matrix. If this assumption does not lead to convergence we will 
instead use compound symmetry. The secondary analyses will compare the change in the MCCB 
Composite score and GFS (Role) ratings between the two medication groups over the 12-month study 
period.  
The data analytic methods for the exploratory measures will in general parallel those of the secondary 
measures.  
 


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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS .............................................................................................7 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................10 
LIST OF ABBREVIATIONS ........................................................................................................11 
4. 
INTRODUCTION ......................................................................................................13 
5. 
STUDY OBJECTIVES ..............................................................................................14 
5.1. 
Primary Objective .......................................................................................................14 
5.2. 
Secondary Objectives .................................................................................................14 
5.3. 
Exploratory Objectives ...............................................................................................14 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................15 
6.1. 
Inclusion Criteria ........................................................................................................15 
6.2. 
Exclusion Criteria .......................................................................................................15 
6.3. 
Discontinuation of Assigned Medication ...................................................................16 
6.4. 
Over-enrollment of Patients ........................................................................................17 
7. 
STUDY DESIGN .......................................................................................................18 
7.1. 
Overall Study Design ..................................................................................................18 
7.2. 
Treatment Initiation ....................................................................................................19 
7.2.1. 
Initiation of ARI-ORAL Treatment Arm after Randomization ..................................19 
7.2.2. 
Initiation of AL-LAI Treatment Arm after Randomization .......................................19 
7.3. 
Continuation of Treatment ..........................................................................................20 
7.4. 
Study Procedures ........................................................................................................20 
7.4.1. 
Visit and Assessment Schedule ..................................................................................20 
7.4.2. 
Informed Consent .......................................................................................................24 
7.4.3. 
Eligibility Review .......................................................................................................24 
7.4.4. 
Demographics and Medical History ...........................................................................24 
7.4.5. 
Prior and Concomitant Medication Review ...............................................................24 
7.4.5.1. 
Substance Use .............................................................................................................24 


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7.4.6. 
Primary Endpoint Measurements ...............................................................................25 
7.4.6.1. 
APPRAISE Study Criteria for Reemergence of Positive Symptoms .........................25 
7.4.7. 
Secondary Endpoint Measurements ...........................................................................26 
7.4.7.1. 
Functional Assessment -The Role ratings on the Global Functioning Scale ..............27 
7.4.7.2. 
Cognitive Assessment- The MATRICS Consensus Cognitive Battery ......................27 
7.4.8. 
Exploratory Endpoint Measurements .........................................................................27 
7.4.8.1. 
Heinrichs-Carpenter Quality of Life Scale .................................................................27 
7.4.8.2. 
Personal and Social Performance Scale ......................................................................28 
7.4.8.3. 
Clinical Global Impressions-Severity .........................................................................28 
7.4.8.4. 
Scale for the Assessment of Negative Symptoms ......................................................28 
7.4.8.5. 
Scale to Assess Unawareness of Mental Disorder-Revised .......................................28 
7.4.8.6. 
Glasgow Antipsychotic Side-effect Scale ..................................................................28 
7.4.8.7. 
Modified Medication Satisfaction Questionnaire .......................................................28 
7.4.8.8. 
Service Engagement Scale (SES) ...............................................................................29 
7.4.8.9. 
The Family Caregiver Medication Administration Hassles Scale ..............................29 
7.4.8.10. 
Modified Version of the All-Cause Discontinuation ..................................................29 
7.4.9. 
Safety Assessments .....................................................................................................29 
7.4.9.1. 
Overview of Safety Assessment Procedures ..............................................................29 
7.4.9.2. 
Extrapyramidal Symptoms .........................................................................................30 
7.4.9.3. 
Columbia Suicide Severity Rating Scale ....................................................................30 
7.4.9.4. 
Laboratory Assessments .............................................................................................30 
7.4.10. 
Vital Signs ..................................................................................................................31 
7.4.11. 
Physical Examination, Body Height, Weight .............................................................31 
7.4.12. 
Adverse Event Monitoring .........................................................................................32 
7.4.13. 
Randomization ............................................................................................................32 
7.5. 
Study Requirements and Restrictions .........................................................................32 
7.5.1. 
Prohibited Medications and Restricted Concomitant Medications ............................32 
7.5.2. 
Contraception and Pregnancy .....................................................................................34 
8. 
TREATMENT OF PATIENTS ..................................................................................35 
8.1. 
Study Drug Dose and Administration .........................................................................35 
8.1.1. 
AL-LAI and AL-NCD Administration .......................................................................35 
8.1.2. 
ARI-ORAL Drug Dose and Administration ...............................................................36 
8.2. 
Measurement of Medication Treatment Adherence ...................................................36 


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8.3. 
Study Drug Dose Adjustment and Stopping Rules .....................................................36 
8.3.1. 
Aripiprazole Prospective Tolerability Screening ........................................................36 
8.3.2. 
Cross-Over from Other Oral Antipsychotics ..............................................................36 
8.3.2.1. 
Other Concomitant Medications .................................................................................37 
8.3.3. 
Treatment for Patients Randomly Assigned ARI-ORAL ...........................................37 
8.3.3.1. 
Starting Dose of ARI-ORAL ......................................................................................37 
8.3.4. 
Treatment for Patients Randomly Assigned to AL-LAI .............................................37 
8.3.4.1. 
Starting dose of AL-LAI .............................................................................................37 
8.3.5. 
Does Adjustments .......................................................................................................38 
8.3.5.1. 
ARI-ORAL Dose Adjustments ...................................................................................38 
8.3.5.2. 
AL-LAI Dose Adjustments.........................................................................................38 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................39 
9.1. 
Storage ........................................................................................................................39 
9.2. 
Handling of Study Drug ..............................................................................................39 
9.2.1. 
AL-LAI Medication Group .........................................................................................39 
9.2.2. 
ARI-ORAL Medication Group ...................................................................................39 
10. 
ASSESSMENT OF EFFICACY ................................................................................40 
10.1. 
Primary Endpoint ........................................................................................................40 
10.1.1. 
Primary Endpoint Measurements ...............................................................................40 
10.1.2. 
Primary Endpoint Rationale .......................................................................................40 
10.2. 
Secondary Endpoints ..................................................................................................40 
10.2.1. 
Secondary Endpoint Measurements ...........................................................................40 
10.3. 
Exploratory Endpoints ................................................................................................40 
10.3.1. 
Exploratory Endpoint Measurements .........................................................................40 
11. 
ASSESSMENT OF SAFETY .....................................................................................42 
11.1. 
Definition of Adverse Event .......................................................................................42 
11.2. 
Definition of Serious Adverse Events ........................................................................42 
11.3. 
Reporting of Serious Adverse Events and Pregnancy ................................................42 
12. 
STATISTICS ..............................................................................................................43 
12.1.1. 
Sample Size Considerations .......................................................................................43 
12.2. 
General Statistical Methodology ................................................................................44 
12.2.1. 
Intent-to-Treat Population ..........................................................................................44 
12.2.2. 
Medication Adherence as a Dimension ......................................................................44 


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12.3. 
Demographics and Baseline Data ...............................................................................44 
12.4. 
Efficacy Analysis ........................................................................................................44 
12.5. 
Safety and Tolerability Analyses ................................................................................45 
13. 
ETHICAL CONSIDERATIONS................................................................................46 
13.1. 
Ethics Review .............................................................................................................46 
13.2. 
Ethical Conduct of the Study ......................................................................................46 
13.3. 
Written Informed Consent ..........................................................................................46 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................47 
14.1. 
Data Capture ...............................................................................................................47 
15. 
REFERENCES ...........................................................................................................48 
 
LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
Schedule of Visits and Assessments ...........................................................................21 
Table 3: 
Criteria for Relapse or Exacerbation of Symptoms ....................................................26 
Table 4: 
Clinical Laboratory Assessments ...............................................................................31 
Table 5: 
Prohibited Medications: Pre- and Post-randomization ...............................................32 
Table 6: 
AL-LAI Dosing Frequency and Site of Injection .......................................................35 
Table 7: 
Power Calculations by Analysis with N=35 Each Group (N=28 at 
completion) .................................................................................................................44 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................19 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACD 
All-cause discontinuation 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
AL-LAI 
Aripiprazole lauroxil, long-acting injectable (ARISTADA®) 
AL-NCD 
Aripiprazole lauroxil NanoCrystal® Dispersion (ARISTADA INITIO®) 
ARI-ORAL 
Oral aripiprazole 
BARS 
Barnes Akathisia Rating Scale  
BPRS 
Brief psychiatric rating scale 
C-SSRS 
Columbia suicide severity rating scale 
CATIE 
Clinical Antipsychotic Trials of Intervention Effectiveness 
CGI-S 
Clinical global impression – severity 
CYP 
Cytochrome P450  
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
EPS 
Extrapyramidal symptoms 
ESRS-A 
Extrapyramidal symptom rating scale 
FDA 
Food and Drug Administration 
GASS 
Glasgow Antipsychotic Side-effect Scale 
GFS 
Global functioning scale 
GLMM 
General linear mixed models 
ICF 
Informed consent form 
IRB 
Institutional review board 
IM 
Intramuscular 
ITT 
Intent-to-treat 
MCCB 
Matrics consensus cognitive battery 
MSQ 
Medication satisfaction questionnaire 
NIMH 
National Institute of Mental Health 
PANSS 
Positive and Negative Syndrome Scale 
PSP 
Personal and Social Performance 
QLS 
Quality of Life Scale 
RAISE 
The Recovery After an Initial Schizophrenia Episode (study) 
SAE 
Serious adverse event 


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Abbreviation 
Definition 
SANS 
Scale for the Assessment of Negative Symptoms 
SCID 
Structured Clinical Interview for DSM-5 
SES 
Service engagement scale 
SIStat 
Semel institute biostatistics core 
SUI-Brief 
Brief substance use inventory 
SUMD-R 
Scale to Assess Unawareness of Mental Disorder-Revised 
UCLA 
University of California, Los Angeles 
WTAR 
Wechsler Test of Adult Reading 
 
 


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4. 
INTRODUCTION 
Long-acting injectable antipsychotic medications are a critical tool for clinicians treating 
schizophrenia patients. There is a growing consensus that long-acting injectable options should 
not be reserved only for the very ill who have demonstrated nonadherence to oral antipsychotic 
medication. Additional research into their effectiveness may be required in order to inform 
physicians of the use long-acting injectable medications early in the course of the disorder. 
Ensured adherence using long-acting injectables allows the clinician to better judge the 
effectiveness of the medication and dosage, and guide the pharmacologic treatment early in 
disease. 
Aripiprazole lauroxil, long-acting injectable (AL-LAI; ARISTADA®) is an atypical long-acting 
injectable for the treatment of schizophrenia. It is a covalently bonded, non-ester modification of 
aripiprazole, a second generation atypical antipsychotic agent, to form N-lauroyloxymethyl 
aripiprazole. It is formulated as an extended-release suspension to be administered via 
intramuscular (IM) injection into either the gluteal or deltoid muscles. After injection, 
aripiprazole lauroxil is converted to aripiprazole by dissolution of the aripiprazole lauroxil drug 
crystal from the injection site and subsequent enzyme-mediated cleavage, ultimately releasing 
aripiprazole into the plasma circulation.  
Therapy may be initiated by a one-day initiation regimen (a single IM injection of 675 mg 
aripiprazole lauroxil NanoCrystal® Dispersion [AL-NCD; ARISTADA INITIO®] with a single-
dose of 30 mg oral aripiprazole [ARI-ORAL]) or by 21 consecutive days of supplementation 
with ARI-ORAL. AL-NCD is a different IM formulation of AL. The two IM formulations 
predominantly differ in the particle size of the drug substance, the AL-LAI in the micrometer 
range and AL-NCD in the nanometer range. The smaller particle size of the AL-NCD 
formulation is designed to accelerate the rate of dissolution of AL to provide earlier appearance 
of circulating aripiprazole following administration compared to the micron formulation. 
In clinical trials, treatment with AL-LAI demonstrated statistically significant reductions from 
baseline in Positive and Negative Syndrome Scale (PANSS) total scores at Week 12, compared 
with placebo. AL-LAI was generally well tolerated for patients with schizophrenia at monthly 
IM dosing of 441 mg and 882 mg with the most common adverse events (AEs) being insomnia, 
akathisia, and headache.  
This study is an open label, 12-month prospective evaluation comparing ARI-ORAL to AL-LAI 
conducted by the University of California, Los Angeles (UCLA).  
 
 


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5. 
STUDY OBJECTIVES  
5.1. 
Primary Objective 
The primary objective is to assess whether schizophrenia patients who recently experienced their 
first psychotic episode that are randomized to AL-LAI are less likely to experience a  
re-emergence of positive psychotic symptoms compared to those randomized to ARI-ORAL.  
5.2. 
Secondary Objectives 
The secondary objectives are to: 
1. Examine differences in functional outcome between the two treatment groups. We 
anticipate that role functioning will improve more in the group randomized to AL-LAI 
than those assigned to the ARI-ORAL group.  
2. Evaluate and compare the cognitive changes of the AL-LAI vs. ARI-ORAL group over 
the 12-month Treatment period. It is hypothesized that patients assigned to AL-LAI will 
demonstrate relatively better performance on a standardized measure of cognition than 
those assigned to ARI-ORAL.  
5.3. 
Exploratory Objectives 
Additional exploratory objectives are to determine whether the two medication groups differ in 
other symptoms domains, adherence, and tolerability  (eg, negative symptoms, suicidality, self-
reported awareness of having a mental disorder, service engagement, sexual/ prolactin-related 
side effects, treatment engagement, and quality of life). 


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6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Approximately 128 patients will be recruited for the study as defined by consenting to a full 
screening assessment with the goal of randomization to a treatment group. Based on prior long-
acting injectable versus oral studies, we expect an attrition rate of 30% prior to Randomization, 
so that a total of 90 eligible patients will be randomized to either ARI ORAL (N=45) or AL-LAI 
(N=45).  
6.1. 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be qualified to participate in this 
study. 
3. Is willing and able to provide informed consent. 
4. Is between 18 and 45 years of age, inclusive, at Screening. 
5. Has a diagnosis of schizophreniform disorder, schizophrenia, or schizoaffective disorder, 
depressed type, as defined by Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition [DSM-5] (American Psychiatric Association 2013) criteria at Screening.  
6. Has a first episode of a psychotic illness that occurred within the 24 months before entry 
into the UCLA Aftercare Research Program. 
7. Sufficient acculturation and fluency (oral and written) in the English language to avoid 
invalidating research measures of thought, language, and speech disorder or of verbal 
abilities. 
8. Exhibits tolerability to ARI-ORAL during the Stabilization period, according to 
Investigator judgment (to be randomized). 
9. Resides within commuting distance of the UCLA Aftercare Research Program in a stable 
living situation where the patient can be located.  
10. Agrees to abide by the contraceptive requirements of the protocol. 
6.2. 
Exclusion Criteria 
Each patient must not have any of the following conditions to be qualified to participate in this 
study. 
1. Evidence of a known neurological disorder (e.g., epilepsy) or significant head injury with 
loss of consciousness of more than one hour. 
2. Has mental retardation (i.e., premorbid IQ less than 70) as estimated by the Wechsler 
Test of Adult Reading (WTAR) completed at screening or as documented in medical 
records conducted in childhood. The WTAR assesses word pronunciation, which is 
thought to be unaffected by cognitive decline associated with neurological damage and is 
thus a good proxy for premorbid intelligence.  
3. Is currently pregnant or breastfeeding, or is planning to become pregnant during the 
study. 


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4. Is currently on a long-acting injectable antipsychotic medication and it is clinically 
contra-indicated due to the risk of becoming a danger to self or others if the patient 
discontinued treatment with the long-acting injectable in order to participate in this trial. 
5. Has a history of poor or inadequate response to an adequate trial of oral or injectable 
aripiprazole (does not exclude patients whose aripiprazole exposure was too brief or at 
sub-therapeutic doses). 
6. Has received AL-LAI or IM depot aripiprazole within two months prior to 
Randomization (unless Stabilization period is extended beyond 90 days to 
accommodate). 
7. Has alcohol or substance abuse as a prominent clinical problem or makes the primary 
diagnosis not possible to confirm. Evidence of alcohol or substance use is not, in and of 
itself, exclusionary.  
8. Is currently being treated with clozapine. 
9. Has participated in a clinical trial involving any drug within the past two months prior to 
screening, or is currently participating in a clinical trial involving an investigational 
medication. 
10. Has a history of psychopathology based on the screening SCID other than 
schizophreniform disorder, schizophrenia, or schizoaffective disorder, mainly depressed 
type as indicated by any primary DSM-5 diagnosis within the 12 months prior to 
Screening or Randomization (e.g. primary diagnosis of bipolar disorder, schizoaffective 
disorder, bipolar type, bipolar disorder, or neurocognitive disorder) based on our research 
diagnostic procedures. 
11. Is in the opinion of the Investigator or prescribing psychiatrist, the patient is an imminent 
danger to himself/herself. Patient must not be an imminent danger to himself/herself for 
two weeks prior to entry. The Stabilization period may be extended until the potential 
patient participant has not been in imminent danger to himself/herself for at least two 
consecutive weeks. A prior history of suicidal ideation or suicidal attempt is not 
exclusionary.  
12. Has any of the following conditions or abnormalities at screening: History of neuroleptic 
malignant syndrome, malignant hyperthermia, or clinically significant tardive dyskinesia. 
6.3. 
Discontinuation of Assigned Medication  
If the randomly assigned medication must be discontinued and/or switched to a different 
antipsychotic medication, the patient may remain in the study until the 12-month assessment 
point. End of Assigned Treatment assessment point measures will be completed as close to and if 
possible, just prior to, the discontinuation/switch. Decision to switch medication will be recorded 
on a modified Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) All-Cause 
Discontinuation (ACD) assessment completed by the treating psychiatrist (Stroup et al, 2003). 
The switch to another antipsychotic medication will be guided by clinician judgment using the 
mediation selection recommendation adapted from the oral antipsychotic guidance used in the 
RAISE study (Kane et al, 2015). The date the new medication is prescribed will be recorded and 
used in the analyses. Patients who choose to discontinue study medication will be allowed to re-


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initiate study medication at any time during the 12-month follow-up. All other regular 
assessments will be completed throughout the remainder of the 12-month study.  
6.4. 
Over-enrollment of Patients 
Over-enrollment (beyond 90 patients) will occur to ensure that there are at least 14 patients who 
had a relapse in the 12-month Treatment period. 
 


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7. 
STUDY DESIGN 
7.1. 
Overall Study Design 
This is an open-label study of approximately 90 patients with schizophrenia who will be 
randomly assigned to 12 months of treatment with either ARI-ORAL or AL-LAI to take place at 
the UCLA Aftercare Research Program (300 UCLA Medical Plaza, Los Angeles, CA 90095), 
which is a program that specializes in the treatment and study of individuals with a recent onset 
of schizophrenia. The study design is presented in Figure 1. Potential patients will be evaluated 
for eligibility according to the inclusion and exclusion criteria at Screening.  
For patients who have never taken aripiprazole, tolerability must be established during the 
Stabilization period. The Stabilization period will be once-a-day ARI-ORAL with flexible 
dosing. All patients will receive ARI-ORAL for at least two weeks to establish full tolerability 
before Randomization, and patients who cannot tolerate ARI-ORAL 10 mg/day will not be 
randomized. Eligibility to be randomized will be determined at the end of the Stabilization 
period of up to 90 days. 
The Stabilization period will allow time for the oral antipsychotic medication to be cross-tapered 
to ARI-ORAL, if needed, and allow time for the patient to obtain some clinical stability prior to 
Randomization. Further, the Stabilization period will allow the baseline testing for this and the 
overlapping National Institute of Medical Health (NIMH) protocol to occur at a pace appropriate 
for someone who is in the middle, or tail-end of, a psychotic episode.  
Randomization (1:1 [AL-LAI: ARI-ORAL]) will take place after the Stabilization period. The 
NIMH overlapping study is a psychosocial intervention treatment. To balance the overlapping 
NIMH treatment groups in the AL-LAI and ARI-ORAL treatment groups, the randomization of 
patients in the APPRIASE study will be stratified by their participating role in the NIMH study 
(randomized to computerized cognitive training with or without aerobic exercise). Once 
randomized, patients will be treated per prescribing recommendations for a 12-month Treatment 
period. 
Efficacy will be evaluated based on the Brief Psychiatric Rating Scale (BPRS) scored for 
symptom exacerbation or relapse following Subotnik et al. (Subotnik et al, 2015) and 
Nuechterlein et al. (Nuechterlein et al, 2006). Because patients will not be withdrawn from the 
study if relapse criteria are met, there will be no need to score the BPRS for relapse 
contemporaneously throughout the study. Secondary outcomes will be role functioning and 
cognition. Exploratory outcomes will be negative symptoms, suicidality, awareness of having a 
mental disorder, extrapyramidal and prolactin-related side effects, service engagement, treatment 
satisfaction, and quality of life. Safety assessments will be collected and monitored. 


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Figure 1: 
Study Design 
 
a 1 to 3 months of stabilization on oral aripiprazole.  
b For 2 weeks prior to Randomization, all patients must be on oral aripiprazole 
c Initiation of treatment per Section 7.2.2  
Abbreviations: ARI-ORAL: aripiprazole oral; AL-LAI = aripiprazole lauroxil long-acting injectable; ET = End 
Treatment; EoS = End of Study   
7.2. 
Treatment Initiation  
During the last two weeks of the Stabilization period, all patients must be on ARI-ORAL to 
assess tolerability. At the initiation of ARI-ORAL during the Stabilization period, patients will 
be provided a prescription and prescription coupon to cover aripiprazole costs. 
7.2.1. 
Initiation of ARI-ORAL Treatment Arm after Randomization 
Patients will start or continue (from the Stabilization period) with ARI-ORAL doses within the 
recommended oral dosage range for the treatment of schizophrenia per the prescribing 
information (Abilify USPI). ARI-ORAL dosage will be flexible and dosage will be at the 
discretion of the treating psychiatrist. Patients assigned to this treatment arm will receive a 
written prescription for a 30-day supply along with a medication coupon so there will be no 
medication cost to the patient.  
7.2.2. 
Initiation of AL-LAI Treatment Arm after Randomization 
Initiation of AL-LAI will begin with a one-day initiation regimen (675 mg AL-NCD and 30 mg 
oral aripiprazole) per prescribing information (Initio USPI) unless the alternative initiation is 
selected (see Section 8.3.4.1.2). Dosing of AL-LAI will be flexible based on clinician judgment 
per prescribing information (Aristada USPI). The first AL-LAI injection may be administered on 
the same day as the one-day initiation regimen or up to ten days thereafter. Treatment with AL-
LAI can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg 
administered every six weeks or 1064 mg administered every two months. Patients assigned to 
the AL-LAI treatment arm will return to the clinic for injections during scheduled visits. 


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7.3. 
Continuation of Treatment  
Both treatment arms will be seen for routine monthly medication management visits with the 
prescribing psychiatrist who is affiliated with the UCLA program, and urgent visits can be 
scheduled as per clinical circumstances.  
7.4. 
Study Procedures  
7.4.1. 
Visit and Assessment Schedule 
The schedule of assessments is shown in Table 2. For a missed visit, the site should attempt to 
contact the patient to reschedule.  


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Table 2: 
Schedule of Visits and Assessments 
 
 
Screening 
Stabilization 
Treatment Period1 
Month 
13 
Follow-
up 
Day 1 
(Randomization 
baseline) 
 
Months 1-52 
 
Month 6 
 
Months 7-11 
 
Month 12 
EoT/EoAT3 
Clinical Visit Number 
V1 
 
V2 
V3, 4,5,6,7 
V8 
V9,10,11,12,13 
V14 
V15 
Study Drug Administration  
 
Ongoing throughout study 
 
Psychiatrist Medication Visit 
X 
Every month throughout study 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Criteria Review 
X 
 
X 
 
 
 
 
 
Demographics and Medical 
History4 
X 
 
 
 
 
 
 
 
SCID-5 
X 
 
 
 
 
 
 
 
ARI-ORAL 2-Week 
Tolerability Assessment5 
 
X 
 
 
 
 
 
 
Pregnancy Testing6  
X 
 
X 
X (3 months) 
X  
X (9 months) 
X 
X 
Urine Drug Screen 
X 
 
X 
 
X 
An additional test if needed 
for clinical purposes 
 
Physical Exam7 
X 
 
  
 
 
 
 
 
AE Monitoring 
 
Ongoing throughout study 
X 
Concomitant Medication 
Review 
X 
Every month throughout study 
X 
Vital Signs8, Weight, Waist 
Circumference 
X 
 
Every 3 months throughout study 
X 
Fasting Clinical Lab Tests9 
X 
 
X 
 
X 
 
X 
 
Plasma aripiprazole 
measurement 
 
 
 
 
X 
 
X 
 
MCCB 
 
 
X 
 
X 
 
X 
 
GFS:Role10 
X 
 
X 
Every 3 months throughout study 
 
QLS10 
 
 
X 
 
X 
 
X 
 
SUI-Brief11 
X 
 
X 
X 
X 
X 
X 
 


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Screening 
Stabilization 
Treatment Period1 
Month 
13 
Follow-
up 
Day 1 
(Randomization 
baseline) 
 
Months 1-52 
 
Month 6 
 
Months 7-11 
 
Month 12 
EoT/EoAT3 
Clinical Visit Number 
V1 
 
V2 
V3, 4,5,6,7 
V8 
V9,10,11,12,13 
V14 
V15 
Modified MSQ 
 
 
X 
 
X 
 
X 
 
ESRS 
X 
 
X 
 
X 
 
X 
X 
AIMS 
X 
 
X 
 
X 
 
X 
X 
BARS 
X 
 
X 
X 
X 
X 
X 
X 
GASS  
 
 
X 
 
X 
 
X 
 
C-SSRS12 
X 
 
X 
X 
X 
X 
X 
X 
SES 
 
 
X 
 
X 
 
X 
 
CGI-S 
 
 
X 
 
X 
 
X 
 
BPRS 
X 
 
X 
Every 2 weeks throughout study 
 
MCCB 
 
 
X 
 
X 
 
X 
 
SANS 
 
 
X 
 
X 
 
X 
 
PSP 
 
 
X 
 
X 
 
X 
 
SUMD-R 
 
 
X 
 
X 
 
X 
 
Hassles 
 
 
X 
 
X 
 
X 
 
ACD 
 
 
Ongoing throughout study if assigned medications are discontinued 
 
Abbreviations: ACD= Modified Version of the All-Cause Discontinuation; AIMS = Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating 
Scale; BPRS= Brief Psychiatric Rating Scale; CGI-S= Clinical Global Impressions-Severity; C-SSRS= Columbia Suicide Severity Rating Scale; GASS= 
Glasgow Antipsychotic Side-effect Scale; EoT= end of study treatment; ESRS-A=Abbreviated Extrapyramidal Symptom Rating Scale; EoAT = end of 
aripiprazole treatment; GFS: Role=Global Functioning Scale: Role; Hassles= Family Caregiver Medication Administration Hassles Scale; MCCB=MATRICS 
Consensus Cognitive Battery; MSQ= Medication Satisfaction Questionnaire (Modified); QLS = Quality of Life Scale; PSP= Personal and Social Performance 
Scale; SAE = Serious Adverse Event; SANS= Scale for the Assessment of Negative Symptoms; SCID-5= Structured Clinical Interview for DSM-5; SUI-
Brief=Brief Substance Use Inventory; SUMD-R= Scale to Assess Unawareness of Mental Disorder-Revised; SES= Services Engagement Scale 
1 For all visits other than Screening and Day 1, the visit will be anchored to the previous visit (based on dosing regimen schedule) 
2 In the event that a visit is missed or skipped, the additional assessments required at the visit should be conducted (via unscheduled assessment) at the patient’s 
next visit 
3 EoT= end of study treatment (may include therapies other than aripiprazole, if changed); EoAT = end of aripiprazole treatment 
4 The Psychiatric and Social History Schedule will be administered to record basic demographic information as well as past work and school history. 
Assessment5ARI-ORAL will be prescribed with flexible dosing. The first dose should be administered at the UCLA Aftercare Research Program. 


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6 Urine pregnancy testing will be completed for ALL women. At Visit 1 and 14, a serum pregnancy test will be performed. At Visit 1, the pregnancy test should 
be completed prior to the administration of the first ARI-ORAL dose. A urine pregnancy test will be conducted at mid-study indicated time points.  
7 Full physical examination at screening; brief physical examination on Day 1; symptom directed physical exams may be performed as needed at the 
Investigator’s discretion. 
8 Vital signs include blood pressure, heart rate, respiratory rate, and body temperature 
9 Clinical Lab Tests include biochemistry (including prolactin) and hematology 
10 Will be administered at baseline, Month 3, Month 6, Month 9, and Month 12/ET 
11 Will be administered every 2 weeks throughout the treatment period 
12 “Baseline/Screening” version used at screening; “since last visit” used at all subsequent visits 
 
 
 
 
 


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7.4.2. 
Informed Consent   
The nature of the study and its risks and benefits will be explained to the patient by the Principal 
Investigator or designated study personnel as outlined in Section 13.3.  
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent from each potential patient and caregiver. 
7.4.3. 
Eligibility Review 
An eligibility review will be conducted by the Investigator at the visits specified in Table 2 using 
the patient inclusion criteria in Section 6.1 and exclusion criteria in Section 6.2. The Structured 
Clinical Interview for DSM-5 (SCID; (First et al, 2002)) will be used to establish entry 
diagnosis. The SCID was developed for use in research by trained clinicians. The SCID 
incorporates the use of obligatory questions, operational criteria from the DSM-5, a categorical 
system for rating symptoms, and an algorithm for arriving at a final diagnosis. The SCID is 
organized in sections that include an overview of the individual’s psychiatric history, an 
assessment of mood disorder symptoms, psychotic symptoms, anxiety, alcohol abuse, substance 
abuse, and other Axis I disorders. The SCID has two sections that provide an algorithm for 
making a differential diagnosis of psychosis and mood disorder. Recent modifications of the 
SCID allow the interviewer to incorporate all relevant sources of information that are gathered 
from the patient’s chart and reliable informants in making a diagnosis. Published levels of 
inter-rater reliability when using the SCID were very high for schizophrenia (kappa = 0.94) and 
major depression (kappa = 0.93; (Skre et al, 1991)). The SCID interview takes 1-2 hours to 
complete.  
7.4.4. 
Demographics and Medical History 
Patient demographic data and medical history will be reviewed and documented at the time 
point(s) specified in Table 2. The Psychiatric and Social History Schedule will be administered 
at the Screening to record basic demographic information as well as past work and school 
history.  
7.4.5. 
Prior and Concomitant Medication Review 
At Screening, all medications (prescription and nonprescription, including vitamins and herbal 
supplements) taken by a given patient within 30 days prior to screening through follow-up will 
be recorded. At all other time point(s) specified in Table 2, prospective patients will be asked 
about the medications they have taken since the last visit and are currently taking (including 
prescription and nonprescription medications, vitamins, and supplements). 
The Investigator will record the following data on all medications used by the patient: name, 
dose, regimen, route of administration, start and stop dates, and the indication for use. 
7.4.5.1. 
Substance Use 
The Brief Substance Use Inventory (SUI-Brief) will be administered every two weeks during the 
randomized treatment period to document amount and frequency of alcohol, substance, and 
tobacco use. 


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7.4.6. 
Primary Endpoint Measurements 
The primary endpoint will be time to first positive symptom exacerbation and/or relapse 
following a period of absence or relatively low levels of psychotic symptoms based on the 
expanded 24-item version Brief Psychiatric Rating Scale (BPRS) (published UCLA relapse 
criteria (Nuechterlein et al, 2006) that are summarized below). 
7.4.6.1. 
APPRAISE Study Criteria for Reemergence of Positive Symptoms 
The BPRS is a semi-structured instrument that is internationally recognized and accepted for 
rating the presence and severity of psychiatric symptoms. The BPRS assesses various domains of 
psychiatric symptoms. Ratings are based on information obtained from self-report and 
observation of the patient’s behavior and speech. Symptoms and signs are rated along a severity 
and impairment in functioning dimension using a seven point rating scale. The BPRS has been 
used extensively to assess changes over time in the severity of the symptoms of schizophrenia 
and other major psychiatric disorders. In a comprehensive review, Hedlund and Vieweg 
(Hedlund Jl 1980) found that most studies reported excellent inter-rater reliability for the BPRS. 
Median Pearson and Intraclass correlation coefficients on the BPRS have ranged from 0.67 to 
0.88 (Bech et al, 1988; Tarell and Schulz 1988). The UCLA research team has developed a 
training and quality program for the expanded BPRS that has led to excellent inter-rater 
reliability at the completion of training (Ventura et al, 1993). The case managers will complete 
the BPRS at Screening and every two weeks as identified in Table 2.  
The BPRS includes ratings from 1 to 7 on each of these symptom dimensions. However, for 
positive symptom exacerbation, the three key BPRS ratings for predicting and evaluating 
psychotic relapse or significant exacerbation are: 
1. Hallucinations 
2. Unusual Thought Content 
3. Conceptual Disorganization 
It is these three items that are scored into the relapse algorithm. 
Because patients will vary based on their relative stability over time as well as the degree of 
change in positive symptom severity, the actual relapse outcome will be based on both current 
and prior BPRS evaluations as specified by one of the three exacerbation/relapse categories. 
Meeting criteria for any of the following three categories will be considered a psychotic 
relapse/exacerbation. 
Criteria for relapse or exacerbation of symptoms are summarized in Table 3. These criteria have 
established reliability, predictive validity and reactivity to medication nonadherence. 
Assessments are done every 2 weeks and scoring done by computer program. 


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Table 3: 
Criteria for Relapse or Exacerbation of Symptoms 
Remission  
followed by relapse  
Remission followed by 1 psychotic item ≥ 6 
(severe) at any BPRS assessment visit  
Section 7.4.6.1.1  
Remission  
followed by significant 
exacerbation  
Remission followed by 1 psychotic item 
rated 5 (marked) for more than 4 weeks (2 
consecutive BPRS assessments) 
Section 7.4.6.1.2  
Persistent symptoms 
followed by significant 
exacerbation 
Psychotic item rated 4 or 5 and then ≥ 2 
point increase to severe level (6 or 7) at any 
BPRS assessment visit  
Section 7.4.6.1.3  
 
7.4.6.1.1. Remission Followed by Relapse  
The patient achieves remission on all BPRS key symptoms by being rated 3 (which is below 
clinical threshold) or lower for more than four consecutive weeks at some point following project 
entry.  A rating of ≥ 6 (severe) on any one of these items following this period of remission 
would meet this relapse criterion. 
7.4.6.1.2. Remission Followed by Significant Exacerbation of Symptoms   
 
The patient is rated 3 or lower on the BPRS key symptom items for more than four weeks and 
the patient subsequently (a) is rated 5 on one of the key symptom items and increases at least two 
points on another key symptom item within the same four-week period while the initial 
exacerbating symptom is still in the clinical range (4 or higher) or (b) is rated 5 on one of the key 
symptom items for more than four weeks. 
7.4.6.1.3. Persisting Symptoms Followed by Significant Exacerbation of Symptoms 
The patient has persisting clinically significant symptoms in the 4 to 5 range on one or more 
BPRS key items but not in the 6 or 7 range for more than four weeks (not necessarily always the 
same item) during the Treatment period without achieving remission (by criteria above), and:  
a. shows an increase of two points within an eight-week period to a rating of 6 or 7, or 
b. shows an increase of one point on this item to a 6 and an accompanying two-point 
increase on another key symptom item within the same four-week period. 
These criteria are not made in real time, but are entered into the database and determined at a 
later time. 
7.4.7. 
Secondary Endpoint Measurements 
The secondary endpoints of this study are: 
• Role ratings on the Global Functioning Scale (GFS: Role) 
• Overall Composite T-score MATRICS Consensus Cognitive Battery (MCCB) 


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7.4.7.1. 
Functional Assessment -The Role ratings on the Global Functioning Scale  
The GFS: Role (Cornblatt et al, 2007; Niendam et al, 2006) will serve as the measure of 
functional outcome for this secondary objective. The GFS: Role is a 10-point rating scale for 
evaluating school and job functioning. This outcome scale has strong psychometric 
characteristics and the anchors were developed to be appropriate for adolescents and young 
adults in a large prodromal schizophrenia study, and are especially suited for the younger age 
group of our young-adult first-episode sample. GFS: Role will be administered at entry, baseline, 
and every three months throughout the 12-month Treatment period.  
7.4.7.2. 
Cognitive Assessment- The MATRICS Consensus Cognitive Battery  
The Overall Composite T-score from the MCCB is a secondary endpoint and will be the overall 
index of cognitive performance. This battery is the result of the efforts of a national committee of 
experts to develop a NIMH-recommended battery for evaluation of interventions designed to 
improve cognition in schizophrenia (Kern et al, 2008; Nuechterlein et al, 2008). By using the 
MCCB, the results of our attempts to improve cognition in schizophrenia can be directly 
compared to attempts to do so through pharmacological and other learning-based interventions. 
The Overall Composite Score summarizes performance across 10 tests of Speed of Processing, 
Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and 
Problem Solving, and Social Cognition (Nuechterlein et al, 2008). 
7.4.8. 
Exploratory Endpoint Measurements 
The exploratory endpoints of this study are: 
• Heinrichs-Carpenter Quality of Life Scale (QLS)  
• Personal and Social Performance Scale (PSP)  
• Clinical Global Impressions-Severity (CGI-S) 
• Scale for the Assessment of Negative Symptoms (SANS)  
• Scale to Assess Unawareness of Mental Disorder-Revised (SUMD-R)  
• Glasgow Antipsychotic Side-effect Scale (GASS)  
• Modified Medication Satisfaction Questionnaire (Modified MSQ)  
• Service Engagement Scale (SES) 
• Family Caregiver Medication Administration Hassles scale 
• Modified Version of the ACD 
7.4.8.1. 
Heinrichs-Carpenter Quality of Life Scale  
The QLS is a clinician-rated scale based on a patient’s report during a semi-structured interview. 
It is used to assess health-related quality of life and functioning in patients with schizophrenia 
during the preceding four weeks (Heinrichs et al, 1984). The QLS consists of 21 items in four 
major domains (Intrapsychic Foundations, Interpersonal Relations, Instrumental Role, and 
Common Objects and Activities). Following a semi-structured interview, each item is rated on a 
7-point scale, from 0 (severe impairment) to 6 (normal or unimpaired functioning). Reported 


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inter-rater reliabilities range from 0.84 to 0.97 on the summary scales. The QLS will be 
completed every three months after the onset of randomized treatment. This measure revealed an 
advantage for aripiprazole monohydrate compared to paliperidone palmitate for improving 
quality of life in schizophrenia (Naber et al, 2015). The Intrapsychic Foundations subscale will 
be the primary one analyzed for this objective. This scale will be completed at the time points 
specified in Table 2.  
7.4.8.2. 
Personal and Social Performance Scale  
The Investigator or designee will complete the 5-point PSP scale (Patrick et al, 2009) at the time 
points identified in Table 2.  
7.4.8.3. 
Clinical Global Impressions-Severity  
The Investigator or designee will complete the CGI-S scale (Guy 1976) at Screening and at the 
time points as identified in Table 2.  
7.4.8.4. 
Scale for the Assessment of Negative Symptoms 
A SANS manual describes each symptom and provides anchor point definitions. Each of the 
SANS items are scored on a 6-point Likert-type scale (from 0 to 5). The SANS contains 20 items 
within five domains of negative symptoms: Alogia; Affective flattening; Avolition-Apathy; 
Anhedonia-Asociality; and Attention. Each group of symptoms has several component items 
relevant to the assessment of positive symptoms and a global rating. Negative symptoms will be 
rated during the administration of the SANS and will be based on observations, information 
provided by the patient, and from all reliable sources of information. The SANS manual contains 
a set of specific interview questions, supplemented by our group that will be used by the 
assessment team to elicit reported negative symptoms (eg, impersistence and asociality). This 
scale will be completed at the time points specified in Table 2.  
7.4.8.5. 
Scale to Assess Unawareness of Mental Disorder-Revised 
The SUMD-R will be used to assess insight in the early course of schizophrenia. To reduce the 
time burden on patients, the SUMD-R has been shortened to include key items found to be the 
most useful in previous studies. The SUMD-R measures three aspects of insight for each 
psychiatric symptom: unawareness that the symptom is present, the attribution as to the cause of 
the symptom, and unawareness of whether others would perceive the symptom as being present. 
Unawareness of concentration, memory, and speed of processing deficits are also assessed. The 
Overall Unawareness of Mental Illness item will be the primary one used for this outcome 
measure. This scale will be completed at the time points specified in Table 2.  
7.4.8.6. 
Glasgow Antipsychotic Side-effect Scale  
The GASS scale will be completed by the patient at the time points specified in Table 2.  
7.4.8.7. 
Modified Medication Satisfaction Questionnaire  
The Modified MSQ is a 3-item self-report patient satisfaction questionnaire which assesses the 
level of patient satisfaction with medication. Patients rate their satisfaction with their current 
medication, their preference for their current medication versus the one taken prior to the study, 


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and their opinion on the side effects of their current medication versus the one taken prior to the 
study. Ratings are on a 5-point Likert scale. The Modified MSQ will be collected every six 
months following randomization. This scale will be completed at the time points specified in 
Table 2.  
7.4.8.8. 
Service Engagement Scale (SES) 
The SES is a 14-item questionnaire to evaluate engagement with clinical services and to evaluate 
areas of engagement difficulties that might pose obstacles to treatment. The scale has been 
shown to have good validity and test-retest reliability (Tait et al, 2002; Tait et al, 2018). This 
scale will be completed at the time points specified in Table 2.  
7.4.8.9. 
The Family Caregiver Medication Administration Hassles Scale 
The Family Caregiver Medication Administration Hassles scale is a 24-item scale that identifies 
hassles and frustrations that occur for family caregivers who are responsible for administering 
medications to their family members. Four subscales have been identified: Information 
Seeking/Information Sharing, Safety Issues, Scheduling logistics, and Polypharmacy. The 
overall scale reliability is 0.95, and the test-retest reliability at 2 weeks is 0.84 (Travis et al, 
2003). This scale will be completed at the time points specified in Table 2.  
7.4.8.10. Modified Version of the All-Cause Discontinuation  
A modified version of the ACD measure used in the CATIE schizophrenia study will be used to 
track the reasons for medication changes. The modification of this measure pertains to the 
addition of further nuances in the decision-making process.  
7.4.9. 
Safety Assessments 
7.4.9.1. 
Overview of Safety Assessment Procedures 
Each patient will have a treating psychiatrist who is a part of the clinical team for UCLA 
Aftercare Research Program. The psychiatrist will be responsible for the medical and 
psychopharmacologic management of patients. The one-on-one medication assessment 
appointments are scheduled at least monthly, and may be more frequent as per the clinical status 
and needs of the individual patient. The treating psychiatrists have specialty practice experience 
in schizophrenia and psychotic disorders, and will be trained in all of the ongoing safety 
assessments for the study, including: 
• Extrapyramidal symptoms (Abnormal Involuntary Movement Scale [AIMS], Barnes 
Akathisia Rating Scale [BARS], and the Extrapyramidal Symptom Rating Scale 
[ESRS-A]) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• AE collection 
• Serious adverse event (SAE) reporting 
The treating psychiatrists also attend the UCLA Aftercare Research Program weekly case 
conferences where the entire clinical team, including the clinical assessors, meets to review the 
clinical status of all patients in the program. Patients will be reviewed for any SAEs or other 


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clinical changes on a weekly basis. However, the BPRS assessments that are the basis of the 
relapse criteria are not specifically reviewed within the case conferences, but salient clinical 
information gleaned from the biweekly BPRS ratings will be shared at that time and will be used 
along with all other relevant clinical information for further medication management and patient 
treatment decisions.  
Semi-annual review of all safety assessment responses will be conducted by a Data and Safety 
Monitoring Committee at UCLA who are not study investigators per the UCLA IRB standards.  
7.4.9.2. 
Extrapyramidal Symptoms 
Extrapyramidal Symptom Scales will include AIMS, BARS, and ESRS-A. The Investigator or 
designee will administer the extrapyramidal symptom scales at time points specified in Table 2.  
After administration of the first dose of study drug, if a patient complains of extrapyramidal 
symptoms (EPS) on days when the abnormal movement scales are not scheduled to be 
performed, an unscheduled assessment should be performed.  
The AIMS will primarily be used to assess dyskinesia. The BARS will primarily be used to 
assess akathisia. The ESRS-A will primarily be used to assess Parkinsonism and dystonia. 
7.4.9.3. 
Columbia Suicide Severity Rating Scale  
The Investigator or designee will administer the C-SSRS according to the schedule in Table 2. At 
Screening, the “Baseline/Screening” version will be administered (Mundt et al, 2013; Posner et 
al, 2009; Posner et al, 2011), and at all other visits, the “Since Last Visit” version will be 
administered (Posner K et al, 2009). For “Since Last Visit” versions, patients should be asked to 
report on ideation and behavior since the last scheduled C-SSRS assessment. The C-SSRS will 
be administered by a clinician trained to assess and manage suicidal ideation and behavior. 
7.4.9.4. 
Laboratory Assessments 
7.4.9.4.1. Drug Testing 
A urine drug test for drugs of abuse, including amphetamines, barbiturates, cocaine, 
methamphetamine, opiates, and phencyclidine will be performed at the time points specified in 
Table 2. Results must be negative, or if positive, there must be additional evidence that the abuse 
is not persistent and will not make treatment in this outpatient program contraindicated. 
7.4.9.4.2. Hematology, Biochemistry, Metabolic, and Prolactin Assessments 
Blood and urine samples for laboratory assessments will be collected at the time points specified 
in Table 2. Specific hematology, biochemistry, metabolic, and prolactin assessments are listed in 
Table 4. Samples will be collected in accordance with the site’s usual procedures at the UCLA 
Department of Pathology phlebotomy station on the first floor of the 200 UCLA Medical Plaza 
building next door to the Aftercare Research Program, thereby facilitating convenient blood 
drawing for laboratory tests.  


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Table 4: 
Clinical Laboratory Assessments  
Hematology 
Biochemistry 
Hematocrit 
Hemoglobin 
Red blood cell count 
Total and differential (absolute) white 
blood cell count 
Platelets 
Sodium 
Potassium 
Glucose 
Creatinine 
Total protein 
Blood urea nitrogen 
Albumin 
Total bilirubin 
Alanine transferase  
Aspartate transferase  
Lactic dehydrogenase  
Gamma-glutamyl transferase  
Alkaline phosphatase  
Creatinine phosphokinase  
A1c 
Blood sugar 
Fasting lipid panel 
Prolactin 
7.4.9.4.3. Plasma Aripiprazole Concentrations 
Plasma samples will be collected at the visits indicated in Table 2  and will be kept for 
measurement of aripiprazole concentrations in plasma assays. The clinicians will not be updated 
on the outcome of the measurement. 
7.4.9.4.4. Pregnancy Testing 
A serum pregnancy test will be conducted at Screening and at the last study visit for all women. 
A urine pregnancy test will be administered to all women every 3 months during the Treatment 
period, as specified in Table 2. At the Screening visit, results must be negative for the patient to 
be eligible for the study.  
7.4.10. 
Vital Signs 
Vital signs (i.e., blood pressure, pulse, respiratory rate, and oral body temperature) will be 
assessed at the time points specified in Table 2. Blood pressure, pulse, and respiratory rate will 
be measured after the patient has been resting in a seated or supine position for at least 
five minutes. 
7.4.11. 
Physical Examination, Body Height, Weight 
A physical examination will be performed at the time points specified in Table 2. 


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7.4.12. 
Adverse Event Monitoring 
Continuous monitoring of AEs will take place from the time a patient signs the informed consent 
document until the completion of the final study visit. Additional information on the assessment 
of safety is provided in Section 11. 
7.4.13. 
Randomization 
Randomization will occur after the Stabilization period in a 1:1 ratio by an automated method at 
UCLA. Patients successfully completing the Stabilization period will be randomized to one of 
two medications groups: converting from oral antipsychotic to AL-LAI vs continuing on (ARI 
ORAL). Each medication group will be further randomized to the cognitive remediation or 
healthy behavior training condition. Patients do not need to be free of psychosis at the time of 
randomization and the severity of psychosis is not a variable for stratification.  
7.5. 
Study Requirements and Restrictions 
Prohibited medications are defined in Section 7.5.1. Other restrictions are outlined in the 
Exclusion Criteria (Section 6.2). If at any point a patient is no longer eligible per the entry 
criteria, they will be discontinued from the study.  
7.5.1. 
Prohibited Medications and Restricted Concomitant Medications 
Prohibited mediations and restrictions are detailed in Table 5. Refer to the prescribing 
information for the study drug (Abilify USPI ; Aristada USPI ; Initio USPI) and each 
concomitant medication for interactions and dose restrictions.  
Concomitant use of potent oral CYP3A4 inhibitors and CYP2D6 inhibitors is to be avoided. In 
addition, patients with known CYP2D6 poor metabolism should not receive strong oral CYP3A4 
inhibitors during the study. During the study, dose adjustment may be necessary in the event of 
use of potent oral CYP2D6 inhibitor, or a CYP3A4 inhibitor or inducer. For example, the use of 
CYP3A4 inducers may require dose escalation. Investigators should consult the prescribing 
information for questions regarding any such dose adjustments.  
Table 5: 
Prohibited Medications: Pre- and Post-randomization 
Class (medication) 
Prescribed before 
randomization  
Started Post-randomization  
Antipsychotics 
Other first-line  
oral antipsychotic 
all prior (non-aripiprazole) 
antipsychotics must be 
discontinued within 2 weeks 
prior to the Randomization visit  
Not allowed123 
 
Clozapine 
Not allowed  
Not allowed  
Other long-acting injectables 
Not allowed  
Not allowed  
Antidepressants 


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Class (medication) 
Prescribed before 
randomization  
Started Post-randomization  
 
Generally allowed but sertraline 
(Zoloft®), citalopram (Celexa®) 
or escitalopram (Lexapro®) 
preferred  
Sertraline (Zoloft®), citalopram 
(Celexa®) or escitalopram 
(Lexapro®) preferred 
Mood Stabilizers (Starting mood stabilizer not encouraged) 
Lithium carbonate  
Allowed  
Allowed  
Lamotrigine  
Allowed  
Allowed  
Valproate  
Allowed for men 
Not allowed for women  
Allowed for men 
Not allowed for women 
Carbamazepine/oxcarbazapine  
Not allowed  
Not allowed  
Anti-anxiety medications  
Lorazepam PRN 
anxiety/insomnia  
Allowed  
Allowed4 
Lorazepam standing  
Allowed  
Allowed 
Clonazepam PRN  
Not allowed  
Not allowed  
Clonazepam standing  
Allowed5 
Allowed  
Alprazolam  
Not allowed  
Not allowed  
Diphenhydramine (for 
insomnia) 
Allowed6 
Allowed  
Anti-EPS and anti-akathisia 
Propranolol (akathisia only) 
Allowed  
Allowed/preferred  
Lorazepam (akathisia or acute 
dystonia only) 
Allowed  
Allowed  
Benztropine (antipsychotic-
induced parkinsonism) 
Allowed  
Allowed  
Diphenhydramine (akathisia and 
acute dystonia only) 
Allowed  
Allowed  
ADHD therapies  
Methylphenidate-based ADHD 
treatments  
Allowed with review  
Not allowed  
Amphetamine-based ADHD 
treatments  
Not allowed  
Not allowed  
Abbreviations: PRN= as needed; ADHD= Attention-deficit/hyperactivity disorder; EPS= Extrapyramidal symptoms 
1 For patients in the ARI-ORAL arm, dose increases for persistent symptoms and/or symptom exacerbations is 
permitted. However, prescribing another non-aripiprazole oral antipsychotic for “rescue” medication will be 
criteria for stopping the treatment assignment.  


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2 For patients in the AL-LAI arm, ARI-ORAL for ≤ 2 weeks will be allowed for transient exacerbations that are 
deemed to be caused by external stressors. ARI-ORAL prescribed for > 2 weeks will be criteria for AL-LAI failure  
3 Patients receiving up to 2 days of oral or short acting antipsychotic IM medication because they presented to an 
ER or crisis facility outside of the UCLA program will not be criteria for discontinuation of treatment assignment  
4 Maximum 4mg day Total Daily Dose (TDD)  
5 Maximum is 3mg/day Total Daily Dose (TDD)  
6 Max 100mg  
7.5.2. 
Contraception and Pregnancy 
All male and female patients must agree to use an acceptable method of contraception for the 
duration of the study and 30 days after the final dose of oral study drug, and 90 days following 
the final dose of long-acting injectable antipsychotic unless they are surgically sterile or 
postmenopausal (see below). The following are considered acceptable methods of contraception:  
1. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
2. Intrauterine device  
3. Oral contraceptive pills or other hormonal methods (eg, a vaginal ring, contraceptive 
patch, contraceptive implant); oral contraceptives should have been initiated at least 
30 days prior to Screening. 
Patients who are abstinent are eligible, provided they agree to use an acceptable contraceptive 
method should they become sexually active. 
Patients who are surgically sterile are exempt from the requirement to use contraception. Women 
who have undergone a hysterectomy, bilateral tubal ligation, or bilateral salpingo-oophorectomy 
are considered surgically sterile. Men who have undergone a vasectomy or bilateral orchiectomy 
are considered surgically sterile. Partner vasectomy is not considered an approved acceptable 
method of contraception for a female patient.  
If a patient becomes pregnant while participating in the study, she will be promptly discontinued 
from study drug. Pregnancy is not considered an AE, however pregnancy, whether a female 
study patient or the partner of a male study patient, must be immediately documented on a 
Pregnancy Form and reported to Alkermes, Inc., within 24 hours of the Investigator becoming 
aware of the pregnancy as outlined in Section 11.3. Additional follow-up may be required. 
The pregnancy will be followed until completion or termination, if feasible. If the outcome of the 
pregnancy meets the criteria for classification as a SAE it should be reported following the SAE 
procedure (Section 11.3). 
 
 


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8. 
TREATMENT OF PATIENTS 
Each patient will be provided a prescribing psychiatrist and a case manager/therapist to monitor 
clinical status and provide treatment. Study visits will occur weekly at Screening and 
Stabilization period, and then every two weeks throughout the 12-month randomized Treatment 
period (at each clinical visit and between each clinical visit). The total study duration for each 
patient will be approximately 70 weeks, including a Screening period (up to four weeks), up to 
90-day Stabilization period, and a 12-month randomized Treatment period.  
If the patient is not already on ARI-ORAL at Screening, any prestudy oral antipsychotic 
medication can begin to be tapered off during the Stabilization period, while ARI-ORAL is 
initiated. During the Stabilization period, all patients will receive flexible dosing of ARI-ORAL. 
Patients who find ARI-ORAL intolerable during the Stabilization period will not be randomized.  
8.1. 
Study Drug Dose and Administration 
During the 12-month Treatment period, patients who tolerate the study medication but find that 
after adequate duration and dosage, it is inadequately efficacious per clinical judgment, may be 
switched to another oral antipsychotic at the discretion of the Investigator. Patients who miss 
scheduled injections or visits are allowed to continue in the same assigned treatment group. 
8.1.1. 
AL-LAI and AL-NCD Administration  
Refer to the prescribing information for AL-NCD administration (Initio USPI). Administer 
675mg AL-NCD in either the deltoid or gluteal muscle. 
Refer to the prescribing information for AL-LAI administration (Aristada USPI).  In summary, 
administer AL-LAI either in the deltoid muscle (441 mg dose only) or gluteal muscle (441 mg, 
662 mg, 882 mg or 1064 mg) (Table 6). Clinical staff administering AL-LAI will be licensed to 
give IM injections in the state of California and will be trained and certified on proper injection 
technique for AL-LAI and AL-NCD administration.  
Table 6: 
AL-LAI Dosing Frequency and Site of Injection 
Dose 
Dosing Frequency 
Site of Intramuscular Injection 
441 mg 
Monthly 
Deltoid or Gluteal 
662 mg 
Monthly 
Gluteal 
882 mg 
Monthly or every 6 weeks 
Gluteal 
1064 mg  
Every two months 
Gluteal  
Refer to the current prescribing information for ARISTADA for  the recommended starting dose 
based on ARI-ORAL total daily dose, handling of missed doses of AL-LAI, early dosing of 
AL-LAI and dose adjustments for CYP450 considerations for AL-LAI (Aristada USPI).  
Schedule changes, from monthly to every six weeks (or the reverse) will also be allowed after 
the second injection. Dose changes due to the medical need to initiate concomitant CYP 
modulators may be performed at any time if the concomitant medication is necessary for more 
than two weeks. 


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8.1.2. 
ARI-ORAL Drug Dose and Administration 
Patients in the ARI-ORAL group will receive vouchers that will need to be given to the 
pharmacy at the time that the study oral antipsychotic medication is first dispensed. When 
ARI-ORAL is prescribed, the generic formulation will be prescribed, instead of the 
commercially available Abilify® brand. This voucher will have instructions for the pharmacy to 
bill Alkermes directly for the medication. Pharmacy billing will also be captured by Alkermes 
and shared with the study team for use as medication possession data, which will be an 
additional source of information used to make medication adherence ratings for the ARI-ORAL 
group patients.  
8.2. 
Measurement of Medication Treatment Adherence 
All study drug injections will be directly administered by clinical study staff. The date, time, 
dosage, and location of each injection will be recorded by the clinical staff. Study staff will 
address non-adherence with the patient as needed. 
Adherence to oral medication will be rated by a team of research assistants who will not inform 
the clinical team of their ratings or determinations. The oral antipsychotic medication adherence 
ratings will rely primarily on pill counts. Patients will be asked to bring their pill bottles to clinic 
appointments, for pills to be counted by a separate, nonclinical staff. Medication poss++ession 
information will be captured through the pharmacy voucher billing and used as an additional 
source of information in the all sources consensus adherence ratings. Adherence ratings will be a 
consensus rating based on all sources of information (pill counts, plasma assays, patient self-
report, clinician judgment based on the occurrence or change in side effects, family or caregiver 
collateral information, and pharmacy billing). Retroactive changes to the all sources consensus 
adherence ratings based on new information is allowed. No changes will be made to the 
quantitative pill counts based on changes in the patient or caregiver reports. Oral medication 
adherence will also be tracked in this way for any other oral antipsychotic medications if the 
initially assigned ARI-ORAL medication needs to be switched. 
8.3. 
 Study Drug Dose Adjustment and Stopping Rules 
8.3.1. 
Aripiprazole Prospective Tolerability Screening  
After Screening but before Randomization (Stabilization period), the patient’s current and past 
medication history will be reviewed carefully. Patients with current or prior exposure to oral 
aripiprazole meeting criteria of a reliable history at least two weeks given at >10 mg day for a 
two-week period will be assessed for their efficacy and tolerability to aripiprazole.  
Tolerability path will involve flexibly dosed aripiprazole prescribed ≥ 2 weeks. Patients will be 
eligible for Randomization upon completing this (and other) required screening procedures.  
8.3.2. 
Cross-Over from Other Oral Antipsychotics 
For patients on other [non-aripiprazole] oral antipsychotics, the clinician and patient can choose 
a cross-taper switch plan ranging from immediate discontinuation to a delayed cross-over during 
Stabilization period.  


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8.3.2.1. 
Other Concomitant Medications 
Most adjunctive psychotropic medications can be continued during the cross-over and after the 
cross-over. Patients receiving anti-EPS or anti-akathisia medications will have these medications 
continued for at least 30 days and then will be evaluated for possible taper and discontinuation if 
the patient has been on ARI-ORAL for ≥ 30 days without EPS or akathisia.  
8.3.3. 
Treatment for Patients Randomly Assigned ARI-ORAL  
8.3.3.1. 
Starting Dose of ARI-ORAL  
The recommended starting dose for ARI-ORAL should be determined per the prescribing 
information (Abilify USPI). Patients will start ARI-ORAL as soon as possible, after filling their 
ARI-ORAL prescription at the local pharmacy. The reasons for dosage changes will be 
documented.  
8.3.4. 
Treatment for Patients Randomly Assigned to AL-LAI  
8.3.4.1. 
Starting dose of AL-LAI  
The recommended starting dose for AL-LAI should be determined per the prescribing 
information (Aristada USPI).  
8.3.4.1.1. Initiation Regimen 
The preferred method of initiating AL-LAI is the one-day initiation regimen consisting of a 
single-dose injection of 675 mg AL-NCD IM plus a single 30 mg oral aripiprazole.  
8.3.4.1.2. Exceptions to the One-day Initiation Regimen 
The alternative to the one-day initiation regimen is prescribing 21-days of oral aripiprazole in 
conjunction with the first injection of AL-LAI. This method will be allowed but needs to be 
documented, with reasons including:  
1. Presence of genetic or drug-drug interactions regarding CYP interactions that exclude 
one-day initiation regimen  
2. Patient refusal to accept the one-day initiation regimen (but agrees to accept the AL-LAI 
starting dose during the same visit) 
8.3.4.1.3. Timing of the First AL-LAI Treatment  
When starting with the one-day initiation regimen, the starting dose of AL-LAI can be given 
within 60 minutes of AL-NCD. Patients will also be asked to take the 30 mg aripiprazole tablet 
with the injections, but clinicians will have the option of giving the oral dose to the patient to be 
taken at bedtime if the patient has family members willing to supervise. 


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8.3.5. 
Does Adjustments 
8.3.5.1. 
ARI-ORAL Dose Adjustments  
Dose adjustments of ARI-ORAL should be made per prescribing recommendations (Abilify 
USPI). 
8.3.5.2. 
AL-LAI Dose Adjustments 
Patients who have successfully received three or more monthly AL-LAI without significant 
tolerability problems will be eligible to change to a 1064 mg/two month interval regimen. Dose 
adjustments should be made per prescribing information (Aristada USPI). The following are also 
required to dose adjust: 
• Patient request with clinician assent  
• Clinician recommendation  


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT  
9.1. 
Storage 
Study drug must be stored in a locked area at 20°C to 25°C (68°F to 77°F); excursions between 
15°C and 30°C (59°F and 86°F) are permitted. 
Note that AL-NCD has a specific instruction “Do not freeze” on its packaging. 
9.2. 
Handling of Study Drug 
9.2.1. 
AL-LAI Medication Group 
AL-LAI and AL-NCD will be provided by Alkermes, Inc. and should be shipped to: 
UCLA Investigational Drug Pharmacy 
Ronald Reagan UCLA Medical Center 
Dept. Of Pharmaceutical Services 
662 Gayley Ave., B1-504A 
Los Angeles, CA 90095 
Phone Number: 310-267-8522 
AL-LAI and AL-NCD will be stored and dispensed by the UCLA Investigational Drug 
Pharmacy. Both will be stored in a locked cabinet after it is dispensed up until the time of 
injection.  
9.2.2. 
ARI-ORAL Medication Group 
The ARI-ORAL group will be given paper or electronic prescriptions, or the prescription may be 
telephoned to, or faxed to, the pharmacy of the patient’s choice. Prescriptions will typically be 
for 30 day supplies, unless otherwise indicated by the treating psychiatrist. Side-effect 
medications, such as anti-parkinsonians, beta-blockers, and benzodiazepines will also be billable 
through the voucher system. The patient will be provided a payment coupon that s/he will 
present to the pharmacy. The payment coupon will direct the pharmacist to Alkermes for 
reimbursement. Subsequent refills will not require a new coupon. Patients will be seen by the 
Aftercare Research Program clinical team every two weeks. This prescribing routine as outlined 
for this study is consistent with standard pharmacologic treatment for patients in clinical care at 
the same site who are prescribed oral antipsychotic medication.  
Deliberate over-prescribing or stockpiling is not permitted. Patients who are discontinuing 
ARI-ORAL will be allowed to overlap antipsychotic for a maximum of one month; otherwise 
co-prescribing two oral antipsychotics is not allowed.   


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10. 
ASSESSMENT OF EFFICACY 
10.1. 
Primary Endpoint 
10.1.1. 
Primary Endpoint Measurements 
The primary endpoint will be time to first positive symptom exacerbation and/or relapse 
following a period of relative remission of psychotic symptoms based on expanded 24-item 
version Brief Psychiatric Rating Scale (BPRS) (published UCLA relapse criteria (Nuechterlein et 
al, 2006) that are summarized in Section 7.4.6. 
10.1.2. 
Primary Endpoint Rationale 
The expanded BPRS (Ventura et al, 1993) will be rated every two weeks, with each item rated 
from 1 (not present) to 7 (extremely severe). Positive symptom exacerbation or relapse will be 
identified based on increases of the BPRS items Unusual Thought Content, Hallucinations, or 
Conceptual Disorganization using computer scoring algorithms (Nuechterlein et al, 2006). The 
three scoring categories considered to be a psychotic symptom return are: “Remission Followed 
by Relapse”, “Remission Followed by Significant Exacerbation”, or “Persisting Symptoms 
Followed by Significant Exacerbation.” These definitions do not consider other aspects of 
outcome often part of “treatment failure” definitions, such as: hospitalization or increased 
treatment to prevent hospitalization; harm to self, others, or property; arrest; or treatment 
discontinuation, as these other negative outcomes might not be secondary to psychotic symptoms 
per se. These classifications have been shown to be sensitive measures of the return of psychotic 
symptoms and differentiated oral and long-lasting injectable treatment groups in our previous 
research (Subotnik et al, 2015). Patients in the proposed study will continue in the protocol even 
if a psychotic relapse or exacerbation occurs, although the medication regimen might change at 
the discretion of the Aftercare Research Program treating psychiatrist. Our experience has been 
that the majority of psychotic exacerbations or relapses can be managed on an outpatient basis 
unless the patient has concurrent imminent suicidality, and often the prescribed medication does 
not change (although the dosage might). Continuing patients in the protocol after a return of 
symptoms will allow us to assess secondary outcomes at the 6- and 12-month points.  
10.2. 
Secondary Endpoints 
10.2.1. 
Secondary Endpoint Measurements 
The secondary endpoints of this study are: 
• GFS: Role 
• Overall Composite T-score MCCB 
10.3. 
Exploratory Endpoints  
10.3.1. 
Exploratory Endpoint Measurements 
The exploratory endpoints of this study are: 
• Heinrichs-Carpenter QLS  


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• PSP  
• CGI-S 
• SANS  
• SUMD-R  
• GASS 
• Modified MSQ  
• SES 
• Family Caregiver Medication Administration Hassles scale 
• Modified Version of the ACD 


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11. 
ASSESSMENT OF SAFETY 
11.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient who has 
been administered a pharmaceutical product. The occurrence may or may not have a causal 
relationship with the investigational treatment, may include any clinical or laboratory change that 
does not commonly occur in that patient and is considered clinically significant. 
Pregnancy is not considered an AE, although a patient will be withdrawn from the study if a 
pregnancy occurs. The pregnancy, including a partner’s pregnancy, must be reported to 
Alkermes, and additional follow-up may be required. 
11.2. 
Definition of Serious Adverse Events 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
• Results in death 
• Is life-threatening. The patient is at immediate risk of death from the reaction as it 
occurs. This does not include reaction that, had it occurred in a more severe form, 
might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (eg, a substantial disruption of 
a person’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be immediately life threatening, or require 
hospitalization may be considered to be SAEs when, based upon appropriate medical judgment, 
may jeopardize the patient and may require intervention to prevent one of the other outcomes 
listed above. 
Admission to a hospital or an inpatient unit for a non-medical reason (i.e., social stay admission) 
during the study in the absence of untoward medical occurrence will not be considered as an 
SAE.  
Hospitalization due to worsening of behavioral health related issues should be reported as an 
SAE. 
11.3. 
Reporting of Serious Adverse Events and Pregnancy 
Investigator is responsible for timely reporting of Adverse Drug Experiences, Serious Adverse 
Drug Experiences and pregnancy in a Study patient to the Food and Drug Administration (FDA), 
Institutional Review Board (IRB), data safety monitoring board, Institution, grant agency, etc. as 
applicable to the Study and according to FDA, Institution and/or grant agency guidelines and 
procedures. 


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12. 
STATISTICS 
12.1.1. 
Sample Size Considerations 
Ninety first-episode patients will be randomized (1:1) fashion to either AL-LAI or ARI-ORAL, 
and based on our previous RCT, assume a 20% attrition rate over 12 months. Statistical power 
considerations are based on the effect sizes observed when comparing long-acting injectable 
risperidone vs. oral risperidone (survival analysis for psychotic relapse: 5% relapse in the 
risperidone long-acting injectable group and 33% relapse in the oral risperidone group). On the 
basis of hazard function rates of 5.0% (AL-LAI) and 33% (ARI-ORAL), the study has 87% 
power (α=0.05). On a more conservative basis of hazard function rates of 7.5% (AL-LAI) and 
33% (ARI-ORAL), the study has 78% power (α=0.05) (Table 6). 
For the secondary hypothesis for the relative changes in the MCCB Composite score and the 
GFS: Role, we will use a two-sided significance level of α=.025 to account for type 1 error 
inflation. For the MCCB Composite score, assuming a within-patient correlation between 
repeated measurements of r=0.89 (based on a prior study), the proposed design provides us 
sufficient power (>=0.80) for Group X Time interaction effects as small as Cohen’s f=0.09. 
Based on our previous work, we anticipate a medium effect size (Cohen’s f=0.25 or d=0.50), and 
this design provides a power of >0.99 for an effect of this size. For the GFS rating, if we assume 
a within-patient correlation of r=0.5, with α=0.025, our GLMM will have 80% power to detect 
an interaction corresponding to an effect size of f=.20. Based on a prior study, we anticipate an 
effect size of f=0.32 or d=0.63 for the GFS: Role ratings, for which we would have >99% power.  
Thus, for both primary and secondary outcome measures we will be able to detect differential 
treatment effects based on our proposed design and expected sample size.  


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Table 7: 
Power Calculations by Analysis with N=35 Each Group (N=28 at completion) 
Clinical assumption for each group 
Power 
Alpha  
Primary Analyses 
Hazard ratio 
between the two 
groups 
Difference in hazard functions similar 
to that of our previous RCT: Long-
acting injectable: 5%, oral 
antipsychotic: 33% 
87% 
.05 
 
For rates of hazard function rates of 
7.5% (AL-LAI) and 33% (ARI-ORAL) 
78% 
 
Secondary 
Analyses: MCCB 
Overall Composite 
score 
change from BL in 
MCCB Overall 
Composite score 
Based on our previous work, we 
anticipate a medium effect size 
(Cohen’s f=.25 or d=.50) 
>99% 
.025 
Secondary 
Analyses: GFS Role 
Functioning 
Change from BL in 
GFS Role 
Functioning 
Based on a prior RCT, we anticipate an 
effect size of f=.32 or d=.63 for the 
GFS: Role ratings.  
>99% 
.025 
12.2. 
General Statistical Methodology 
12.2.1. 
Intent-to-Treat Population 
The Intent-to-treat (ITT) population will include all patients in the AL-LAI group who received 
at least one dose of AL-LAI, and all patients in the ARI-ORAL antipsychotic medication group 
who filled at least one prescription of ARI-ORAL after random treatment assignment. This 
population will be used for efficacy and safety analyses. 
12.2.2. 
Medication Adherence as a Dimension 
The measurement of medication adherence (see Section 8.2) will allow analyses within the oral 
medication group, as well as within the total combined sample, to examine the relationship of the 
variables of interest with degree of medication adherence.  
12.3. 
Demographics and Baseline Data 
Demographics and baseline characteristics such as gender, age, race, weight, height, and body-
mass index will be summarized using descriptive statistics. Medical history will be summarized 
using the number of observations and percentage of patients reporting each category. 
Concomitant medications as well as any protocol deviations will be recorded.  
12.4. 
Efficacy Analysis 
The primary hypothesis, that the hazard function (i.e. the risk of an event per unit of time) of the 
two medication groups differs between AL-LAI than the ARI-ORAL group, will be examined in 
a Cox regression analysis on the time to first relapse. We will include medication group 
membership, participation status in the NIMH exercise study, and length of stabilization period 
as predictors in the model. 
For the secondary hypotheses involving the MCCB composite score, the GFS: (Role) we will use 
general linear mixed models (GLMMs). We will include participation status in the NIMH 
exercise study, medication group as a between-patient variable and time as a within-patient 


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variable in the model, and time*group as a within-between interaction term. Additionally, we 
will include length of stabilization period as person level time invariant covariate. The primary 
effect of interest is the difference in the pattern of change over time of the dependent variable 
between the medication groups, i.e. the time*group interaction term. GLMMs properly account 
for correlations induced by repeated measurements within patients and automatically handle 
missing data, producing unbiased estimates as long as observations are missing at random. The 
GLMM will use Satterthwaite’s approximation to estimate degrees of freedom for the tests of the 
fixed and random effects, and model the variance-covariance matrix as a Toeplitz matrix. If this 
assumption does not lead to convergence we will instead use compound symmetry. The 
secondary analyses will compare the change in the MCCB Composite score and GFS: (Role) 
ratings between the two medication groups over the 12-month study period.  
The data analyses for the exploratory measures will parallel those of the secondary measures.  
All statistical tests and confidence intervals, unless stated otherwise, will be two-sided and will 
be set at α=0.05.  
12.5. 
Safety and Tolerability Analyses 
The following safety and tolerability measures monitored throughout the study and summarized: 
• AEs  
• EPS Scales (AIMS, BARS, and ESRS-A) 
• Presence of akathisia  
• C-SSRS 
 


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13. 
ETHICAL CONSIDERATIONS 
13.1. 
Ethics Review 
The study, the informed consent procedures, and the informed consent form (ICF) must be 
approved by the UCLA IRB prior to enrolling patients into the study. The Investigator is 
responsible for submitting all protocol changes and SAE reports to the IRB according to local 
procedures. At a minimum, all SAEs requiring an investigational new drug safety report must be 
immediately reported according to IRB requirements. 
13.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol and all applicable local regulatory 
requirements. UCLA is committed to assuring that the rights, safety, and well-being of study 
patients will be protected, consistent with the principles having their origin in the Declaration of 
Helsinki.  
13.3. 
Written Informed Consent 
Each prospective patient (or the patient’s legal representative) will be given full and adequate 
oral and written information about the nature, purpose, potential and possible risks and benefits 
of the study. Each prospective patient will receive an IRB-approved ICF that summarizes the 
pertinent study information and will be given ample time to read the form and ask questions 
about the study. All information is to be provided in a language understandable to the patient and 
must not include any language that waives the patient’s legal rights. Prospective patients must 
also be informed of their right to withdraw consent without prejudice at any time during the 
study. If the patient chooses to participate, he or she must sign the ICF before any study-specific 
procedures are conducted. The Investigator must maintain the original signed ICF in the patient’s 
source documents. A copy of the signed ICF must be given to the patient. 
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and approved by the IRB. The revised ICF will be signed by 
current patients for who the significantly revised procedures and risks apply.  


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14. 
DATA HANDLING AND RECORD KEEPING 
Quality control of data, protocol deviation process, data monitoring and auditing will be UCLA 
standard operating procedures and/or IRB requirements. 
14.1. 
Data Capture 
The Semel Institute Biostatistics Core (SIStat) will be responsible for study data management, 
storage, and statistical analysis. SIStat has developed and maintains a centralized database for the 
PI’s projects that is available on a secure, password-protected dynamic website on the Internet. 
All systems are on the UCLA network and reside behind the UCLA School of Medicine 
(Mednet) firewall. All the SIStat servers have 128-bit SSL certificates installed to provide 
security for transmission of any sensitive or confidential data. Administrative control is built into 
the databases by establishing password-protected classes of users with access privileges 
appropriate to their study roles. The systems support both manual entry and electronic upload of 
data generated by external sources. Use of a centralized LAN makes the data instantly available 
to all authorized researcher personnel. Data or summary reports are immediately available for 
viewing and automatically “updated” as the database changes. Extensive JavaScript-based 
validity checking is built in to maximize data quality.  
 


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