Comprehensive Treatment of Early Course Schizophrenia: A Nonrandomized Study of Long Acting Injectable Antipsychotic Medication Combined With Cognitive and Functional Skills Training
Phase: PHASE4
Conditions: Schizophrenia
Sponsor: University of Miami

Comprehensive Treatment of Early Course 
Schizophrenia:
A Nonrandomized Study of Long Acting Injectable 
Antipsychotic Medication Combined with Cognitive 
and Functional Skills Training
IRB Protocol ID Number:
20211098
Principal Investigator:
Dante Durand, MD
Co-Investigator:
Philip Harvey, PhD
Funded by:
Alkermes Inc.
Version Number:
V 11
Version Date:
01 April 2024
NCT Number:
NCT05662306
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Comprehensive Treatment of Early Course Schizophrenia
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Rationale. 
First episode patients with schizophrenia are very likely to respond well to antipsychotic medications at 
their first treatment1.  However, attaining clinical remission does not guarantee either functional 
recovery or sustained remission2.  The failure to sustain remission is nearly always due to failures to 
maintain adherence to treatment3.  Failure to achieve functional recovery is due to the fact that sustained 
remission is only one of several factors that are required to achieve recovery, including skills training 
and other elements of support4.  Functional recovery rates at the time of the first episode of 
schizophrenia are below 20% when standard pharmacological treatments are relied as the primary 
intervention.
There are potential solutions to the shortcomings of prior treatment for first episode schizophrenia.  For 
instance, the use of long-acting injectable medications has been shown to have substantial benefits for 
early-course patients, similar to their substantial benefits for more chronic patients5.  Several studies 
have shown notable evidence of sustained clinical remission and improvement of both brain structure6 
and cognitive functioning7 in first episode schizophrenia patients receiving these treatments.  
Accessibility and patient (and family) acceptance of the treatments are current barriers to greater use of 
these medications in first episode schizophrenia.  However, in some studies, acceptance of LAI was as 
high as 70%8.
As far as solutions to enhance recovery, combined treatments with psychosocial interventions and 
computerized cognitive training, referred to as cognitive remediation, have led to substantial gains in 
chromic patients9-10  with even greater gains in early-course patients11.   In a recent study of first episode 
patients12, combined LAI treatment, cognitive remediation, and skills training led to substantially higher 
rates of return to work and school than interventions that did not contain all three of the components. 
These gains have actually translated into improved social outcomes.  As the participants in the Ventura 
et al. study were all receiving background psychosocial interventions, this suggests again that a 
combined therapy may be the best approach.
More than with LAI interventions, combined psychosocial and cognitive remediation interventions have 
had limited access.  One possible reason is cost, in that in-person delivered skills training requires a 
trained professional and may not be covered by insurance.  While computerized cognitive training is 
now available and inexpensive, skills training interventions have lagged behind, possibly because they 
need to be focused on specific skills, rather than on the global target of cognitive performance.  In this 
study, we will use a newly developed13 and recently validated14 computerized functional skills 
assessment and training program to deliver skills training in concert with computerized cognitive 
training.
Specific Issues impacting Efficacy of Computerized Cognitive training.
Although meta-analyses have suggested that computerized cognitive training has efficacy in wide-
ranging samples of people with schizophrenia15, there have been some negative studies.  One of the 
common themes of the failed studies is that of poor engagement on the part of some trainees16.  As we 
reported, participants with early course schizophrenia, bipolar disorder, and major depression manifested 
training gains that were correlated with the average of training gains per training day, with number of 
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days trained not correlated with gains17.  Further, in a study of people with MCI trained with the skills 
training software, the average gain in time to completion per training session ranged 0.8% to 9%, with 
a median score of 5%.18 Thus, we will monitor both cognitive and skills training in real time to identify 
participants who are not exerting adequate effort.
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Special Features of the Protocol.
End of Study
(Week 48)
Study Aristada Lauroxil 1064mg injection discontinued; PT can continue LAI under standard of care
Follow-up Period
(Week 13 - 47)
4 clinic visits following interventional period
Aristada Lauroxil 1064mg continues to be 
administered every 2 months 
Intervention
(Baseline - Week 12)
4 clinic visits following baseline
-12 weeks (3 surveys 3x per week) of at-home 
cognitive and functional skills training
-Aristada Lauroxil 1064mg IM at Day 56 (Wk 8)
Baseline Visit
Aristada Initio & Aristada Lauroxil (1064mg) intramuscular (IM) injections administered
Screening Visit 
(at least 1 week prior to baseline)
Eligibility determined by study doctor
Lead-in period with oral aripiprazole to determine 
tolerability prior to LAI administration (if treatment 
naive)
Enrollment
Recruitment of early course schizophrenia 
participants (n=60)
Informed Consent completed by participant and their 
informant
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In this study we intend to offer an enhanced intervention compared to treatment as usual and to offer it 
to all patients who are being discharged from the hospital who meet inclusion criteria as described 
below.  In this intervention, we will offer Aristada Initio®  combined with Aristada Lauroxil ® 2-month 
(1064 mg) at the time of discharge to early course patients. We will also offer a bundled cognitive and 
functional skills training program. Patients who are discharged from the inpatient services can receive 
computerized cognitive training through our clinical services.  However, the computerized functional 
skills training software is not currently delivered at JHS and there is presently no systematized process 
by which newly discharged patients are referred for the training-based interventions, probably because 
clinicians are uncertain about the benefits.   
As a result, participants who are eligible and agree to participate will receive long-acting injectable 
treatment and will be followed for at least one year with clinical and functional assessments.  The skills 
and cognitive training program will be offered for 12 weeks, which is a standard course of cognitive 
remediation treatment.  We will index improvement in cognition and functional skills with a structured 
cognitive and functional assessment at entry to the study, after the 12 weeks of training, and at the end 
of the one-year period.  Functional assessments will be used to index functional recovery.  Clinical 
assessments using the PANSS will be used to examine symptomatic remission and emergency room 
visits, changes in levels of care, and other milestones will be used to index general clinical stability.
It is difficult to index the extent to which participants will choose to enter the enhanced care research 
study.  Studies cited above have suggested as many as 70% of similar participants chose the LAI option 
when offered.  Given the base-rates of acceptance of other service offers following discharge from JHS, 
we are anticipating an approximately 30% acceptance rate per admission.  As a we will use a rolling 
entry design, such that participants who decline to participate are recruited at their next admission. Work 
to date shows our expected patient flow.  As noted in specific aims, we anticipate that the earlier a 
participant accepts participation, the better their outcome will be in terms of remission, recovery, and 
cognitive and functional capacity performance.
Methods.
Study Design:
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Overview.  We plan on a sample of 40 early-course patients with schizophrenia who will complete the 
pharmacological and training interventions.  We anticipate that we will need to recruit 60 participants to 
identify this sample of 40 who meaningfully participate in program.  This sample size is selected it is 
practical to recruit, assess, and follow this sample. They will be recruited at discharge from an acute 
admission or from outpatients who have experienced a relapse after successful treatment. First, eligible 
subjects will undergo a lead-in period with oral aripiprazole (if treatment naïve) for at least 7 days.  The  
participant will be provided/prescribed the complimentary generic oral aripiprazole by one of our study 
psychiatrists. They will be assessed at baseline, with clinical, cognitive, and functional assessments, 
after which they will be treated with the long-acting injectable version of aripiprazole also known by its 
brand name Aristada Initio and Aristada Lauroxil.  They will receive an initial treatment with an 
injection of Aristada Initio (675mg) and Aristada Lauroxil 2-month formulation (1064 mg).  They will 
receive cognitive and functional skills training for a three-month period and will be followed up for 12 
months, while receiving injections of Aristada Lauroxil 1064mg every 8 weeks.  Primary outcomes will 
be sustained clinical remission and evidence of progress toward functional recovery, with secondary 
outcomes being performance-based assessments of cognition and functional capacity.
Participants: Male and female inpatients with a DSM-V diagnosis of schizophrenia will be recruited.  
They will have been discharged from inpatient admissions three or fewer times prior to the current 
episode, unless their total duration of illness is less than 2 years, in which case they will be considered 
eligible.  We will prioritize recruitment of patients who have informants available and willing to 
participate.  We anticipate that we will be able to retain 40 patients to completion if we recruit 60 
participants. Patients will be contacted to complete an eligibility screener over the phone per the phone 
• Comprehensive treatment of early course schizophrenia using 
long acting injectibles with computerized cognitive and 
functional skills training.
Primary Purpose
• Single group, offered to all patients discharged from the 
hospital who meet the criteria for the study.
Interventional 
Study Model
• We will not be masking in this study since the medication and 
computerized cognitive and functional skills training will be 
administered to all participants.
Masking
• Nonrandomized
Allocation
• Total enrollment of 60, with anticipation that 40 of these 
early-course patients with schizophrenia will meaningfully 
participate in the program.
Enrollment
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screening script. Only patients who have expressed interest in participating in the study will be contacted 
to complete an eligibility screener. 
We will be including the use of MyUHealthChart as a recruitment tool to the study. This tool will 
allow study team members to send recruitment messages to UHealth patients who agreed to be 
contacted if there are studies where they meet the initial study eligibility criteria. Including the 
UMiamiHealthResearch.org (the URL): https://umiamihealthresearch.org/studies/20211098 Please 
review the following documents for further information on this procedure: 1) C-Cog_UMHR_InfoPage 
& 2) C-Cog_UMHR_InclExcl.
Diagnostic Assessment. We will use the Mini International Neuropsychiatric inventory (MINI19) to 
confirm the diagnosis.  
Clinical Assessments.  We will use the Positive and Negative Syndrome Scale  (PANSS 20 ) to assess 
clinical symptoms of schizophrenia. We will use the Columbia Suicide Severity Rating Scale (CSSRS21) 
to examine suicidal ideation and behavior.
Cognitive Assessment.  We will use the Brief Assessment of Cognition-iPad app version (iPad BAC22).  
This fully automated app will be administered at baseline, end of the training protocol, and at the one-
year follow-up. There are six tests in the i-Pad BAC and they are automatically scored and recorded.  
Dependent variable will be the composite score. There are six different forms of the BAC and we will 
use three different versions for this study.
Functional Capacity Assessment. We will employ the Virtual reality Functional Capacity Assessment 
Tool, iPad version (VRFCAT23). The VRFCAT measures four different functional abilities: checking for 
the availability of items to complete a recipe, taking a bus, shopping in a store, and managing currency.  
There are 12 different objectives and for each objective the dependent variable is time to completion.  
There are six different forms of the VRFCAT and we will use three different versions for this study.
Functional Assessment.   There are multiple possible functional rating scales, but many are not suitable 
for early course assessments. We will use the SOFAS24.  The SOFAS was the scale used in the 
Singapore high risk study.  It performed remarkably in the study, identifying baseline differences 
between controls and high-risk cases.  Further, it also was sensitive to both decline in the converters and 
improvements in the remitters.  It also showed convergence in course with cognitive performance.  it 
meets all of the criteria that a scale should have. It requires someone who knows the participants well 
enough to generate ratings, but self-reports are dubious in any case.
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Definition of Remission.   We will use the widely adopted Andreasen et al. criteria for remission. The 
clinical information will come from the PANSS25. In order to meet criteria for remission, subjects had to 
have scores of 3 (Mild) or less on all of the critical PANSS (Delusions (P1), Hallucinations (P3), 
Unusual Thought Content (G9), Conceptual Disorganization (P2), Mannerisms and Posturing (G5), 
Blunted Affect (N1), Social Withdrawal (N4), and Lack of Spontaneity (N6).  This determination will 
initially be made at the 6-month follow-up of the patients, thus requiring that patients be in remission 6 
months after initiating treatment with Aristada Lauroxil regimen. 
Definition of Recovery.  By its definition, recovery is a long-term concept and not suitably addressed in 
a one-year study. We will define progress toward remission based on our previously published criteria 
for functional remission26.  We will identify the proportion of cases who are making progress and 
achieving success across functional domains.  Information for these determinations will come from the 
SOFAS assessments conducted with their informants.  The SOFAS is well suited for collection of these 
data because the assessment is structured to examine these three central domains of everyday 
functioning.  As noted above, the SOFAs has shown excellent sensitivity in informant-based interviews 
in cases whose clinical and functional state was fluctuating.
Interventions
This is a single group study. All participants will be given the same dose of the LAI (unless study doctor 
determines it is in the best interest of the patient to have the dose reduced, unrelated to an independent 
study arm) and will be administered both of the following computerized cognitive and functional 
interventions:
Computerized Cognitive Training. The CCT training will consist of the Posit Science Brain HQ CCT 
Double Decision. Double Decision was the training protocol in the ACTIVE study27 that was associated 
with major and persistent cognitive gains after 14 hours of training in healthy older people. We choose 
this CCT package as it is evidence-based, easily deliverable without customization, and accessible to 
schizophrenia participants as evidenced by our prior studies. The initial training will take place at the 
data collection site (i.e., Brain Fitness Center at UM) until the participant demonstrates an ability to use 
Study Endpoint
Primary Outcome Measure: Functional 
Remission of General Schizophrenia 
Score
• Description: The Positive and Negative 
Syndrome Scale (PANSS) is a # item scale where 
a score of 3 or less would indicate remission
• Measure Timeframe: 6 month follow-up
Exploratory Outcome Measure: 
Functional Recovery of General 
Schizophrenia
• Description: Participants continuing to make 
progress and achieve success across functional 
domains, measured by the informant's SOFAS 
assessment, in comparison to available data
• Measure Timeframe: 12 month follow- up
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the program independently. Once it is established that they can launch the program and proceed through 
the modules, training will occur in the participants’ home setting. 
Functional Skills Assessment and Training (FUNSAT).  This training system was developed at UM 
and contain six different modules: ATM and Internet Banking, Telephone and Internet prescription 
Refill, Ticket Kiosk Purchase, and Medication Management. FUNSAT is being delivered on a tablet 
device or a full-size laptop or desktop computer. The FUNSAT training consists of six separate training 
modules, which include subtasks increasing in difficulty, covering 4 different functional skill domains.  
Training occurs over 12 weeks with a recommended dose of two, one-hour sessions per week, which are 
split between 30 minutes of skills training and 30 minutes of Brain HQ.
 
Study Assessments and Procedures
 
Participants will train on two FUNSAT tasks per day, with the order of training determined by the 
program. The training component will: 1) Identify the current levels of an individual’s ability on the 
functional task of interest with Item response theory (IRT)-based  strategies and start training there; 2) 
Use dynamic-titration feedback from immediately proximal task performance to adjust the difficulty of 
task demands to optimize training potential; and 3) Provide immediate trial by trial feedback and, most 
critically, instructional responses following errors, followed by repetition of the previously failed item.  
Training occurs on the FUNSAT until they “graduate” from the program or 12 weeks has elapsed. We 
are defining “graduation” on a task as the completion of all of the modules of the task two times in a row 
with no more than one error per module.  This definition captures task completion without any 
instructions, because a single error in the training conditions leads only to repetition of the instructions. 
Thus, “graduation” from the program as a whole means that the participant has completed all tasks twice 
in a row with no more than one error per module. After graduation participants will continue to train for 
their full complement of 24 sessions on Brain HQ.
Figure 4
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Measurement of Training Engagement.  As noted above failure to engage in training leads to poor 
gains.  Both of our training software programs allow for remote monitoring or training engagement, 
through cloud-based portals.  We have identified threshold levels for minimal training engagement and 
will provide feedback to all participants who are training below that level.  Subthreshold trainees will be 
encouraged to make more effort, but we will not eliminate them from the study, in order to be able to 
relate levels of engagement to training gains, cognitive improvements, and remission and recovery.  
Study coordinators will send messages to trainees who are not making progress in training.
Pharmacological Treatment Protocol. 
For patients who have never taken aripiprazole, the participant—with prescription from our study 
psychiatrist --will establish tolerability with oral aripiprazole prior to initiating treatment with Aristada 
® Initio. Due to the half-life of oral aripiprazole, it may take at least 7 days to assess tolerability (lead-in 
period). After establishing tolerability with oral aripiprazole, we will administer the first Aristada 
intramuscular injection (1064 mg) in conjunction with both: One 675 mg injection of Aristada Initio ® 
in the deltoid or gluteal muscle. We will aim for concurrent administration to minimize non-adherence 
to the protocol.   Subsequent 8-week injections of Aristada Lauroxil ® 1064 mg will be scheduled and 
will coincide with assessment visits (See schedule of events).  We will only adjust the Aristada Lauroxil 
® dose based on tolerability, as this dose is required for full 8-week duration of efficacy. This may 
require the participant to adjust his/her injection frequency to maintain clinical efficacy.
Ecological Momentary Assessment (EMA) surveys
Participants will be asked to complete ecological momentary assessment (EMA) surveys on a smart 
device, either their own or one provided by the investigators. Surveys will be sent 3 times per day, 3 
days per week, during the 12-week cognitive and skills training period. Thus a total of 108 possible 
surveys will be sent. The window to answer the survey will be 60 minutes, with reminders every 15 
minutes. Days where there are no surveys answered will be pushed to the next day and the entire 
procedure survey will be repeated verbatim, so that at least one survey is answered every day. The time 
frame for the survey is “Today” for the first survey and “In the last hour” for the next two. Participants 
are asked about their typical wake-up hour and the first survey is launched one hour or more after this 
time. The EMA application will be downloaded from the App Store and will not interact in any way 
with any of the other applications on the participants’ phones. Data will be uploaded directly to an 
Amazon Web Services (AWS) encrypted portal. No personal health information is attached to the 
surveys.
Surveys begin with a query regarding location (home vs away) and social context (alone vs. with 
someone). Then a customized activity survey is presented, customized for the combination of location 
and social context (home alone, home with someone, away). Following the activity survey, 4 mood 
questions are asked (Happy, Sad, Relaxed, anxious) and rated for intensity.  Then four psychosis 
questions will be asked (Hearing voices, feeling paranoid, getting messages, having special powers), 
which are answered on a yes/no basis. Surveys take approximately 3 minutes to answer, and participants 
are compensated $1.00 per survey, payable at their next in-person visit.
Inclusion criteria
Adults (Age 18 years and older)
Fluent and literate in English and able to consent
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Diagnosis of schizophrenia (Confirmed by the M.I.N.I. assessment)
Current Hospitalization or outpatient relapse
Fewer than four previous admissions 
Willing to accept long-acting injectable treatment and participate in rehabilitation
Willing to undergo a lead-in period of oral aripiprazole (if treatment naïve)
Informant willing to participate
Participant willing and able to provide written informed consent
Exclusion Criteria
Primary diagnosis other than schizophrenia
Prior failed or intolerable LAI treatment
Current Suicide Risk
Hypersensitivity to Aripiprazole
Pregnancy
Positive illicit drug screen other than cannabis (rescreening allowed in 4 weeks for drug positive cases)
Unable to give personal informed consent
History of treatment resistance as evidenced by clozapine treatment
Unable to stop treatment with medications that are strong CYP2D6 or CYP 3A4 inhibitors and or strong 
CYP3A4 inducers (2.3, 7.1) for at 14 days prior to initiation. 
Have any condition that, in the opinion of the investigator, would compromise the well-being of the 
patient or the study or prevent the patient from meeting or performing study requirements.
Side Effect Assessment. As the occurrence of significant side effects with Aristada Lauroxil has been 
reported to be low: insomnia (8.4%), increased weight (5.0%), Akathisia in (3.8%), and AEs related to 
metabolic parameters (4.6%) of patients, we will not perform formal side effects rating scales but rather 
will inquire at visits about sleep, akathisia, and weight gain using structured queries.
General Methodological Approach.  Providers from both UM and Jackson will introduce the research 
to patients under a physician-patient relationship. If a patient is interested in learning more about the 
study, the provider will reach out to the study team with the patient’s permission (ie. Using a pre-
screening authorization form). The designated study team member will approach interested inpatients or 
outpatients at JMH who we know to possibly meet criteria and explain the study to them and their 
caregivers/informants.  All interested participants will have the procedures explained by designated 
study staff.  Patients who meet criteria and are eligible and interested will sign an informed consent form 
approved by the University of Miami Institutional Review Board. Initial assessments will be performed 
by trained study coordinators.  Those participants meeting diagnostic criteria will receive PANSS and 
CSSRS assessments performed by the same coordinators. Assessments of cognition and functional 
capacity and the SOFAS will be performed by different assessors. Testing of tolerability, if needed,  will 
happen as soon as informed consent is obtained. Injections of Aristada Initio and Aristada Lauroxil will 
be administered immediately after baseline assessments of cognition, clinical symptoms, and everyday 
functioning.  
Individuals who decline to participate will be approached after any readmissions to JHS and offered the 
opportunity to join the study at that time.  Potential participants will be approached at all future 
admissions.  Further, the “admissions clock” will not advance for these cases after the first time that they 
are approached for participation, such that a potential participant with three previous admissions when 
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they are first approached will not be disqualified from participation regardless of the number of 
additional admissions they experience prior to agreement to participate.
Reassessments will be performed in line with the schedule of events below.  There are a total of 11 in 
person assessments over the one-year study period. After the first 4 weeks of the protocol these 
assessments are linked to injection events. Training will start at the Brain Fitness Pavilion at UM, in the 
same building as the inpatient units at JHS, and training will be delivered in person by the staff at the 
Pavilion.  These trained staff members will also determine when they believe that the participants are 
ready to train at home.  When they are ready, the participants will be provided with a tablet device and 
an account for FUNSAT and Brain HQ, both of which are accessed through the cloud.  
In order to avoid recruiting participants who are overly interested in receiving compensation and not 
interested in training gains, we will not compensate participants for training sessions. Instead, we will 
compensate participants based on training gains. Further, there are no payments for screening and 
payments for in-person assessments (visits 3-12) are budgeted at $25.00 each other than baseline, which 
will be compensated at $50.00 because of its length.  Each of the 6 simulations graduated by the 
participants will lead to a payment of $20.00.  As Brain HQ training happens the same time as skills 
training, we will not be compensating participants for Brain HQ training until after graduation from all 6 
skills training modules.  
Participants who no longer want to continue training will be continued in the pharmacological protocol 
if they want to.  They will be allowed to resume training at any time in the 12 months after their study 
entry.
Data Management
We will use UM REDCap to capture the clinical assessment data and retain de-identified variables for 
this research project. Source documents will be retained in paper format in appropriate study binders. 
We will keep a scanned copy of source documents in BOX. Data from the BAC-App, VRFCAT, Brain 
HQ, and Funsat are directly uploaded to the cloud (Microsoft® Azure) and are stored without identifiers.
Statistical Approach. 
A sample size of 40 participants is generally consistent with the ability to identify a moderate effect size 
compared to other treatments.   However, we will compare our results to previous outcomes because of 
the lack of a control group (due to cost).  Previous data regarding rates of functional recovery for first 
episode patients are 15-20%.  Thus, if compare our expected rate of recovery, based on the results of the 
UCLA studies, as 60% compared to 18%, we find that at p<.05, n=40, power =1.0 for detecting this 
difference.  If we drop our expected recovery rate to 50%, power=.95, and if we drop it to 40%, double 
the previous rates, power is .90.
In this study we collect both categorical information (Remission, Y/N; Recovery, Y/N) and quantitative 
data (PANSS scores, Cognitive Performance, Functional capacity performance, and Functional 
outcomes ratings).  There are also several covariates, such number of previous admissions, 
demographics, and the number of times participation was offered to the participant before they agree to 
participate.
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For the categorical information, we will use Logistic regression models for binary outcomes.  For the 
quantitative variables we will use a Mixed Model Repeated Measures (MMRM) to compare changes in 
the outcomes variables across visits and to evaluate possible covariate influences.
PANSS total and subscale scores are collected at all visits from 2-12.  Cognitive performance, VRFCAT 
performance, and SOFAS scores are collected at visits 2, 7, and 12.  
We will examine the time course of clinical response on the PANSS from visits 2-12 using MMRM.  
To examine reduced risk of relapse, a Cox proportional Hazards model (i.e., survival analysis) will 
examine the group who agreed to participate to those who declined participation for time to readmission 
to the hospital.  The dichotomous variable of relapse will be the outcomes measure.
In order to evaluate continued improvement on the BAC app and the VRFCATs across visits, we will 
again use MMRM, with subject as a random term and treatment engagement as the covariate.  These 
analyses will be run separately for the cognitive and functional capacity outcomes.  
In order to evaluate prevalence of functional recovery compared to prior standards, we will compare the 
proportion of cases who manifest evidence of functional recovery at their final assessment to previous 
standards.  We will compare the observed proportion of recovery and compare it to a very liberal prior 
criterion of 20% and use a Mantel Hansel test to compare the two proportions.  
Protection of Human Subjects. We will use all possible means to ensure protection of human subjects.  
We will collect signed informed consent from all participants. As we are offering approved medication 
treatments at approved doses, as well as only performing assessments that are in common clinical use, 
the risks of this project are no greater than standard clinical treatments.  Similarly, both the skills and 
cognitive training protocols have been designated as no more than minimal risk for participants by the 
UM IRB in a previous study.
Risks.
The treatments in this study are approved by the US Food and Drug Administration for treatment of 
schizophrenia at the doses administered.  As a result, treatments are in common clinical use and there 
are no more risks than those associated with standard treatments for the condition.  The assessments 
used are also in common clinical use, as are all of the digital treatments delivered. Thus, the only risks 
associated with research participation are threats to confidentiality and avoidance of coercion.  All 
assessments and training procedures that use the cloud have met CFAR part 21 compliance for data 
collection and storage of data.  Signed consent documents will be stored in a locked cabinet in an office 
that is not on the treatment unit nor at the Brain Fitness Center.
We will not use the treating MD or ARNP as the recruiter for the study, so that no one will be recruiting 
their own patients. Consent will be collected by a study team member who has no clinical connection 
with the participants. We will obtain a partial HIPPA waiver so that we can identify potential 
participants from their medical records and be prepared to recruit them when they are readmitted.
Potential participants who decline to participate will be approached with the same recruitment strategies 
if they are readmitted to JHS. They will also be informed that if they want to enroll after discharge, they 
can contact the study team and enter the study at any time if they remain qualified for the study. 
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This trial will be posted on clinicaltrials.gov as soon as the agreement between UM and the sponsor is 
finalized.
Adverse Events:
Almost all research studies involve some risk. These medication treatments, Aristada Initio® and 
Aristada Lauroxil®, have already been approved for this condition and the reported occurrence of side 
effects is low for both:

Akathisia

Insomnia

Weight gain

Problems with metabolism (increased cholesterol, triglycerides, or hyperglycemia)
Serious Adverse Events:
Important safety information about serious adverse events for Aristada Initio® and Aristada Lauroxil® 
that would result in hospitalization or serious medical emergencies are less common, but rare instances 
that have occurred to other patients on these medications are listed below:

Cerebrovascular problems

Neuroleptic Malignant Syndrome

Tardive Dyskinesia

Uncontrollable compulsive urges

Orthostatic hypotension

Risk of falls

Low white blood cell count

Convulsions

Problems controlling body temperature

Difficulty swallowing
Confidentiality.
All information will be kept confidential. All source documents will be kept in a locked cabinet. Only 
UM-approved applications will be used to store de-identified information electronically such as UM BOX 
and UM REDCap, other than the Cloud-Based data collection for the digital measures. 
We are requesting a partial HIPAA waiver to recruit patients at Jackson and UM. In order to follow up 
with potential Jackson patients who may qualify, we are requesting access to a secure JHS SharePoint to 
maintain name and contact information for potential patients. Patients will sign an appropriate 
authorization for pre-screening for the study. 
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Choose the statements below that are applicable to this research: 
 15(a).   ☒  Data will be collected from the EMR or subjects at UHealth or JHS.  If checked, answer 
the following: 
   ☒ Research Subjects will sign a HIPAA Authorization before the research will collect 
this data. 
   ☐ Research Subjects will not sign a HIPAA Authorization for this data collection and the 
research is requesting a waiver of HIPAA authorization from the IRB.  (Complete 
Section 17 below)
   15(b).  Data collected:
 Will not include Protected Health information or Personally Identifiable Information
 Will include Protected Health information or Personally Identifiable Information
15(c).  How will the research store the data?                
☐  On a University of Miami electronic device (e.g. encrypted, password-protected computer)
☒  On a cloud-based storage system that is approved by the University of Miami 
☒  Other, specify:  paper source
Select one of the following: 
☐  The Principal Investigator (and/or Study Team members) will record (e.g. write down, 
abstract) data acquired in a manner that does not include any indirect or direct identifiers 
(listed in the instructions for Section 15 of this protocol), and the recorded data will not be 
linked to the individual’s’ identity.  
   OR
☒  The Principal investigator (and/or Study Team members) will record (e.g. write down, 
abstract) the data collected in a manner that does not include any direct identifiers (see list in 
the instructions for Section 15 of this protocol) of any subject. Instead, the Principal 
Investigator and/or Study Team members shall will assign a code (that is not derived in whole 
or in part from any direct or indirect identifiers of the individual) to each study subject and 
link the code to the study subject’s identity. The link to each subject’s identity and/ or 
other identifiable information will be maintained on a document separate from the 
research data. 
15d.  Jackson Health System additional requirement
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 This section is not applicable because the research is not collecting health information from JHS 
under a waiver of authorization (without obtaining a HIPAA authorization from the participant)
If health information, including Protected Health Information and/or Personally Identifiable Information 
are collected from JHS without a signed authorization from the subject (with a waiver of authorization 
from an IRB or Privacy Board), you must agree to the following:  
 JHS data, including Protected Health Information (PHI) and/or Personally Identifiable 
Information (PII), acquired from JHS for this research with a waiver of the requirement for 
an authorization under HIPAA shall only be stored on the secured JHS SharePoint 
environment made available by JHS. I and the Study Team members shall not copy or store 
the JHS sourced personally identifiable information (PII), including protected health 
information (PHI) data to any other system, including any systems maintained or provided 
by the University of Miami. I and the Study Team shall only copy or transfer JHS-sourced 
data that has been properly de-identified in accordance with all requirements contained in 
the HIPAA Rules by removing all of the identifiers listed in the instructions for Section 15 
of this protocol.
If the data obtained for this research will be acquired from a retrospective “chart review” involving health 
information from JHS with a waiver of authorization (without obtaining an signed HIPAA authorization 
from the subject) then the data and the link and/or key to each subject’s identity shall only be maintained 
in the secure JHS SharePoint environment made available by JHS. 
Provisions to Protect the Privacy Interests of Subjects
All authorized staff will be CITI-trained and will be limited to only 1-2 staff who 
are on the protocol as the main coordinators.  Any staff that will use UChart or 
Cerner will receive the appropriate trainings and clearance before receiving 
access. 
Waiver of Authorization for Use and Disclosure of Protected Health Information 
(HIPAA) 
 This section is not applicable, we are not requesting a waiver of authorization.  
We are requesting a partial HIPAA waiver. For Jackson patients, we will ask patients to sign a 
JHS pre-screening authorization form. 
A partial waiver of HIPAA authorization is requested to access medical records, in-person screening, 
and phone screening of potential participants for the purpose of pre-screening inclusion/exclusion 
criteria by Dr. Harvey or his backup in addition to study coordinators and research assistants. Pre-
screening: Potential participants will be given information about the study, asked brief screening 
questions conforming to the inclusion/exclusion criteria, and asked if they are willing to come in or be 
visited in the community to learn more about the study and undergo the informed consent process. For 
preparatory research for the phone screening, we are requesting a partial waiver of documented consent 
and partial waiver of HIPAA authorization, and requesting to obtain oral consent. PHI collected at 
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phone screening includes name, phone number to recontact after eligibility is determined, and email 
address to send directions to their first visit (if eligible). All PHI will be kept locked in the offices of the 
PIs or their study staff and only PIs and study staff will have access to PHI. This study cannot be 
conducted without partial waiver of consent and HIPAA authorization as it is necessary to collect PHI 
and screening questions in order to: determine eligibility, limit subject burden on those that are not 
eligible, and communicate (e.g., call back with eligibility status) with potential subjects. 
Confirm that you will destroy the Protected Health Information (PHI) you and/or your Study Team 
acquire receive from JHS and/or UHealth at the earliest opportunity. 
☒    I confirm 
Confirm that the Protected Health Inform (PHI) you acquire from JHS and/or UHealth will not be 
re-used or disclosed to any other person or entity, except as required by law or for authorized 
oversight of the research study or for other research for which the use or disclosure of PHI is 
permissible.           
☒     I confirm  
If you are collecting health information from JHS under a waiver of authorization, you must read the 
paragraph below and sign the signature block to indicate your agreement:  
Notwithstanding the preceding “I confirm” statements above, I agree that neither I nor any member of 
the study team listed on the IRB submission for this Protocol shall ever re-use or re-disclose any of the 
information acquired from Jackson Health System in any format, whether identifiable or de-identified, 
to any individual or entity without first obtaining written permission from Jackson Health System, even 
if such re-use or re-disclosure is permissible by law (e.g., HIPAA).
  
 
                   07/22/22
______________________________________________
PI Signature                                                               Date
Benefits.
In addition to providing commercially available long-acting injectables and cognitive trainings at no cost, 
participants would be monitored over the course of one year and actively monitored for suicidal ideations. 
The generalizable knowledge from evaluating the effect of combined therapy on patients with 
schizophrenia will help investigators advance future treatments. 
Compensation.
Participants will be paid by either cash or debit card or alternative method (e.g. Money order, gift card, 
Zelle). If by debit card, they will be issued a reloadable debit card that can be used for studies at the 
University of Miami. The study staff will provide information about how the card works. The card will 
be loaded according to the payment schedule. The company administering the card requires name, 
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address and date of birth entered online for payment; mobile phone number and/or email address are 
optional and only for study related communications. This information will only be used for payment and 
communication purposes and will not be given to another company or linked to any of the study data.
DSMB  
We will establish a DSMB from UM faculty members who have no connection with the protocol and no 
connection with i-Function.  As the trial is not randomized, there is no blind to protect.  As the medications 
are approved for their uses, all adverse events will be reported through the U.S. FDA surveillance system, 
as well as to the study sponsor.  
Resources Available
All study staff involved in subject assessments will be CITI-certified and IRB-approved. 
Each study team member will complete protocol and scales training with our investigator(s) 
or with our senior research staff. Our senior staff have 3-5 years of experience in psychiatric 
protocols and scale administration. 
Setting
All consenting and assessment administration will be done in our Psychiatry space at the Jackson 
Behavioral Health Building. The University of Miami has three rooms that are rented 3302A, B, 
and D. All procedures will be conducted in our UM space. 
Process to Document Consent in Writing
Documentation of the initial consent discussion and any re-consenting discussions must be adequately 
documented in the subject’s records and should include the following:

The subject’s current capacity to give informed consent should be evaluated and 
documented prior to the consenting discussion. Documentation should include how 
competency was evaluated.

Date of the consent discussion.

Statement confirming that no study-specific procedures were performed prior to obtaining 
informed consent or assent (if applicable).

Name of person conducting the consent discussion and the names of the persons involved 
in the consent discussion, and their relationship to the subject (e.g., subject, LAR, witness).

Summary of significant questions asked by the subject.

Statement confirming that the subject were given a copy of the fully-signed informed 
consent document.
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References
1. Robinson DG, Woerner MG, Alvir JM, et al. Predictors of treatment response from a first 
episode of schizophrenia or schizoaffective disorder. Am J Psychiatry. 1999;156(4):544–549. 
doi:10.1176/ajp.156.4.544
2. Lieberman JA, Koreen AR, Chakos M, et al. Factors influencing treatment response and 
outcome of first-episode schizophrenia: implications for understanding the pathophysiology of 
schizophrenia. J Clin Psychiatry. 1996;57 Suppl 9:5–9.
3. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first 
episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56(3):241–247. 
doi:10.1001/archpsyc.56.3.241
4. Nuechterlein KH, Subotnik KL, Ventura J, et al. Enhancing return to work or school after a first 
episode of schizophrenia: the UCLA RCT of Individual Placement and Support and Workplace 
Fundamentals Module training. Psychol Med. 2020;50(1):20–28. 
doi:10.1017/S0033291718003860
5. Subotnik KL, Casaus LR, Ventura J, et al. Long-Acting Injectable Risperidone for Relapse 
Prevention and Control of Breakthrough Symptoms After a Recent First Episode of 
Schizophrenia. A Randomized Clinical Trial. JAMA Psychiatry. 2015;72(8):822–829. 
doi:10.1001/jamapsychiatry.2015.0270
6. Bartzokis G, Lu PH, Raven EP, et al. Impact on intracortical myelination trajectory of long 
acting injection versus oral risperidone in first-episode schizophrenia. Schizophr Res. 
2012;140(1-3):122–128. doi:10.1016/j.schres.2012.06.036
7. Nuechterlein KH, Ventura J, Subotnik KL, Bartzokis G. The early longitudinal course of 
cognitive deficits in schizophrenia. J Clin Psychiatry. 2014;75 Suppl 2(0 2):25–29. 
doi:10.4088/JCP.13065.su1.06
8. Weiden PJ, Schooler NR, Weedon JC, Elmouchtari A, Sunakawa A, Goldfinger SM. A 
randomized controlled trial of long-acting injectable risperidone vs continuation on oral atypical 
antipsychotics for first-episode schizophrenia patients: initial adherence outcome. J Clin 
Psychiatry. 2009;70(10):1397–1406. doi:10.4088/JCP.09m05284yel
9. Bowie CR, McGurk SR, Mausbach B, Patterson TL, Harvey PD. Combined cognitive 
remediation and functional skills training for schizophrenia: effects on cognition, functional 
competence, and real-world behavior. Am J Psychiatry. 2012;169(7):710–718. 
doi:10.1176/appi.ajp.2012.11091337
10. Lindenmayer JP, Fregenti S, Kang G, et al. The relationship of cognitive improvement after 
cognitive remediation with social functioning in patients with schizophrenia and severe cognitive 
deficits. Schizophr Res. 2017;185:154-160. doi:10.1016/j.schres.2017.01.007
11. Bowie CR, Grossman M, Gupta M, Oyewumi LK, Harvey PD. Cognitive remediation in 
schizophrenia: efficacy and effectiveness in patients with early versus long-term course of 
illness. Early Interv Psychiatry. 2014;8(1):32–38. doi:10.1111/eip.12029
12. Nuechterlein KH, Ventura J, Subotnik KL, et al. A randomized controlled trial of cognitive 
remediation and long-acting injectable risperidone after a first episode of schizophrenia: 
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improving cognition and work/school functioning [published online ahead of print, 2020 Sep 
28]. Psychol Med. 2020;1-10. 
13. Czaja SJ, Loewenstein DA, Lee CC, Fu SH, Harvey PD. Assessing functional performance using 
computer-based simulations of everyday activities. Schizophr Res. 2017;183:130-136. 
doi:10.1016/j.schres.2016.11.014
14. Harvey PD, Tibiriçá L, Kallestrup P, Czaja S J. A Computerized Functional Skills Assessment 
and Training Program Targeting Technology Based Everyday Functional Skills. J. Vis. 
Exp. (156), e60330, doi:10.3791/60330 (2020).
15. Harvey PD, McGurk SR, Mahncke H, Wykes T. Controversies in Computerized Cognitive 
Training. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3(11):907–915. 
doi:10.1016/j.bpsc.2018.06.008
16. Mahncke HW, Kim SJ, Rose A, et al. Evaluation of a plasticity-based cognitive training program 
in schizophrenia: Results from the eCaesar trial. Schizophr Res. 2019;208:182–189. 
doi:10.1016/j.schres.2019.03.006
17. Harvey PD, Balzer AM, Kotwicki RJ. Training engagement, baseline cognitive functioning, and 
cognitive gains with computerized cognitive training: A cross-diagnostic study. Schizophr Res 
Cogn. 2019;19:100150. Published 2019 May 13. doi:10.1016/j.scog.2019.100150
18. Czaja SJ, Kallestrup P, Harvey PD. Evaluation of a Novel Technology-Based Program Designed 
to Assess and Train Everyday Skills in Older Adults. Innov Aging. 2020;4(6):igaa052. Published 
2020 Dec 9. doi:10.1093/geroni/igaa052
19. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, et al.  The Mini International Neuropsychiatric 
Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric 
interview. J. Clin. Psychiatry. 1998, 59:22–33.
20. Kay SR, Fiszbein A, Opler LA.. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr. Bull. 1987; 13, 261–276.
21. Posner K, Brown GK, Stanley B, et al.  The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am. J. Psychiat. 2011; 168:1266-1277.
22. Atkins AS, Tseng T, Vaughan A, et al. Validation of the tablet-administered Brief Assessment of 
Cognition (BAC App). Schizophr Res. 2017;181:100–106. doi:10.1016/j.schres.2016.10.010
23. Keefe RSE, Davis VG, Atkins AS, et al. Validation of a Computerized test of Functional 
Capacity. Schizophr Res. 2016;175(1-3):90–96. doi:10.1016/j.schres.2016.03.038
24. Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and 
acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment 
Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000;101(4):323–
329.
25. Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission 
in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 
2005;162(3):441–449. doi:10.1176/appi.ajp.162.3.441
26. Harvey PD, Bellack AS. Toward a terminology for functional recovery in schizophrenia: is 
functional remission a viable concept?. Schizophr Bull. 2009;35(2):300–306. 
doi:10.1093/schbul/sbn171
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27. Rebok GW, Ball K, Guey LT, Jones RN, Kim H-Y, King JW, et al.Ten-year effects of the 
Advanced Cognitive Training for Independent and Vital Elderly cognitive training trial on 
cognition and everyday functioning in older adults. J Am Geriatr Soc. 2014; 62: 16–24.
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Schedule of Events and Assessments
Screening
Baseline
1m
2M
4M
6M
Visit Day
-7 (at least)
0
Day
 7
Day 
14
Day 
28
Day 
56
Day 
112
Day 
168
Day 
224
Day
280
Day
336/
EOS
Visit Number
1
2
3
4
5
6
7
8
9
10
11
Visit window (days)
0
0
3
3
3
7
7
7
7
7
7
Type of Visit
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history and demographics
X
Psychiatric and neurological history
X
Physical examination 
X
PANSS
X
X
X
X
X
X
X
X
X
Orthostatic vital signs, weight, and BMI
X
X
X
X
X
X
X
X
Height
X
Pregnancy test
X
X
Urine drug screen
X
X
SOFAS
X
x
X
BAC App
X
x
X
VRFCAT
X
x
X
At-home Cognitive training 
(Brain HQ, FUNSAT) 
2 weekly sessions for 12 weeks 
Inject study drug
X
 
 
 
X
X
X
X
X
CSSRS
X
X
X
X
X
X
X
X
X
X
X
Side Effect Assessment
X
X
X
X
X
X
X
X
X
X
Note.  Weeks 1-12 will include 2x weekly cognitive and functional skills training.
Note.  Aristada Initio and Aristada 2-month formulation on BL day
PI or psychiatric resident will collect the psychiatric history and perform the physical examination if no recent examination is 
available.

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Medical History will be collected by the study co-ordinator
Drug screens and pregnancy tests are budgeted into the protocol.
Clinic visits on days 7, 14, and 28 will involve meeting with study the co-ordinator only unless and issue arises with suicidal ideation 
or behavior.
At each injection visit, the injection will be performed either by the PI, a psychiatric resident under his/her supervision, or the Nurse 
Practitioner assigned to the participant, who ask about side effects.  At each injection visit, we will perform the PANSS and the 
CSSRS (Study co-ordinator).
All injectable Aristada Initio and Aristada Lauroxil doses are provided by the sponsor.