Conditions: Schizophrenia Schizoaffective Disorder Substance Use Disorders
Keywords: Schizophrenia Schizoaffective Disorder Substance Use Disorders Alcohol Use Disorder Cannabis Use Disorder Cocaine Use Disorder Heroin Use Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

Brief summary:
The proposed study is a 4-site, 12-week, novel, feasibility, investigation of patients who have co-occurring diagnoses of schizophrenia and current substance use disorder (alcohol, cocaine, heroin, or cannabis). Thirty-nine participants will be randomly assigned to switch to brexpiprazole (the brexpiprazole group) or remain on the same antipsychotic treatment (the control group). The study will be conducted at 4 sites in the US. The investigators expect to enroll 80 subjects across 3 sites. UMass Medical School, Worcester MA is the lead site. Sub-sites include Massachusetts General Hospital (MGH) and the University of North Carolina at Chapel Hill (UNC).

Detailed description:
STUDY OBJECTIVES

The primary objectives of the study include:

1. examine the effect of brexpiprazole treatment on the number of days of substance use in the past week as measured by the Timeline Follow-Back (TLFB) assessment;
2. examine the effect of brexpiprazole treatment on substance craving using 100-mm visual analogue scale (VAS).

The secondary objectives are to examine the effect of brexpiprazole treatment on:

1. the dollar amount spent on substances in the past week;
2. the psychiatric symptoms as measured by various clinical rating scales
3. quality of life

Arms:
arm 1: Brexpiprazole 4mg daily for 12 weeks arm 2: Stay on current antipsychotic medication for 12 weeks

Interventions: intervention 1: Brexpiprazole intervention 2: Treatment as Usual
Intervention descriptions: intervention 1: Brexpiprazole 4mg daily for 12 weeks intervention 2: Current antipsychotic medication for 12 weeks

Protocol document:
Prot_SAP_000.pdf: 
1 
 
A multi-center, randomized, controlled trial of brexpiprazole for the treatment of 
co-occurring schizophrenia and substance use disorder 
 
 
Document date: Version 6.2 – January 7th, 2022 
 
NCT Number: NCT03526354 
 
PRINCIPAL INVESTIGATOR: 
 
XIAODUO FAN, MD 
 
Funding Provided by: 
Otsuka Pharmaceuticals 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
 
TABLE OF CONTENTS 
 
 
A. INTRODUCTION AND BACKGROUND 
 
 
 
 
 
6 
 
B. RATIONALE AND STUDY DESIGN  
 
 
 
 
 
7 
 
C. STUDY OBJECTIVES 
 
 
 
 
 
 
 
7 
 
D. STUDY POPULATION 
 
 
 
 
 
 
 
8 
 
E. SCHEDULE OF EVENTS AND STUDY ASSESSMENTS  
 
 
10 
 
F. STUDY VISIT PROCEDURES 
 
 
 
 
 
 
17 
 
G. TREATMENT OF SUBJECTS 
 
 
 
 
 
 
20 
 
H. DATA SAFETY AND MONITORING PROCEDURES 
 
 
 
22 
 
I. DOCUMENTATION OF DATA 
 
 
 
 
 
 
26 
 
J. MONITORING AND OVERSIGHT 
 
 
 
 
 
 
28 
 
K. ETHICAL CONSIDERATIONS 
 
 
 
 
 
 
28 
 
L. STATISTICS AND DATA ANALYSIS 
 
 
 
 
 
29 
 
M. REFERENCES 
 
 
 
 
 
 
 
 
31 
 
 


3 
 
Synopsis 
Protocol Number: 
 
Title:   
A multi-center, randomized, controlled trial of 
brexpiprazole for the treatment of co-occurring 
schizophrenia and substance use disorder 
Design: 
The proposed study is a 4-site, 12-week, 
feasibility, “proof of concept” investigation of 
patients who have co-occurring diagnoses of 
schizophrenia 
and 
current 
substance 
use 
disorder (alcohol, cocaine, heroin, or cannabis). 
Primary Objectives: 
The primary objectives of this study:  
1) examine the effect of brexpiprazole treatment 
on the number of days of substance use in the 
past week as measured by the Timeline Follow-
Back (TLFB) assessment;  
2) examine the effect of brexpiprazole treatment 
on substance craving using 100-mm visual 
analogue scale (VAS). 
Secondary Objectives 
The secondary objectives are to examine the 
effect of brexpiprazole treatment on: 1) the dollar 
amount spent on substances in the past week; 2) 
the psychiatric symptoms as measured by 
various clinical rating scales; 2) quality of life.  
Enrollment: 
50 subjects total  
 
Clinical Sites: 
 4 US sites  
Timeline 
Initial enrollment (expected): February 15, 2018 
Last enrollment (expected): November 20, 2023 
Last anticipated follow-up contact: February 29, 
2024 
Patient Population: 
Men and women, 18-65 (inclusive) years of age 
Age 18-65 years old. Meets the DSM-5 criteria 
for diagnoses of schizophrenia or schizoaffective 
disorder and substance use disorder (alcohol, 


4 
 
cocaine, heroin, or cannabis) based on the  Mini 
International Neuropsychiatric Interview (MINI).  
Primary and Secondary 
Outcomes: 
The number of days of substance use in the past 
week as measured by the Timeline Follow-Back 
(TLFB). 
Substance 
craving 
using 
100-mm 
visual 
analogue scale (VAS). 
Psychiatric symptoms will be assessed using: 
1)  The Positive and Negative Symptoms 
Scale (PANSS),  
2) the Schedule for the Assessment of 
Negative Symptoms (SANS),  
3) the Calgary Depression Rating Scale 
(CDRS), and 
4)  the Clinical Global Impression Scale 
(CGI);  
Quality of life as measured by the Heinrichs 
Carpenter Quality of Life Scale (QOL). 
 
Inclusion Criteria:  
 
 
 
 
1) Age 18-65 years old 
2) Meets the DSM-5 criteria for diagnoses of 
schizophrenia or schizoaffective disorder 
and substance use disorder (alcohol, 
cocaine, heroin, or cannabis) based on 
the Mini International Neuropsychiatric 
Interview (MINI).  
3) Uses substance on at least 4 of the past 
30 days prior to randomization with at 
least one use in the week prior to 
randomization for one of substances 
(cocaine, heroin, cannabis or alcohol) 
assessed by the TLFB interview 
4) Stable dose of antipsychotic agent for at 
least one month 
5) Well 
established 
compliance 
with 
outpatient medications 
6) Female subjects of child-bearing potential 
are required to practice appropriate birth 
control methods during the study. 
 


5 
 
Exclusion Criteria: 
 
1) Psychiatrically unstable 
2) Currently meets DSM-5 criteria for any 
substance 
use 
disorder 
other 
than 
caffeine, nicotine, alcohol, cocaine, heroin 
and cannabis 
3) Significant, unstable medical conditions 
including severe cardiovascular, hepatic, 
renal or other medical diseases 
4) History of a seizure disorder 
5) Pregnancy or breastfeeding 
6) Currently on aripiprazole or cariprazine 
7) Currently 
on 
medications 
to 
treat 
substance use (disulfiram, naltrexone, 
acamprosate,methadone, buprenorphine, 
varenicline or bupropion) 
 
Statistical Methodology 
Intent-to-treat analysis and a mixed model 
approach will be conducted to estimate the 
pragmatic effects of brexpiprazole treatment on 
the number of days of substance use in the past 
week, substance craving, psychiatric symptoms 
and quality of life. Polynomial time trends (e.g., 
slopes) will be used to fit the population mean 
response curve for the control group. Group-by-
time interactions will be modeled as a function of 
time to fit between-group effects. Subject-specific 
parameters will be estimated to model individual 
subject deviations from the group mean. Baseline 
measures 
of 
substance 
use 
and 
clinical 
symptoms will also be included in the model as 
covariates. 
 
 
 


6 
 
A. INTRODUCTION AND BACKGROUND 
 
The lifetime prevalence of substance use disorders in patients with schizophrenia 
has been reported ranging from 10 to 60% (1). The lifetime prevalence of Alcohol 
use disorder is at least three times more common in patients with schizophrenia 
than in the general population. The co-occurrence of cannabis use disorder 
happens in 13-42% of patients with schizophrenia. Co-occurring substance use 
is associated with increased relapse and re-hospitalization rates, non-compliance 
with treatment, an increased risk for violence, and poorer global functioning (2, 
3). Clearly, substance use adds greatly to the financial costs and emotional toll 
that schizophrenia places on patients, families, and the entire mental health 
system.  
 
Treatment challenges for schizophrenia and co-occurring substance use 
Patients who present with schizophrenia and co-occurring substance abuse can 
be difficult to manage in the outpatient setting. The lack of integrated care to 
address both psychotic symptoms and substance problems and the poor 
treatment compliance are two major challenges. Poor treatment compliance is 
contributed by the active positive and negative symptoms and ongoing use of 
substance. In spite of the high association between the two conditions, there is a 
surprising paucity of studies to explore optimal treatment and outcome for this 
patient population. Most antipsychotic agents are of limited value in controlling 
substance use in these dual diagnosis patients. Studies have suggested that 
clozapine decreases alcohol and cannabis use in dual diagnosis patients with 
schizophrenia. However, significant side effects produced by clozapine severely 
limit its clinical use (4, 5). 
 
The promise of Dopamine D2 receptor partial agonists 
Recent research has suggested that the dopamine D2 receptor partial agonists, 
such as aripiprazole, decrease drug addiction in several animal models (6, 7).  
Studies have also reported that aripiprazole can reduce substance craving and 
use in patients with schizophrenia or bipolar disorder (8). It has been suggested 
that aripiprazole can lessen alcohol and substance use in dual diagnosis patients 
in part because of its mechanism of action that includes release of dopamine in 
the prefrontal cortex which helps normalize dysfunctional brain reward circuits 
(BRC) that may underlie the co-occurring alcohol and substance use in patients 
with schizophrenia (9).  
 
Brexpiprazole is a newly approved dopamine D2 receptor partial agonist for 
schizophrenia treatment. It shows partial agonism with lower intrinsic activity at 


7 
 
the D2 receptor and stronger antagonism at the 5-HT2A receptor than aripiprazole 
(10). We hypothesize that brexpiprazole, similar as aripiprazole, can decrease 
the level of craving and reduce the use of substance in patients with 
schizophrenia; further, brexpiprazole may be even more efficacious than 
aripiprazole in reducing substance use given its relatively lower potential to 
induce D2 partial agonist-mediated activating adverse effects such as 
restlessness, insomnia, and nausea (11), which are common substance 
withdrawal symptoms.    
 
B. RATIONALE AND STUDY DESIGN 
 
The proposed study is a 4-site, 12-week, novel, feasibility, “proof of concept” 
investigation of patients who have co-occurring diagnoses of schizophrenia and 
current substance use disorder (alcohol, cocaine, heroin, or cannabis). Fifty 
patients not treated with aripiprazole or cariprazine (the other two dopamine 
receptor partial agonists) at the time of consent will be randomly assigned to 
switch to brexpiprazole (the brexpiprazole group) or remain on the same 
antipsychotic treatment (the control group).  
 
C. STUDY OBJECTIVES 
 
The primary objectives of the study include:  
1) examine the effect of brexpiprazole treatment on the number of days of 
substance use in the past week as measured by the Timeline Follow-Back 
(TLFB) assessment;  
2) examine the effect of brexpiprazole treatment on substance craving using 100-
mm visual analogue scale (VAS).  
 
The secondary objectives are to examine the effect of brexpiprazole treatment 
on:  
 
1) the dollar amount spent on substances in the past week;  
2) the psychiatric symptoms as measured by various clinical rating scales;  
3) quality of life.  
 
Additional objectives of this study include collection of additional safety data on 
brexpiprazole using safety parameters (ECG, metabolic labs, vital signs, 
suicidality, EPS, side effects measured by the SAFTEE) throughout the study 
 
D. STUDY POPULATION 


8 
 
The study will be conducted at 4 sites in the US. We expect to enroll 50 subjects 
across 4 sites. We anticipate a 20% discontinuation for this study. Hence we will 
randomize 50 subjects so we will have 40 subjects completing the study.  
Eligibility Criteria 
 
Inclusion criteria:  
 
Each subject must meet all study inclusion criteria prior to randomization. 
 
1) Age 18-65 years old 
2) Meets the DSM-5 criteria for diagnoses of schizophrenia or schizoaffective 
disorder and substance use disorder (alcohol, cocaine, heroin, or cannabis) 
based on the  Mini International Neuropsychiatric Interview (MINI).  
3) Uses substance on at least 4 of the previous 30 days prior to randomization with 
at least one use in the week prior to randomization for one of the substances 
(cocaine, heroin, marijuana or alcohol) as assessed by the TLFB interview 
4) Stable dose of antipsychotic agent for at least one month 
5) Well established compliance with outpatient medications 
6) Female subjects of child-bearing potential are required to practice appropriate 
birth control methods during the study. 
7) Male subjects who are sexually active must agree to use appropriate birth control 
measure to avoid partner pregnancy 
 
       Exclusion criteria: 
       Each subject must not have the following exclusion criteria prior to randomization in 
the study.        
1) Psychiatrically unstable 
2) Currently meets DSM-5 criteria for any substance use disorder other than 
caffeine, nicotine, alcohol, cocaine, heroin and cannabis. 
3) Significant, unstable medical conditions including severe cardiovascular, hepatic, 
renal or other medical diseases 
4) History of a seizure disorder 
5) Pregnancy or breastfeeding 
6) Currently on aripiprazole or cariprazine 
7) Currently on medications to treat substance use (disulfiram, naltrexone, 
acamprosate, methadone, buprenorphine, varenicline or bupropion) 
8) Patients previously exposed to brexpiprazole 
 
Exclusionary Lab values: 
Comprehensive Metabolic Panel 
Sodium 
<1.1 times the lower limit or >1.1 times upper 
limit of the reference range 


9 
 
Potassium 
 
<1.1 times the lower limit or >1.1 times upper 
limit of the reference range 
Blood Urea Nitrogen 
(BUN) 
>1.3 times upper limit of the reference range 
Creatinine 
>1.3 times upper limit of the reference range 
Aspartate amino 
transferase (AST) 
>3 times upper limit of the reference range 
Alanine amino 
transferase (ALT) 
>3 times upper limit of the reference range 
Glycated Hemoglobin 
(HbA1c) 
Patients with a value > 9.0% (at screening only) 
eGFR  
< 35 ml/min 


10 
 
E. SCHEDULE OF EVENTS AND STUDY ASSESSMENTS 
 
 
Table 1. Schedule of Events 
 
Procedu
re 
Visit 
Screening 
Visit 1 
(basel
ine) 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13/EO
T 
Early 
Termin-
ation 
(ET)  
Study 
Week 
 
Week 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6  
or ET 
at 
week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11 
Week 
12 
Any 
visit 
other 
than at 
week 6 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(Females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Screening 
Pregnancy 
Checklist 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Labs (CMP, Lipid 
Panel, CBC, Hs-
CRP, IL6, TNFα) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X (only 
CMP, 
Lipid 
panel, 
and 
CBC) 
Lab (HbA1C)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist 
Circumference 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
TLFB1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


11 
 
VAS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fagerstrom Test 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PANSS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
SANS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
CDRS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
CGI-S and CGI-I2 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
CSSRS 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
QOL 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
EPS Scales (BAS, 
SAS, AIMS) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Drug dispensing 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Supportive 
Counseling 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
1- TLFB at screening will be completed for the past 30 days. All other visits the TLFB will collect information for the past week. 
2- CGI-I will not be administered at baseline. Only CGI-S is administered at baseline. 
3- EOT – end of treatment 
4-  Lab (HbA1C) will only be performed at the screening visit  
5- If ET falls on week 6, the visit should follow regular week 6 protocol. If ET falls on any other visit, follow ET protocol 


12 
 
 
Informed Consent Process: All subjects will sign IRB approved informed consent 
form (ICF) prior to starting any study related screening procedures. The written 
informed consent will be obtained by authorized study personnel. The authorized 
study staff will explain the study objectives, risks and benefits and overview of 
the study procedures to all subjects as part of the consent process. 
 
Eligibility Review: An eligibility review will be conducted by the investigator at 
each site as per the inclusion exclusion criteria listed in section D of the protocol. 
All subject eligibility criteria will be reviewed by UMass designee prior to subject 
randomization. 
 
Demographics and Medical/Psychiatric History: Subject’s demographics, medical 
and psychiatric history will be collected as part of the screening process. All 
patient medical and psychiatric history will be reviewed by the investigator. 
 
Mini International Neuropsychiatric Interview (MINI v7.0): The MINI 7.0 is used 
for evaluation of major Axis I psychiatric disorders in DSM-5TM.It is a short 
clinician-administered structured diagnostic interview with an administration of 
around 20 minutes. The MINI will be administered by the investigator. 
 
Concomitant Medication Review: All medication (prescription or non-prescription, 
including vitamin and herbal supplements) taken by subject 30 days prior to 
screening must be recorded and reviewed. At each visit the concomitant 
medications will be recorded and reviewed by investigator or their designee as 
per the concomitant medication sheet (appendix ) 
 
Vital Signs: Vital signs will be assessed by designated study staff after the 
subject is seated for 5 minutes. Vital sign assessment will include sitting and 
standing systolic and diastolic blood pressure, heart rate (sitting and standing) 
and oral temperature. Vital signs must be assessed as per the schedule of 
events (SOE) and reviewed by the study MD. Effort should be made to 
consistently use the same arm to measure blood pressure throughout the study. 
Any clinically significant vital signs will be recorded as an adverse event and 
documented in the source document and eCRF. 
 
Physical Examination: A complete physical exam will be conducted at screening 
by the PI or a medically qualified designee. The examination should include 
assessment of head, neck, eyes, ears, nose, throat, lymph nodes, skin, 
extremities, respiratory, gastrointestinal, cardiovascular and nervous systems. 


13 
 
 
Anthropometric measurements: Height and weight will be recorded. Height is 
recorded at screening visit only. Weight (kg) will be recorded at every visit. BMI 
will be calculated at all visits and is defined as weight in kilograms divided by the 
square of the height in meters (kg/m2). Waist circumference will be measured at 
baseline, week 6 and week 12. 
 
12- Lead Electrocardiogram (ECG): A 12-lead ECG will be administered after the 
patient is supine for 5 minutes. ECG will be administered as per the schedule of 
events. The ECG will be reviewed by PI or medically qualified sub-investigator for 
any abnormalities. The ECGs findings will be marked as normal, abnormal-not 
clinically significant or abnormal-clinically significant by PI or medically qualified 
sub-investigator. 
Any clinically significant change noted from screening or if an ECG is considered 
abnormal and clinically significant, it will be reported as an AE and will be 
appropriately recorded in both the source documents and the eCRF.  
 
Laboratory Procedures: Most of the lab procedures will be done at the site. All 
blood work will be done as fasting.  
 
Routine lab panels done at site include: Hematology (CBC with diff), 
comprehensive metabolic panel (CMP) and lipid panel. These labs will be 
assessed at screening, week 6 and week 12. Routine lab panels will be collected 
for subjects who are early terminated. Additionally, an HbA1c test will be 
conducted at screening only. Approximately four tablespoons of blood will be 
taken at each blood draw.  
 
Lab samples  for Hs-CRP, IL6 and TNF -alpha will be collected by sites and 
stored at -80F. It will be batch shipped to UMass every 6 months. These will be 
analyzed at UMass Memorial labs. CRP, IL-6 and TNF-α are well established 
inflammatory markers that are associated with both psychopathology and 
metabolic side effects in patients with schizophrenia. We will analyze how 
brexpiprazole treatment might affect these inflammatory markers. 
 
Routine Lab Assessments at site: 
Hematology 
(CBC) 
Comprehensive 
metabolic panel 
Lipid Panel 
Hematocrit 
Hemoglobin 
Platelets 
Alanine transferase 
(ALT) 
Albumin 
Total protein 
Total cholesterol 
Chol, HDL 
Triglyceride 
Chol, LDL 


14 
 
Red blood cell 
count 
Total and 
differential 
(absolute) white 
blood cell count 
Alkaline 
phosphatase (ALK-
P) 
Aspartate 
transferase (AST) 
Bicarbonate 
Blood urea nitrogen 
(BUN) 
Creatinine 
Glucose 
Potassium 
Sodium 
Chloride 
Estimated 
glomerular 
glomerular filtration 
rate (eGFR) 
Chol, VLDL 
Cholesterol/DL ratio 
 
 
 
Future Testing: Blood samples will be collected at screening, week 6 and week 
12 for use in future research related to schizophrenia. All samples will be labelled 
with a study ID. Only members of the research team will be able to derive an 
individual’s identity from their study ID code. The key to the code is stored on 
secure server and can only be accessed through password-protected computer 
Sub-sites will store these at -80F and batch ship them to the UMass Psychotic 
Disorders Research Program at UMass Medical School for storage and future 
extraction/genotyping. The lead site will store all samples indefinitely. 
 
Pregnancy Tests: A urine dip stick pregnancy tests will be administered to all 
women at screening. The pregnancy test can be repeated at any time during the 
study as per PI discretion. All subjects must test negative for pregnancy tests to 
be eligible for the study. 
 
Urine Drug Tests: All subjects must undergo urine drug tests for a panel of 
substances at every study visit. The urine drug test will be completed prior to 
administering the timeline follow-back (TLFB). 
The urine drug screen will include opioids, cocaine, methamphetamines, 
cannabinoids, barbiturates, benzodiazepines, methamphetamine, and 
phencyclidine. 
 
Supportive Counseling: Qualified staff will provide supportive counseling to study 
subjects at weekly visits. Brief supportive counseling sessions about substance 
use will be provided as part of study visits. The content and structure is adapted 


15 
 
from the Individual Resiliency Training (IRT) manual that was originally 
developed for the RAISE (Research to identify, optimize and personalize early 
treatment for people affected by schizophrenia) study (Mueser et al., Psychiatric 
Services 2015; 66:680-690). Counseling will be provided to all subjects. 
Counseling is not manualized and no fidelity check is planned. Counseling will 
focus on: 
1) substance abuse counseling to encourage a reduction in or abstinence from 
alcohol consumption;  
2) Medication management counseling to encourage compliance with the 
treatment. 
 
 
Efficacy Assessments 
 
Timeline Follow-back (TLFB): Substance use will be recorded using the timeline 
follow-back method at every study visit. At screening visit, TLFB will assess 
substance use and dollar amount spent on substances for the past 30 days. All 
other visits will collect substance use data and dollar amount spent in the past 
week or for the period between the last visit and the current visit. The subject’s 
drug screen results will be conveyed to the subject prior to administration of the 
TLFB. If the subject’s self-report is at odds with the drug screen results, then the 
subject’s report will not be challenged. All reported data from the subject and 
drug test results will be collected and used in exploratory analyses 
 
Visual Analog Scale (VAS): The VAS will be used to assess craving for 
substance use as per the schedule of events and administered as per the 
schedule of events. The VAS is a horizontal line with a unipolar scale, anchored 
on the right side with 
“No desire at all” (marked with a “0”) and on the left side with “Worst imaginable 
desire” (marked with a “100” with a line connecting the two ends. Subjects will 
mark the appropriate point to indicate where their “desire for substance” falls on 
this line. 
 
Fagerstrom Test: The Fagerstrom Test for Nicotine Dependence will be used to 
assess smoking status. Data on subjects will be collected using the Fagerstrom 
test as per the schedule of events. 
 
Positive and Negative Syndrome Scale (PANSS): PANSS is a measure used to 
assess symptom severity in patients with schizophrenia. It consists of three 
sections: Positive scale has 7 items, Negative scale has 7 items and General 


16 
 
Psychopathology has 16 items. Each item (symptom) will be scored on a 7-point 
scale with higher scores representing increasing levels of psychopathology: 1) 
Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, and 7) 
Extreme. The PANSS will be administered by a designated study staff at time 
points specified in the schedule of events.  
 
Schedule of Assessment of Negative Symptoms (SANS): SANS is a 24-item 
scale used to assess negative symptoms based on observation and a structured 
interview in patients with schizophrenia. Designated study staff will administer the 
SANS at baseline, week 6 and week 12. 
 
Calgary Depression Rating Scale (CDRS): The Calgary Depression Rating Scale 
is used to depression symptoms in subjects. The PI or a designated staff will 
administer the CDRS at baseline, week 6 and week 12. 
 
Clinical Global Impression – Severity and Clinical Global Impressions – 
Improvement Scales (CGI-S and CGI-I): The CGI-S and CGI-I are observer rated 
scales. The CGI-S measures illness severity on a 7-point Likert scale 1) Normal, 
not at all ill, 2) Borderline mentally ill, 3) Mildly ill, 4) Moderately ill, 5) Markedly ill, 
6) Severely ill, and 7) Among the most extremely ill patient. The CGI-I is used to 
measure improvement in illness and also uses a 7 point Likert scale: 1) Very 
much improved, 2) Much improved, 3) Minimally improved, 4) No change 5) 
Minimally worse, 6) Much worse, 7) Very much worse. The PI or a designated 
study staff will administer this at time points as per the schedule of events. 
 
Heinrichs Carpenter Quality of Life Scale (QOL): The QOL is a 21-item scale 
providing information on symptoms and functioning in patients with 
schizophrenia. A trained designated study staff will administer the QLS at 
baseline, week 6 and week 12. 
 
Safety Assessments 
 
Extra Pyramidal Symptoms (EPS) Scales: The PI or a designee will complete the 
following EPS scales – The Abnormal Movement Scale (AIMS), Barnes 
Akathasia Scale (BAS) and the Simpson Angus Scale (SAS). These movement 
scales will be assessed at baseline, week 6 and week 12. 
 
Columbia Suicide Severity Rating Scale (CSSRS): The PI or a designee will 
administer the C-SSRS.  The C-SSRS will be administered at screening, 


17 
 
baseline, week 6 and week 12. The C-SSRS should be administered by a 
clinician trained to assess and manage suicidal ideation and behavior. 
 
Adverse Events (AE): Adverse events will be monitored at each weekly visit. The 
PI or the sub-investigator will review adverse events at every study visit. AE 
information is collected and recorded starting on the day the consent is signed 
until the end of an individual’s participation in the study.   
 
 
 
F. STUDY VISIT PROCEDURES AND SCHEDULE 
The proposed study is a 4-site, 12-week, novel, feasibility, “proof of concept” 
investigation of patients who have co-occurring diagnoses of schizophrenia and 
current substance use disorder (alcohol, cocaine, heroin, or cannabis). Fifty patients 
not treated with aripiprazole or cariprazine at the time of consent will be randomly 
assigned to switch to brexpiprazole (the brexpiprazole group) or remain on the same 
antipsychotic treatment (the control group). 
Informed consent will be obtained prior to the screening visit and any study 
procedures.  
Screening Visit: Screening visit assessments includes: Fasting blood samples for 
lipid profile, comprehensive metabolic profile, CBC, hs-CRP, IL-6 and TNF-α will be 
obtained at the screening visit. Potential subjects will undergo a diagnostic 
evaluation. Psychiatric diagnosis will be determined using the Mini International 
Neuropsychiatric Interview (MINI).A medical evaluation, including weight, height, 
vital signs, a physical examination, and review of systems will be performed.  A urine 
pregnancy test will be performed on all women of childbearing potential. The 
subjects will be given an appointment card for their next visit which will also provide 
a reminder for the use of appropriate birth control.  In addition, a urine drug screen, 
and a 12-lead EKG will be performed. A 30-day timeline follow-back will be 
administered at screening visit to assess current substance use and Fagerstrom test 
will assess smoking status. 
Following the screening visit and prior to baseline visit, the subject’s primary care 
provider and/or psychiatrist will be notified of their participation in the study in order 
to adequately screen subjects, ensure that only eligible subjects are enrolled, and 
minimize subject risk.  
All screening procedures will be completed and reviewed by PI for eligibility criteria 
prior to randomization/baseline visit.  


18 
 
Randomization: After completion of all screening assessments, all patient eligibility 
screening documents will be sent to UMass for review and eligibility confirmation. 
Once a patient is deemed eligible, a randomization ID and a randomization condition 
(brexpiprazole versus control) for the subject will be generated. The randomization 
condition will be accessible to the site and their pharmacy and will be used to 
prepare the corresponding study treatment. Once a subject has been assigned a 
randomization ID, they will be identified in the CRF by this randomization ID for the 
duration of their study participation.  
Baseline Visit: Subjects will be randomly assigned to switch to brexpiprazole 
(brexpiprazole group) or remain on the same antipsychotic medication (control 
group). 
Study intervention: Brexpiprazole switch: For the brexpiprazole group, an overlap 
and taper switch method will be used. The current antipsychotic medication will be 
tapered following standard clinical practice and discontinued over a time period of 6 
weeks. Brexpiprazole will be started at 1mg/day for 4 days, and 2mg/day for 3 days, 
and then titrate by up to 1mg/day increase every 3 days to reach 4mg/day, or as 
much and as fast as the participant can tolerate. Participants will stay on 4mg/day or 
the highest tolerable dose until the end of the study.    
Medication adherence will be measured via pill counts at weekly visits. The study 
staff will discuss pill count data with participants to emphasize the need to take the 
study medication. 
If participants cannot tolerate brexpiprazole after randomization, it will be stopped, 
though the participant may continue to be followed on another treatment (ideally 
their pre-study antipsychotic medication) for the remaining weeks of the study. The 
subject will then continue the rest of the study on their previous antipsychotic 
medication.  
The following assessments will be completed at baseline visit: 
1) Anthropometric measures (weight, waist circumference and height at screening 
to be used) and Vital signs 
2) Weekly TLFB 
3) Drug screen 
4) Post-Screening Pregnancy Checklist 
5)  AE review 
6) PANSS, SANS, QLS, CGI-S 
7) C-SSRS, EPS scales, CDRS 
8) Supportive counseling 


19 
 
Week 6 and week 12 visits: The following assessments will be done at week 6 and 
12.  
1) Anthropometric measures (weight, waist circumference) and Vital signs 
2) Weekly TLFB 
3) Drug screen 
4) Post-Screening Pregnancy Checklist (Week 6 only) 
5) AE review 
6) PANSS, SANS, QLS, CGI-S 
7) C-SSRS, EPS scales, CDRS 
8) Supportive counseling 
9)  ECG 
10) Labs (CMP, CBC, lipid panel) 
11) Labs – hs-CRP, IL-6 and TNF-alpha collected and stored at -80F 
12) Fagerstrom test 
 
 
Week 2, 3,4,5,7,8,9,10,11 visits: These visits may be completed virtually through a 
secured platform depending on the most current COVID situation. During the virtual 
routine follow up visits, vital signs and urine drug screen will be unable to be 
collected; but all subjects who go through the switch will have demonstrated no 
clinically significant changes in vitals, ECG, or lab results in prior long visits. The 
following assessments will be administered at these weekly visits: 
1) Vital signs and anthropometric measures (weight) 
2) Urine drug screen 
3) Post-Screening Pregnancy Checklist (Week 3 and 9 only) 
4) TLFB 
5) AE review 
6) Supportive counseling 
End of Study / Discontinuation of Study Medication – When a participant who is 
randomized to brexpiprazole completes Visit 12 (or sooner for those discontinuing study 
medication), he or she will no longer receive medications through the study.  There will 
need to be a discussion with the participant and his/her treatment provider as to 
whether or not the participant will continue on the study medication after the subject’s 
study participation is over.  For participants finishing the study at Visit 12, this 
discussion should occur about three weeks prior to the final visit.  If the participant will 
continue on the study medication, the treatment provider can begin to prescribe the 
medications following standard clinical practice. The monitoring and management of 
symptoms, therapeutic response and medication side effects will be the responsibility of 
the treatment provider.    


20 
 
Subjects who do not wish to continue on the study medication after the end of study, the 
treatment provider can begin to manage a cross titration off the study medication and on 
to either the antipsychotic medication prior to the study or a new antipsychotic 
medication following standard clinical practice. The monitoring and management of 
symptoms, therapeutic response and medication side effects will be the responsibility of 
the treatment provider.   
Withdrawal of Subjects 
Subjects are free to discontinue their participation in the study at any time and without 
prejudice to further treatment. The investigator must withdraw any subject from the 
study who requests to be withdrawn or fits the criteria below: 
1) If subject meet any exclusion criteria after enrollment.  
 
2) If subjects have laboratory results that meet the exclusionary criteria range 
during the study, the subject will have his/her labs repeated before being 
withdrawn from the study. 
 
3) Subjects will be withdrawn from the study is there is an increase in their PANSS 
total score greater than or equal to 20 compared to their baseline total score at 
any point during the study.  
 
4) Female subjects may be terminated from the study if they become pregnant at 
any time while participating in the study.  
 
5) If at any time the study sponsor or research personnel at UMass decide 
to terminate the study, subjects’ consent will be withdrawn involuntarily.  
Early Termination Visit 
If the subject is terminated from the study on what would be their week 6 visit, they will 
complete all the assessments that are required in a regular week 6 visit. If the subject is 
terminated from the study at any other point, only safety procedures will be performed 
(listed below).   
1. Vital signs and anthropometric measures (weight) 
2. Urine drug screen 
3. TLFB  
4. AE review 
5. Safety labs (CMP, CBC, lipid panel)  
6. ECG 
7. CSSRS 
 
G. TREATMENT OF SUBJECTS 


21 
 
Study Drug Dose and Administration 
The study drug brexpiprazole (Rexulti) will be administered orally. Subjects will be 
randomly assigned to either switch to brexpiprazole or remain on the same 
antipsychotic medication (treatment as usual). Subjects randomized to brexiprazole 
treatment will be titrated as per section F (study intervention). Study participants 
randomized to brexpiprazole treatment will be titrated to 4mg/day or the highest 
tolerable dose as per the study MD's clinical judgement until the end of the study. Dose 
de-escalation due to tolerability will be allowed in the study. If subjects recover, the dose 
can be increased to the 4mg or the highest tolerable dose as per the MD's clinical 
judgement. Patients who are unable to tolerate a minimum dose of 1 mg will be 
withdrawn from the study 
Study Drug  
Commercially available brexpiprazole will be provided directly to all sites by Otsuka 
Pharmaceuticals. Study drug will be provided as 1mg and 2mg tablets. Subjects will 
take medications as dispensed by their site’s Investigational drug pharmacy. 
Storage and Drug Accountability 
The study drug will be stored as per the drug insert. The sites are required to maintain 
current drug dispensation and accountability logs throughout the study. All unused 
supplies will be checked against the drug movement records during the study and/or at 
the end of the study. 
Prohibited Medications 
Currently on the following antipsychotics 
• Aripiprazole 
• Cariprazine 
 
Currently on medications to treat substance use such as: 
• Disulfiram, 
• Naltrexone,  
• Acamprosate,  
• Methadone,  
• Buprenorphine,  
• Varenicline 
• Bupropion 
 
Special Consideration for Concomitant Medications with Brexpiprazole 
Medications 
Intervention 


22 
 
Strong CYP3A4 inhibitors 
 
Examples: itraconazole, 
clarithromycin, ketoconazole 
With concomitant use of brexpiprazole with a 
strong CYP3A4 inhibitor, reduce the brexpiprazole 
dosage and administration [see drug insert 
dosage and administration (2.5)] 
Strong CYP2D6 inhibitors  
 
Examples: paroxetine, fluoxetine, 
quinidine 
With concomitant use of brexpiprazole with a 
strong CYP2D6 inhibitor, reduce brexpiprazole 
dosage [see drug insert dosage and 
administration (2.5)] 
Both CYP3A4 inhibitors and 
CYP2D6 inhibitors 
 
Examples:  
1) itraconazole+quinidine 
2) fluconazole+paroxetine 
3) itraconazole+duloxetine 
4) fluconazole+duloxetine 
With concomitant use of brexpiprazole with 1) a 
strong CYP3A4 inhibitor and a strong CYP2D6 
inhibitor; or 2) a moderate CYP3A4 inhibitor and a 
strong CYP2D6 inhibitor; or 3) a strong CYP3A4 
inhibitor and a moderate CYP2D6 inhibitor; or 4) a 
moderate CYP3A4 inhibitor and a moderate 
CYP2D6 inhibitor; decrease the brexpiprazole 
dosage [see drug insert dosage and 
administration (2.5)] 
Strong CYP3A4 Inducers 
 
Examples: rifampin, St.John’s 
wort 
With concomitant use of brexpiprazole with a 
strong CYP3A4 inducer, increase the 
brexpiprazole dosage [see drug insert dosage and 
administration (2.5)] 
 
 
H. DATA SAFETY AND MONITORING PROCEDURES 
Evaluation of Adverse Events 
An adverse event (“AE”) is “any untoward occurrence in a human subject participating in 
research”. The event is undesirable and has an unintended outcome, but is not 
necessarily unexpected. The event may have been described in the informed consent 
as a risk of the study. 
 
Adverse events include clinically significant abnormal laboratory or ECG findings, a 
symptom, or disease temporally associated with the use of a study drug, or the 
progression of disease, whether or not related to the study drug. 
 
Illnesses present prior to the subject signing the ICF are considered to be pre-existing 
conditions and are documented on the medical history eCRF. Pre-existing conditions 
that worsen during the study are entered on the AE eCRF. 
 
All out-of-range laboratory values will be deemed as clinically significant or not clinically 
significant by the investigator. Clinically significant values will be considered AEs and 
recorded as such on the eCRFs. 
 
Pregnancy is not considered an AE, although a subject will be withdrawn from the study 
if a pregnancy occurs. 
 


23 
 
Evaluation of Serious Adverse Event:  
 
A serious adverse event (“SAE”) includes: 
• The death of a study subject, whether related to an study drug or not related 
• A reaction which, in the opinion of the investigator, threatens the study subject 
with risk of death 
• A disability or incapacity which, in the opinion of the investigator, causes 
substantial disruption of a study subject's ability to conduct normal life functions 
• Hospitalization or extension of an existing hospitalization (excluding elective  
hospitalization for conditions unrelated to the study) 
• A birth defect in an offspring of a study participant, regardless of the time after 
the study the congenital defect is diagnosed 
• Any intervention required to prevent one of the above outcomes 
 
Relatedness/Expectedness to the Study Drug 
 
Related: Associated of having a timely relationship with the study agent or procedures; 
a reasonable possibility exists that an outcome may have been caused or influenced by 
the study in question (e.g., administration of a study drug), although an alternative 
cause/influence may also be present. Related events may be definitely, probably, or 
possibly related. 
 
Unrelated: Unassociated or without a timely relationship to the study agent or 
procedures; evidence exists that an outcome is definitely related to a cause other than 
the event in question (e.g., underlying disease, environment). 
 
The assessment of study drug relationship to each AE will be reported on the 
appropriate source document (and SAE form, in the event of an SAE) by the 
investigator (or designated sub-investigator) according to his/her best clinical judgment.  
 
Unexpected Adverse Event: - the adverse event is not an anticipated event for the study 
drug (not listed in the drug insert) and is not explained in the Informed Consent 
Statement that the study subject signed. 
 
 
Monitoring and Reporting of Adverse Events 
 
Continuous data and safety monitoring will be conducted by the PI. Any adverse effect 
reported to study personnel will be reviewed with the PI or sub-investigator who will 
determine whether they are mild, moderate or severe and the likelihood 
(definitely/possible/probable) that it is related to the study medication. All AEs will be 
followed until resolution, until deemed stable by the investigator or until the subject is 
deemed by the investigator to be lost to follow-up 
 
Intensity 
Definition 


24 
 
Mild 
Causes transient or mild discomfort ; no limitation of usual 
activities; no medical intervention required. 
Moderate 
Causes mild to moderate limitation in activity; some limitation of 
usual activities: no or minimal medical intervention or therapy is 
required. 
Severe 
Causes marked limitation in activity; some assistance is usually 
required; 
medical 
intervention 
or 
therapy 
is 
required; 
hospitalization is probable. 
 
The PI is ultimately responsible for assessing and reporting all adverse events as outlined 
in the protocol. The assessment of AEs may be delegated to a medically qualified Sub-
Investigator, trained on this study protocol, who is listed on the FDA Form 1572 or 
equivalent document, and on the delegation of authority form. The PI or investigator will 
report adverse events to the IRB in accordance with IRB guidelines. 
 
Reporting of Serious Adverse Events 
 
All SAEs will be reported to UMass by the PI through telephone or email within 24 hours 
of discovery, using the form provided by the lead site, UMass. In the event of a SAE, the 
PI or designee will notify the lead site PI, Dr. Xiaoduo Fan by phone or email within 24 
hours of the event and will email supporting documentation within 48 hours of the event 
and then as relevant data is available within the following week. 
 
The PI must inform the IRB immediately regarding any AE (does not have to be causally 
related) that is both serious and unexpected; or that represents a series of AEs that, on 
analysis, is unanticipated, or occurs at an unanticipated frequency, or otherwise 
represents an unanticipated safety risk to the study subject.  The IRB may subsequently 
choose to modify the informed consent or request changes to the protocol. 
 
Occasionally, after a patient completes the study, a piece of data is missing or that we 
come to understand that it would be helpful to ask an additional question of all 
participants.  For this reason, participants will be asked as part of the consent process if 
they are willing to be contacted after their study participation ends.  
 
 
Protocol Deviations and Waiver 
 
Protocol Waivers 
Protocol waivers will be considered on a case by case basis by the principle investigator 
for this study. 
 


25 
 
Procedure for Non-Compliant Subjects  
 
Problems related to symptoms of schizophrenia and substance dependence can cause 
a number of challenges to carrying out the protocol with a given participant, including: 
missed appointments, visits outside of the window, inability to complete all study 
assessments, not taking medication correctly, and not returning medication containers 
and extra pills.  Such events will not be considered protocol deviations unless they 
impact a participant's safety or the scientific validity of the study. 
 
Subjects who miss a study visit will be allowed (at the discretion of the PI) to make up 
that visit within that week.  Subjects who withdraw consent will no longer have data 
collected for the study.   
 
Protocol Deviation  
Major and Minor Protocol Deviation 
 
 
Major Protocol Deviation 
Minor Protocol Deviation 
Definition 
A deviation that may: 
Impact subject safety, 
Affect the integrity of study data, 
and/ or 
Affect the subject’s willingness to 
participate in the study. 
A deviation that does not: 
Impact subject safety, 
Compromise the integrity of 
study data, and/ or 
Affect the subject’s willingness to 
participate in the study. 
Examples  
(not all-
inclusive) 
Failure to obtain informed 
consent 
 
Informed consent obtained by an 
unauthorized individual 
 
Enrollment of a subject who did 
not meet eligibility criteria for 
whom a protocol exception was 
not obtained 
 
Performing a study procedure 
that is not approved by the IRB 
and/or is not in the protocol 
 
Failure to perform a required lab 
test that, in the opinion of the 
Site Investigator, may affect 
subject safety or data integrity 
 
Failure to perform or follow a 
study procedure that, in the 
opinion of the Site Investigator, 
Implementation of unapproved 
recruitment procedures 
 
Only a photocopy of the signed/ 
dated consent form is available 
(the original is missing) 
 
Pages are missing from the 
signed/ dated informed consent 
form 
 
Use of invalid consent form (i.e. 
without IRB approval or 
outdated/expired form) 
 
Study procedure conducted out 
of sequence 
 
Failure to perform a required lab 
test 
 
Missing lab results 
 


26 
 
may affect subject safety or data 
integrity 
 
Failure to follow safety (AE) 
management plan 
 
Failure to report a SAE to the 
IRB and/or Coordination Center 
Over-enrollment 
 
Enrollment of subjects after IRB 
approval of the study has expired 
 
Failure to submit a continuing 
review application to the IRB 
before study expiration  
Reporting 
Requirements 
Record the date discovered, date 
occurred, description of event in 
the Protocol Deviation Log. 
 
Notify the UMass within 24 
hours. 
Report to local IRB 
Record the date discovered, date 
occurred, description of event in 
the Protocol Deviation Log. 
 
Notify UMass. 
Report to local IRB as per 
institutional policy 
I. DOCUMENTATION OF DATA 
Case Report Forms 
The case report forms (CRF) will be collected using an electronic data capture (EDC) 
system RedCap. The study team will document subject data with paper CRF individual 
subject binders which will serve as the source data. The data entry on RedCap will be 
completed by designated study staff. This should be completed soon after the subject 
completes the study visit.  
Data will be stored on the REDCap servers within the regulated environment at UMass 
Medical School (UMMS). REDCap servers are maintained by Information Technology 
and includes physically secure and electronically protected portion of the data center 
with its own insulated network space labeled “the Regulated Environment” to provide a 
secure environment for the storage and handling of sensitive electronic data including 
protected health information (PHI) and protected personal information (PPI).  The 
Regulated Environment is securely housed within the IT data center meaning physical 
access is limited to only those IT professionals employed by IT with a job related need 
and with proper electronic identification. The servers are backed up nightly, properly 
updated and patched, protected with anti-virus and anti-spyware software.  
Electronic access to sensitive data resources within the regulated environment is 
controlled using the highest standard of proven network architecture. Data will be 
transferred into the regulated environment via direct data entry, controlled web interface 
form-fill-out into a REDCap database. 
Data Capture, Review and Validation 
Study specific data that has been outlined in the protocol will be entered into the clinical 
database via the EDC system by designated site staff in accordance with the eCRF 


27 
 
Completion Guidelines. Data is verified electronically using a series of on-line 
programmed edit checks that have been created by the clinical data manager and 
programmed by the clinical data programmer or designee. Data discrepancies will be 
brought to the attention of the site staff and investigated by the clinical monitor and site 
study coordinator. The clinical monitor(s) will review and verify all eCRF data against 
acceptable source documentation during scheduled monitoring visits. The clinical 
monitor will work closely with the site study coordinator to address any discrepancies 
which have been found so that resolutions can be made and documented into the 
clinical database.   
Database Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures. Data 
queries requiring clarification will be generated and addressed by the investigational 
site.  
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  
Record Retention 
All documents pertaining to the study, including all versions of the approved study 
protocol, copy of the informed consent document and Health Insurance Portability and 
Accountability Act (HIPAA) documents, eCRFs, source documents (i.e., subject records, 
hospital records, laboratory records, medication records, etc.), and other study-related 
documents will be retained at the study site for 5 years after the study ends. 
The PI must notify and obtain approval in writing from the UMass prior to destruction of 
any study records or provide an opportunity for the UMass to collect such records.  If 
the Investigator withdraws from the study (e.g., relocation, retirement) all study-related 
records should be transferred, in a written agreement with  UMass, to a mutually agreed 
upon designee and specified timeframe. 
Data Confidentiality 
Potential risks to data confidentiality will be mitigated by requirements for the de-
identification of all study data and by security protocols for all data capture systems. All 
users of the EDC system will be tracked and provided access in a secure fashion 
following established SOPs for this process.  
As with all research data, information gathered by the study will be used only for 
aggregate analysis; it will not be released with any information that identifies research 
participants.  Pharmacogenetic information, in particular, will be coded and unlinked to 


28 
 
individual respondent identifiers. The lead study site will apply for a Certificate of 
Confidentiality in order to ensure the complete anonymity of subjects with regards to 
their drug use. If approved, the Certificate of Confidentiality will be extended to all other 
study sites. If and when a Certificate of Confidentiality is approved and extended for all 
sub-sites, language specifying this Certificate will be added to the Informed Consent 
Form.  
 Uses and risks related to data collection will be outlined in the informed consent and 
reviewed with the subjects.  
 
J. MONITORING AND OVERSIGHT 
Initiation of Study Sites 
Prior to subject enrollment, site initiation visits will be conducted by UMass at all sub 
sites. The initiation visit is completed to ensure IRB approval is obtained and 
documented; all study staff are trained and clearly understand the protocol.  
Site Monitoring  
Through the study the lead site UMass will conduct investigational site monitoring to 
ensure overall quality and compliance with protocol and applicable regulations by all 
investigators. Such monitoring activities will be conducted on-site and remotely 
including telephone calls and emails. The site will receive notification prior to the on-site 
monitoring visit. The investigator and the study staff are expected to be available on the 
day of site visit to address any queries. During the on-site study visits, subject case 
report forms (CRFs) will be reviewed for completeness and protocol compliance.  
Study Closeout Visit 
Upon completion of the study, a study closeout visit will be completed to review all study 
files and regulatory documents. The monitor will ensure all regulatory documents are 
up-to-date and complete. All study documents should be retained for an appropriate 
time period as stated in the contract.  
Other issues which will be reviewed at this visit include: possibility of site audits, 
publication policy, and ensuring that the Investigator will notify the local IRB regarding 
study closeout. 
Medical Monitoring 
The medical monitor for this trial will be a board certified psychiatrist designated by the 
lead site, UMass. The Medical Monitor will review all adverse events, review issues 


29 
 
related to subject eligibility, assess the benefits and risks of protocols on an ongoing 
basis, and work in collaboration with the IRB to identify safety signals and trends. 
K. ETHICAL CONSIDERATIONS 
Ethics Review 
 
The study protocol, ICF and all relevant documents will be reviewed and approved by 
the local IRB prior to study initiation. A written IRB approval from the committee must be 
received by UMass before starting study enrollment. The protocol must be re-approved 
by the IRB upon receipt of protocol amendments and annually, as part of their IRB 
regulatory requirements and institutional procedures. The PI or designee is responsible 
for submitting all protocol changes, SAE reports, administrative letters etc. to the IRB 
according to their regulatory policies.  
 
Ethical Conduct of the Study 
The study will be conducted as per the protocol and will adhere to the GCP standards. 
The investigators and all study staff should be trained in GCP guidelines. 
Informed Consent 
The PI must ensure to clearly explain and provide oral and written information on the 
study purpose, procedures, risks and benefits of participating (including potential risks 
involving the study medications) to each subject and/or legal guardian. All information 
should be provided in language that is easy to understand. All subjects must be 
informed that their participation is voluntary and they can withdraw from the study at any 
time if they choose.  If the subject chooses to participate, he/she or legal guardian must 
sign the informed consent form and when required, the caregiver must sign the 
caregiver ICF. Any questions, concerns, or ambiguities will be clarified by the site’s PI or 
another study clinician prior to the patient signing consent. 
 
 
L. STATISTICS AND DATA ANALYSIS 
Intent-to-treat analysis and a mixed model approach will be conducted to estimate the 
pragmatic effects of brexpiprazole treatment on the number of days of substance use in 
the past week, substance craving, psychiatric symptoms and quality of life. The entire 
12 week duration of treatment, including the 6-week switchover phase, will be included 
in the analysis. Polynomial time trends (e.g., slopes) will be used to fit the population 
mean response curve for the control group. Group-by-time interactions will be modeled 
as a function of time to fit between-group effects. Subject-specific parameters will be 
estimated to model individual subject deviations from the group mean. Baseline 
measures of substance use and clinical symptoms will also be included in the model as 
covariates.   


30 
 
 
REFERENCES 
 
1. 
Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, et al. Comorbidity of 
mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment 
Area (ECA) Study. JAMA. 1990; 264(19): 2511-8. 
2. 
DeQuardo JR, Carpenter CF, Tandon R. Patterns of substance abuse in schizophrenia: 
nature and significance. J Psychiatr Res. 1994; 28(3): 267-75. 
3. 
van Dijk D, Koeter MW, Hijman R, Kahn RS, van den Brink W. Effect of cannabis use 
on the course of schizophrenia in male patients: a prospective cohort study. Schizophr Res. 2012; 
137(1-3): 50-7. 
4. 
Albanese MJ, Khantzian EJ, Murphy SL, Green AI. Decreased substance use in 
chronically psychotic patients treated with clozapine. Am J Psychiatry. 1994; 151(5): 780-1. 
5. 
Buckley P, Thompson P, Way L, Meltzer HY. Substance abuse among patients with 
treatment-resistant schizophrenia: characteristics and implications for clozapine therapy. Am J 
Psychiatry. 1994; 151(3): 385-9. 
6. 
Sorensen G, Sager TN, Petersen JH, Brennum LT, Thogersen P, Hee Bengtsen C, et al. 
Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice. 
Psychopharmacology (Berl). 2008; 199(1): 37-46. 
7. 
Wee S, Wang Z, Woolverton WL, Pulvirenti L, Koob GF. Effect of aripiprazole, a partial 
dopamine D2 receptor agonist, on increased rate of methamphetamine self-administration in rats 
with prolonged session duration. Neuropsychopharmacology. 2007; 32(10): 2238-47. 
8. 
Brown ES, Jeffress J, Liggin JD, Garza M, Beard L. Switching outpatients with bipolar 
or schizoaffective disorders and substance abuse from their current antipsychotic to aripiprazole. 
J Clin Psychiatry. 2005; 66(6): 756-60. 
9. 
Moreira FA, Dalley JW. Dopamine receptor partial agonists and addiction. Eur J 
Pharmacol. 2015; 752: 112-5. 
10. 
Maeda K, Sugino H, Akazawa H, Amada N, Shimada J, Futamura T, et al. Brexpiprazole 
I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J 
Pharmacol Exp Ther. 2014; 350(3): 589-604. 
11. 
Fleischhacker WW. Aripiprazole. Expert Opin Pharmacother. 2005; 6(12): 2091-101. 
 
 
PROTOCOL SIGNATURE PAGE 
 
I have read this protocol and agree to adhere to the requirements. I will provide copies 
of this protocol and all pertinent information to the study personnel under my 
supervision. I will discuss this material with them and ensure they are fully informed 
regarding the conduct of the study according to 21 CFR parts 50, 54, 56 and 812, 45 
CFR 46, to GCP as described in ICH guideline E6 and to hospital Institutional Review 
Boards/Ethics Committees. 


31 
 
 
 
 
 
_____________________________ 
 
Clinical Site  
 
_____________________________ 
 
 
_____________________ 
Principal Investigator Signature 
 
 
 
Date 
 
_____________________________ 
Principal Investigator  
Printed Name