Clinical trial NCT02773212
Conditions: Cocaine-Related Disorders Anhedonia
Sponsor: University of Illinois at Chicago
Start date: 2017-02-01; Completion date: 2022-04-04
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine anhedonia as a potential moderator of treatment outcomes for Cocaine Use Disorder (CUD). Specifically, this study will investigate how anhedonia affects outcomes in contingency management (CM) treatment for CUD and whether anhedonia mediates the effects of adjunctive treatment with a dopaminergic (DAergic) drug, d-amphetamine, on outcomes in CM for CUD, as well as investigate the contribution of anhedonia to overall CUD severity.

Detailed description:
Recent research suggests that anhedonia is a key neurobehavioral dysfunction in Cocaine Use Disorder (CUD) that contributes to treatment outcomes. Anhedonia, defined here as lack of interest or pleasure in non-drug rewards, is frequently found in CUD and is related to neural deficits, such as low striatal dopamine and deficient activation to non-drug rewards in mesocortical circuits. Interestingly, not all individuals in CUD have these deficits. Preliminary data suggests that the presence of self-reported anhedonia predicts worse outcome in contingency management (CM) treatment of CUD. Moreover, low baseline dopamine predicts failure to attain abstinence in CM while medications that enhance DA increase CM success rates and responsiveness to rewards.

This study specifically aims to test the contribution of anhedonia to overall CUD severity, the relationship of anhedonia to outcomes in CM treatment, and the mediating role of anhedonia in medication enhancement of CM in CUD. To accomplish these aims, individuals with CUD will be enrolled and will undergo 4 weeks of intensive CM treatment, either with or without treatment with the dopaminergic drug, d-amphetamine. A medication only group will be included to solely measure the effects of d-amphetamine. Anhedonia will be assessed using multi-modal subjective, psychophysiological and behavioral measures of reward functioning at baseline, and each week of treatment. Functional magnetic resonance imaging (fMRI) measures of reward functioning will also be taken at baseline and week 4 in a subset of participants (n = 24)

Arms: arm 1: Participants in this group will receive 4 weeks of treatment with 60mg of sustained release d-amphetamine with contingency management treatment for cocaine use disorder. arm 2: Participants in this group will receive 4 weeks of treatment with 60mg of sustained release d-amphetamine but will not receive contingency management treatment for cocaine use disorder. arm 3: Participants in this group will receive 4 weeks of of placebo treatment, paired with contingency management treatment for cocaine use disorder.
Interventions: intervention 1: d-amphetamine intervention 2: Contingency management intervention 3: Placebo (for d-amphetamine)
Intervention descriptions: intervention 1: Participants in this group will receive 60 mg of d-amphetamine daily for 4 weeks. There will be a 1 week run up dosing and a 1 week run-down medication period. intervention 2: Contingency management is an established cocaine use disorder treatment in which individuals receive monetary rewards for abstinence. intervention 3: 60 mg of riboflavin and cornstarch as needed.

Protocol documents:
ICF_002.pdf: 
Consent Form for Targeting Anhedonia in Cocaine Use Disorder 
Principal Investigator: 
Margaret C. Wardle, Ph.D.  
 
Co-Investigators: 
Erin Berenz, Ph.D.  
Robin Mermelstein, Ph.D. 
 
Study Physician: Christopher Holden, M.D. 
Clinical Consultant: Aneet Ahluwalia, M.D. 
 
 
Sponsor:  
National Institute on Drug Abuse 
Grant K08DA040006 
PO: Will Aklin 
 
NCT02773212 
IND/IDE: 131221 
Version: 8 
Date: 4/18/2024 
 


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University of Illinois at Chicago
Research Information and Consent for Participation in Biomedical Research
Targeting Anhedonia in Cocaine Use Disorder Treatment Study
Principal Investigator/Researcher Name and Title: Margaret Wardle, Ph.D.
Department and Institution: Department of Psychology, University of Illinois at Chicago    
Address and Contact Information: 1007 W. Harrison St., MC 285 Chicago, IL 60607 
Office: 1050B, Email: mwardle@uic.edu, Office Phone: 312-413-5564 
Emergency Contact Name and Information: Margaret Wardle, Ph.D., Phone: 312-413-5564
Sponsor: National Institutes of Health
About this research study
You are being asked to participate in a research study.  Research studies answer important 
questions that might help change or improve the way we do things in the future.     
Taking part in this study is voluntary
Your participation in this research study is voluntary. You may choose to not take part in this 
study or may choose to leave the study at any time. Deciding not to participate, or deciding to 
leave the study later, will not result in any penalty or loss of benefits to which you are entitled 
and will not affect your relationship with the University of Illinois Hospital and Health Sciences 
System (UI Health) and/or University of Illinois at Chicago (UIC).
This consent form will give you information about the research study to help you decide whether 
you want to participate.  Please read this form and ask any questions you have before agreeing to 
be in the study.
Important Information
This information gives you an overview of the research. More information about these topics 
may be found in the pages that follow.
WHY IS THIS 
STUDY BEING 
DONE? 
This research is being done to test possible treatments that may help 
people quit using cocaine, and to better understand how emotions 
relate to using drugs and quitting drugs.
There is no one treatment for cocaine addiction that works for 
everyone. Thus, we are testing two possible treatments. If you take 
part in this study, you will be randomly assigned (e.g. like the flip 
of a coin) to possible treatments:  
APPROVAL
UNIVERSITY OF ILLINOIS AT CHICAGO
INSTITUTIONAL REVIEW BOARD
PROTOCOL #: ______________
   STARTS                  EXPIRES
__________    ----   ___________
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x Medication: One treatment is a medicine called "extended-
release dextroamphetamine".  This medicine is used to treat 
ADHD. Research suggests this medicine may also help 
people quit using cocaine, but this use is still experimental, 
meaning it is NOT approved by the FDA. To help us find 
out if this medication really works, the study is “blinded.” 
This means that you and the researchers will not know if you 
are getting the medication or not. While you're in the study, 
you'll take pills twice a day. They might be the medicine, or 
they might be a placebo, which are pills that look like 
medicine but don’t have any medicine in them. The placebo 
is used to keep people’s expectations about medication from 
influencing the study results. Two in three (66%) of 
participants will get the medication, while one in three 
(33%) will get the placebo. Either way, you’ll help us find 
out if this medicine helps people quit cocaine.    
 
x Rewards Program: The other treatment is a program that 
rewards you for breaking your addiction habits. In this 
treatment, you’ll get gift cards when you meet goals, like not 
using cocaine for a few days, a week, or longer. Research 
suggests this treatment can help people quit using cocaine. 
Two in three (66%) of participants will get the rewards 
program, while one in three (33%) will simply do regular 
checkup visits.  
Some people will get the medicine, some people will get the 
rewards, and some people will get both. Everyone will get a 
treatment. No matter what treatment you get, you’ll also get two 
talk therapy sessions to help you quit.  
WHAT WILL 
HAPPEN TO ME 
DURING THE 
STUDY? 
 
This study takes 7 weeks total to complete. 
 
In this week, which we call the "baseline week", you will complete 
this consent visit and a two-hour long testing session.  At the testing 
session you'll do some tests of your emotional responses to happy 
and sad things before you start treatment. It will take about two 
hours. You’ll wear sticky patches on your face, chest, and hands to 
track your emotions while you do things like looking at happy and 
sad pictures. These tests help us understand how emotions relate to 
drug use and quitting drugs.  
 
For the next 6 weeks you will be in treatment.  During treatment 
you’ll come in every Monday, Wednesday, and Friday. These 
“checkup” visits will be about 30-45 minutes. At each checkup, 
you’ll talk about your drug use and any treatment side effects. 
You’ll give a urine sample that we will test for drugs. You'll have 
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your vitals checked, and you'll get your medication. During the 6 
weeks of treatment you'll follow this schedule: 
 
Next week, which we call the "medication start week”, you'll start 
to get either the medication or placebo. Either way you will get pills 
that you take twice a day by mouth. Over this week we will 
gradually increase the dose of the medication, to make sure you are 
not having serious side effects or bad reactions to the medicine.  
 
For a month after that, which we call the "treatment month", you 
will continue to take the medication and do checkups three times a 
week.  During this month, if you have been assigned to the rewards 
program you will also get rewards as you meet treatment goals. 
Once a week you will redo the two hours of tests to see if your 
emotions are changing during treatment. You will also get two talk 
therapy sessions to help you plan and maintain a quit attempt. One 
therapy session will be in the first week and the second will be in 
the 3rd week of the treatment month. 
 
In the last week of the study, which we call the “medication stop 
week”, we will gradually decrease the medication dose back to zero.  
During this week we will work with you to plan your next steps, 
such as helping you find treatment in the community that you can 
go to after the study ends. 
 
For more information, please see the “What procedures are 
involved?” section below. 
HOW MUCH TIME 
WILL I SPEND ON 
THE STUDY? 
 
Over 7 weeks, you will come into the clinic approximately 20 times. 
We expect the entire study to take about 26 hours of your time. 
ARE THERE ANY 
BENEFITS TO 
TAKING PART IN 
THE STUDY? 
 
Based previous studies of treatments for cocaine addiction, we 
believe they may help people who want to quit or cut down on their 
cocaine use.  However, because people respond differently to 
treatments, no one can know for sure if a given treatment will help 
you. Thus, we cannot promise any benefits to you from taking part 
in this research. 
 
We also hope that the information we get from this study may help 
others with cocaine addiction in the future, because this study may 
help find which types of treatment work best for which people. 
WHAT ARE THE 
MAIN RISKS OF 
THE STUDY? 
The main risks of this study are possible side effects of the 
experimental medication. We will watch for side effects during your 
treatment and do what we can to relieve them. But you should know 
that some side effects can be serious, even life-threatening, or may 
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not go away. The possible side effects will be explained in more 
detail later in this form.  There may also be other side effects we 
don’t know about yet. 
 
For this medication there are some serious but rare side effects that 
you need to know about.  These do not happen often, but they are 
serious when they do.  These are: 
x Heart related problems, including stroke, heart attack, 
increased blood pressure and heart rate.  
x Mental problems, such as hearing voices, believing things 
that are not true, or mania, suspicion or aggression. 
x Circulation problems in fingers and toes, such that fingers or 
toes feel numb, cool, painful, or change color to pale, blue or 
red.  
 
This medication also has a number of more common but less 
serious side effects. The ones we most commonly see in our study 
are decreased appetite, restlessness, anxiety and trouble sleeping.  
 
You should not suddenly quit this medication, as this can produce 
withdrawal symptoms (e.g. depression, irritability, craving). 
 
You should not take this medication while pregnant, lactating, or 
planning a pregnancy. 
 
For details and a list of risks you should know about, please see the 
“What are the potential risks and discomforts?” section below. 
DO I HAVE OTHER 
OPTIONS BESIDES 
TAKING PART IN 
THE STUDY? 
If you decide not to take part in this study, there is other care 
available to you. Although there is no FDA-approved medication 
for cocaine addiction, there are other treatments (such as 
counseling) that are available. Dr. Wardle will discuss these other 
treatments with you if you choose not to take part in this study. You 
do not have to be in this study to be treated for cocaine addiction.  
QUESTIONS ABOUT 
THE STUDY? 
For questions, concerns, or complaints about the study, please contact 
Dr. Wardle at 312-413-5564 or email at mwardle@uic.edu. 
 
If you have questions about your rights as a study subject; including 
questions, concerns, complaints, or if you feel you have not been 
treated according to the description in this form; or to offer input 
you may call the UIC Office for the Protection of Research Subjects 
(OPRS) at 312-996-1711 or 1-866-789-6215 (toll-free) or e-mail 
OPRS at uicirb@uic.edu. 
 
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Please review the rest of this document for details about these topics and additional things 
you should know before making a decision about whether to participate in this research.  
Please also feel free to ask the study team questions at any time.  
 
Who may participate in the study? 
You have been asked to participate in this research because you told us you were interested in 
getting treatment to help you quit or cut down on your cocaine use. 
 
Approximately 55 subjects may be involved in this research at UIC.  Approximately 25 
participants have already taken part in this research at our prior location at the University of 
Texas Health Science Center in Houston, Texas.  
 
What procedures are involved? 
 
 
 
This research will take place in the ART Lab in the Behavioral Sciences Building at 1007 W. 
Harrison St., 3rd Floor, Room 3011A (this is our reception/waiting room).   
 
The total amount of time you will be in the study is about 7 weeks.  Over those 7 weeks you will 
need to come into the clinic around 20 times.  Visits can vary from 30min up to 2.5hrs depending 
on what you are scheduled to do during that visit. All together, we expect the study will take 
approximately 26 hours of your time.   
 
Special considerations for COVID-19 - Don't come to your appointment if you have cold or flu 
symptoms.  Call or text us and we will reschedule you.  You will need to wear a mask to the 
appointment (we can give you one if you don't have one). We will check your temperature at 
each appointment and reschedule you if you have a fever. Our staff will wear protective 
equipment (such as masks and gloves) when working with you. We will use a secure video chat 
software called WebEx to talk with you from another room when we can, such as for your 
therapy sessions. This reduces your risk of getting COVID by reducing the amount of time you 
are close to other people in the clinic. However, for some tests we still need to be within 6ft. of 
you (such as taking your blood pressure).  
 
If you agree here is what you will be asked to do as part of the study:   
 
x Intake Evaluation: You have already completed the intake evaluation. If you agree to take 
part in this study, the information collected during your intake becomes part of your 
records for the current study. 
x Consent and Initial Drug Use Calendar: Today, you will do the consent process, and if you 
decide to take part in the study we will also do a drug use calendar with you, to 
understand your typical patterns of use before starting treatment. We expect the visit 
today to take approximately 1hr, and you will be paid $5.00 for this visit, whether you 
decide to take part in the study or not. 
x Baseline Testing Session: You will then do the Baseline Testing Session. This is a two-
hour session that can be done any day of the week. You will be asked about your recent 
drug use and provide a urine sample to test for drugs. Then, we will attach small sticky 
sensors to your cheek and forehead to monitor electrical activity in your skin during the 
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tests. You will then complete some tests on the computer (similar to computer games).  
These will test your emotions.  As part of these tests, you will view a number of 
pictures, including both pleasant pictures (e.g. puppy dogs, ice cream cones) and 
unpleasant pictures (e.g. war scenes, attacks). You will be paid $20 for doing these tests, 
and you can also win small amounts of money during some tests (ranging from $5.00 – 
$12). 
x Medication Start Week: After the Baseline Testing Session, you will do the “Medication 
Start Week”.  During this week you will: 
o Start Checkups: During this week you will start to come in the ART Lab three 
times a week (Monday/Wednesday/Friday) for checkups. Each checkup should 
take between 30-45 min. At each checkup you will be asked about your recent 
drug use, give a urine sample to test for drugs, talk about your medication, side 
effects, and any health changes, have your vitals checked, and get your assigned 
medication. If you are female, we will also check your urine samples for 
pregnancy every 2 weeks throughout the study. You will keep doing checkup 
visits through the rest of the study. You will be paid $5.00 for each checkup.  
o Gradually Start Medication: During this week we will gradually start the 
medication you will get during the study.  If you are getting the medication, you 
will start receiving extended-release dextroamphetamine. This is a stimulant 
medication that is FDA-approved to treat Attention-Deficit/Hyperactivity 
Disorder (ADHD or ADD). Research suggests it may also help people quit using 
cocaine, although it is not FDA-approved for this. The dextroamphetamine dose 
will be increased gradually up to 60mg/day.  If you are not in the medication 
groups you will get placebo pills. Neither you nor your doctor will know if you 
are receiving dextroamphetamine or placebo, as both will look the same.  All the 
study pills will contain a marker that will appear in your urine. The marker will 
help us know whether you take the pills. We will also give you special pill bottles 
that count the number of times the bottle is opened. Always bring your pill bottle 
and any pills you didn't take to your checkups.  
x  Treatment Month: After the “Medication Start Week”, you will begin the 4-week 
“Treatment Month”. During this month you will: 
o Continue Checkups and Medication: Throughout the Treatment Month you will 
continue to come in three times a week (Monday/Wednesday/Friday) for 
checkups, and you will continue to get your assigned medication.  Each checkup 
will be the same activities, and is expected to take 30-45 min. You will continue 
to get paid $5.00 for each checkup. 
o Get Rewards Program (if assigned): If you were assigned to the rewards 
program, you will also get rewards (gift cards) during the treatment month as you 
achieve treatment goals. Each time your urine sample is negative for cocaine you 
will get a reward. The details of the reward program will be explained to you if 
you are assigned to it. The rewards will be given during your regular checkups, 
and don't require any additional time or visits. 
o Get Individual Therapy: In the 1st and 3rd week of the Treatment Month you will 
get a 1 hour-long session of individual therapy designed to help plan and maintain 
a quit attempt (total of 2 sessions). These sessions may be scheduled on the same 
day as a regular checkup, depending on your availability. We will record these 
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sessions, both for monitoring to ensure the therapy is done right, and to find out 
what parts of therapy sessions are most useful.    
o Repeat Testing Sessions: Once a week during the Treatment Month you will re-
do the 2-hour Testing Session (totaling 4 Testing Sessions during the treatment 
month). These will be just like the Baseline Testing Session described above. 
These may be scheduled on the same day as a regular checkup, depending on your 
availability. You will be paid $20 for doing the tests, and can win additional small 
amounts of money (ranging from $5 – $12) on some tests at each session. 
x Medication Stop Week: After the Treatment Month, you will do the “Medication Stop 
Week”.  During this week you will: 
o  Continue Checkups: You will still come in three times a week 
(Monday/Wednesday/Friday) for checkups.  Each checkups will be the same 
activities as before, and should take 30-45 min. You will be paid $5.00 for each 
checkup. 
o Gradually Stop Medication: During this week we will gradually reduce the 
amount of medication you are receiving until you are receiving none.  
o Get Referrals: In the last week, you will also meet again briefly with your 
therapist (15-30 min.) to wrap up and make a plan for where you will go for any 
further treatment you might need.
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Below is a table that summarizes what you will be asked to do as part of the study: 
 
What? 
During which parts of the study? 
Payment 
 
Baseline  
Week 
Medication 
Start Week 
Treatment Month 
Medication 
Stop Week 
 
Week 1 
Week 2 
Week 3 
Week 4 
Consent and initial drug 
use calendar - 1hr 
Any day 
 
 
 
 
 
 
$5 
Testing Session - 2hrs 
each 
Any day 
 
Any day 
Any Day 
Any Day 
Any Day 
 
$20 plus winnings per 
session for 5 sessions  
(total $100+) 
Checkups - 30-45min each 
- 
give urine sample 
and answer questions 
about drug use 
- 
get vitals checked 
- 
answer questions 
about medication and 
health 
- 
get medication 
 
 
M/W/F 
M/W/F 
M/W/F 
M/W/F 
M/W/F 
M/W/F 
$5 per clinic visit for 
18 visits 
(total $90) 
Pregnancy Test (for 
women) – no extra time 
 
M 
 
M 
 
M 
 
No extra payment 
Rewards Program (if 
assigned)  - no extra time 
 
 
M/W/F 
M/W/F 
M/W/F 
M/W/F 
 
Varies – you will get 
more information if 
you are assigned to 
this treatment 
Individual Therapy (1hr 
Weeks 1 and 3, 15-30 
minutes last week for 
referrals) 
 
 
Any Day 
 
Any Day 
 
Any Day 
No extra payment 
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What are the potential risks and discomforts?  
There are certain risks of participating in this study. We will discuss these known risks with you 
now. This study may also include risks that are unknown at this time.  
 
x Emotional discomfort from questionnaires and tasks: Some of the questions asked during 
the study (e.g. drug use) may be considered sensitive information. Answering these 
questions may cause frustration or distress for some people. You do not have to answer 
any questions you do not want to answer. Some of the pictures that you will see as part of 
the behavioral tasks contain negative content that may be mildly upsetting to some 
people. Please let us know now if you have particular phobias or triggers, or if you are 
still feeling upset after viewing the pictures. 
 
x Confidentiality:  Any time you provide sensitive information, there is a possible risk of 
breach of confidentiality.  Please see following section entitled “CONFIDENTIALITY” 
for further information on how we protect your confidentiality, and the limits of 
confidentiality in this study. 
 
x Sensors and monitoring: About half of people experience mild discomfort or irritation to 
the skin when we clean the sites to apply the sensors used during the Testing Sessions, 
but this should be temporary (lasting a few minutes to a few hours, depending on the 
sensitivity of your skin). In a small number of people (approximately 1 in 100) this 
irritation can last longer, or produce marks that last for up to a week. Please let us know 
now if you have unusually sensitive skin or allergies to any common skin products or 
adhesives. All electrical equipment is appropriately protected, making any electrical 
hazard from the monitoring extremely unlikely.  
 
x Study Medication:  Dextroamphetamine has a modest risk of side-effects. These are 
divided into two groups: effects that are very serious when they occur, but quite rare, and 
effects that are more common but less serious.  There also risks to suddenly stopping the 
medication, and risks during pregnancy. 
o  Serious but rare side effects include: 1. Heart related problems, including 
stroke, heart attack, increased blood pressure and heart rate. To reduce this risk, 
we did a full physical examination before we give you the medication, and we'll 
check your heart rate and blood pressure regularly during the study. Let study 
staff know right away if you have any signs of heart problems, such as chest pain, 
shortness of breath, or fainting while taking the study medication. 2. Mental 
problems, such as hearing voices, believing things that are not true, or mania, 
suspicion or aggression. To reduce this risk, we have asked you about your mental 
health history before we give you the medication, and we ask about these 
symptoms regularly during the study. Let study staff know right away if you are 
experiencing changes in your thinking or behavior while taking the study 
medication. 3. Circulation problems in fingers and toes, such that fingers or toes 
feel numb, cool, painful, or change color to pale, blue or red. To reduce this risk, 
we have done a full physical examination before we give you the medication, and 
we ask about these symptoms regularly during the study.  Let study staff know 
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right away if you experience these signs, or have any unexplained wounds on 
your fingers or toes while taking the study medication.  
o More common but less serious side effects include: allergic reactions, blurred 
vision, fast or irregular heartbeat, decreased appetite, restlessness, anxiety, 
tremors, headache, trouble sleeping, dizziness, stomach upset, weight loss, dry 
mouth, diarrhea or constipation, impotence, changes in sex drive, frequent or 
prolonged erections.  
o Suddenly stopping dextroamphetamine may cause depression, irritability, and 
changes in sleep, appetite and craving.  At the end of the study we will help you 
taper off of the medication to avoid these effects. Please note, even if the study 
medication works for you, after the study ends, the medication may not be 
available to you through your doctor or insurance program. There is a risk that 
you will relapse to using cocaine after stopping the study medication. 
o Risks during pregnancy may exist with dextroamphetamine. Therefore, 
pregnancy testing will be done every two weeks during the study. Female patients 
of childbearing potential must not be pregnant or lactating, and if sexually active, 
must be using acceptable methods of birth control to be enrolled in the study. 
Acceptable methods include: (1) surgical sterilization (such as tubal ligation or 
hysterectomy), 2) approved hormonal contraceptives (such as birth control pills, 
patches, implants or injections), (3) barrier methods (such as a condom or 
diaphragm) used with a spermicide, or (4) intrauterine device (IUD).  If you 
become pregnant while taking part in this study or if you have unprotected sex, 
you must inform the study staff immediately. 
  
Will I be told about new information that may affect my decision to participate?  
During the course of the study, you will be informed of any significant new research findings 
(either good or bad), such as changes in the risks or benefits resulting from participation in the 
research or new alternatives to participation, that might cause you to change your mind about 
continuing in the study.  If new information is provided to you, your consent to continue 
participating in this study may be re-obtained. 
 
Are there benefits to taking part in the research?  
 
Based on experience with these treatments in individuals with cocaine addiction, we believe they 
may help people who want to quit or cut down on their cocaine use.  However, because people 
respond differently to therapy, no one can know in advance if it will be helpful for you. Thus it is 
possible you may not benefit from this research. 
 
It is also hoped that knowledge gained from this research may benefit others with cocaine 
addiction in the future, because this study will help find which types of treatment work best for 
which people. 
 
What other options are there? 
If you decide not to enter this study, there is other care available to you. Although there is no 
FDA-approved medication available for cocaine addiction, there are other treatments (such as 
counseling) that are available in the community. Dr. Wardle will discuss these other treatment 
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options with you if you choose not to take part in this study. You do not have to be in this study 
to be treated for cocaine addiction.  
 
What about privacy and confidentiality?  
The people who will know that you are a research subject are members of the research team. As 
noted above, a possible risk of the research is that your participation in the research or 
information about you and your health might become known to someone outside the research 
team. We take several steps to protect against this.  First, you will be assigned a number, which 
will be used instead of your name on all paper and electronic forms. However, we do keep a list 
that links your name with this number. We do this because sometimes the same person wants to 
take part in a few of our studies, and it is helpful for us to know if someone has been in one of 
our studies before. For example, we would not put people in the same treatment if they had side 
effects from it before.  We store all paper forms in locked cabinets in a locked room in our clinic. 
We store all electronic information on our password protected and encrypted server, which is 
maintained by the University’s IT services. Only authorized study staff have access to paper and 
electronic forms. We do keep your results in your research record indefinitely.  The exception to 
this is the video recordings we will take of your therapy sessions using WebEx. At the 
conclusion of the study we will have these sessions securely transcribed, and we will delete the 
original video recordings. Until that time, they will be stored temporarily on our secure, 
password protected, encrypted servers. After that time, the transcriptions will be similarly stored 
on our secure, password protected, encrypted servers. 
 
To help us protect you and the information we will be collecting from you, this research has been 
given a Certificate of Confidentiality by the U.S. government.  This Certificate means that the 
researchers cannot be forced, even by courts or the police, to disclose any information about you. 
No information about you, or provided by you, during the research, will be disclosed to others 
except if necessary to protect your rights or welfare (for example, if you are injured and need 
emergency care), with the exception of the situations described below: 
 
1. Study information which identifies you and the consent form signed by you may be 
looked at by the following regulatory groups, which monitor the conduct of our studies:  
x The Food and Drug Administration (FDA) 
x The funding agency, the National Institutes of Health 
x UIC Office for the Protection of Research Subjects 
x The Data Safety Monitoring Board for this study 
 
2. You may still disclose, or agree in writing to allow researchers to disclose, information 
about you.  For example, if you would like an employer or insurer to know something 
about you that is documented in this research, you can write and sign a statement telling 
the researchers it is okay to give your employer or insurance company information. 
 
3. If you disclose actual or suspected abuse, neglect, or exploitation of a child, or disabled 
or elderly adult, the researcher or any member of the study staff must, and will, report 
this to the state’s child protective services, adult protective services, and/or the nearest 
law enforcement agency.  
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4. If you tell us that you are seriously thinking about hurting yourself, or hurting someone 
else, we may report this to medical personnel or to appropriate authorities. 
 
We my share data collected as part of this study with other researchers who are interested in 
similar questions.  We will only share your data with other researchers either when that data 
cannot be used to identify you in any way, or when there is a written agreement in place that the 
data will be used solely for research, that no individuals will be identified in any publications, 
that data will be secured by equivalent electronic safeguards, and that once data analysis is 
complete, the data will be returned to us or destroyed. When the results of the research are 
published or discussed in conferences, no information will be included that would reveal your 
identity.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. law.  This web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
  
What if I am injured as a result of my participation?  
You should let any health care provider who treats you know that you are in a research study. If 
you do seek medical treatment, please take a copy of this document with you because it may help 
the doctors where you seek treatment to treat you. It will also provide the doctors where you seek 
treatment with information they may need if they want to contact the research doctors.  
 
UIC has not set aside any money to pay you or to pay for your treatment if you get ill or injured 
from being in the study. There are no plans for the University to provide other forms of 
compensation (such as lost wages or pain and suffering) to you for research related illnesses or 
injuries. The only exception to this policy is if it is proved that your injury or illness is directly 
caused by the negligence of an UIC employee.  
 
By signing this form, you are not giving up any legal rights to seek compensation of injury.   
 
What are the costs for participating in this research study?   
 
There are no costs to you for participating in this research. 
 
Will I be reimbursed for any of my expenses or paid for my participation in this research? 
You will be paid for taking part in this research study. For each of the five 2-hr Testing Sessions, 
you will receive $20, plus your winnings on the tests, which can range from $5 - $12 per session.  
For the consent visit today and each of the 18 regular clinic visits (3 times per week during the 
Medication Start Week, four-week Treatment Phase, and Medication Stop week) you will 
receive $5.00. Thus, if you complete all study visits, your minimum total payment will be 
$195.00, plus your winnings from the Testing Sessions. If you are randomly assigned to be in the 
Rewards Program, you will also have the chance to earn rewards (gift cards) each time you 
provide a urine sample that is negative for cocaine. Finally, you will receive bus or parking 
passes to cover transportation costs each time you need to come into the clinic. We can also send 
an Uber for you once a week during the study, to help you get in if you are having trouble 
coming to a visit. 
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You will receive your payments at the end of each visit.  At each visit you can get up to $25 of 
your payment in cash. Any amount left over $25 will be paid in gift cards. Because your 
payment in the study may exceed the threshold for tax reporting, we will need to collect your 
social security number or Taxpayer Identification Number (TIN) in order to issue your 
compensation and for tax reporting purposes to the United States Internal Revenue Service 
(IRS).   
 
Can I withdraw or be removed from the study?  
If you decide to participate, you are free to withdraw your consent and discontinue participation 
at any time without affecting your future care at UIC. For your safety, however, you should 
consider the investigator’s advice about how to leave the study.  As described above, suddenly 
stopping dextroamphetamine may cause depression, irritability, and changes in sleep, appetite 
and craving.  If you chose to withdraw early we will offer to help you taper off of the medication 
over 1 week to avoid these effects. You may also request to have your information removed from 
our database at any time by contacting Dr. Wardle, at phone number 312-413-5564, and your 
information will be removed.  
 
The researchers and sponsor also have the right to stop your participation in this study without 
your consent if:  
x You are determined to be ineligible; 
x You are unable to follow study guidelines; 
x Your medical condition changes or you have side effects of the medication; 
x New information becomes available that indicates that participation in this study is not in 
your best interest 
x If the study is stopped. 
 
In the event you withdraw or are asked to leave the study, you will still be compensated for visits 
you have already attended, as described above. 
 
What if I am a UIC student? 
 
 
You may choose not to participate or to stop your participation in this research at any time.  This 
will not affect your class standing or grades at UIC.  The investigator may also end your 
participation in the research.  If this happens, your class standing or grades will not be affected.  
You will not be offered or receive any special consideration if you participate in this research. 
 
What if I am a UIC employee?   
 
Your participation in this research is in no way a part of your university duties, and your refusal 
to participate will not in any way affect your employment with the university, or the benefits, 
privileges, or opportunities associated with your employment at UIC.  You will not be offered or 
receive any special consideration if you participate in this research. 
 
What other things should I know? 
Our study physician, Dr. Christopher Holden, is also the Director of the UIC Recovery Clinic, 
and the Medical Director of the Substance Abuse Residential Rehabilitation Treatment Program 
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at the Jesse Brown VA.  If you were referred to the study from one of these clinics, you should 
know that Dr. Holden is a researcher on this study, and as a researcher, is interested in both your 
clinical welfare and in the conduct of this study. Before entering this research study or at any 
time during the research study, you may ask for a second opinion about your care from a health 
care provider who is not associated with this research study. You do not have to participate in 
any research study offered by your healthcare provider. A decision to not participate will not 
affect your clinical care with Dr. Holden now or in the future. You should also know that we 
sometimes refer participants to these clinics for treatment, if they offer services that are 
appropriate for that person (e.g. if an individual needs additional treatment after completing the 
study).  If you are uncomfortable being referred to clinic run by someone affiliated with the 
study, we are happy to provide a different referral. Your decision to accept or decline a referral 
does not affect your ability to participate in this study.  
 
Remember:   
 
 
 
Your participation in this research is voluntary.  Your decision whether or not to participate will 
not affect your current or future relations with the University.  If you decide to participate, you 
are free to withdraw at any time without affecting that relationship. 
 
Signature of Subject 
I have read (or someone has read to me) the above information.  I have been given an 
opportunity to ask questions and my questions have been answered to my satisfaction.  I agree to 
participate in this research.  I will be given a copy of this signed and dated form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Printed Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
 
Date (must be same as subject’s) 
 
 
 
 
 
 
 
 
Printed Name of Person Obtaining Consent 
 
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Prot_SAP_000.pdf: 
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Protocol for Targeting Anhedonia in Cocaine Use Disorder 
Principal Investigator: 
Margaret C. Wardle, Ph.D.  
 
Co-Investigators: 
Erin Berenz, Ph.D.  
Robin Mermelstein, Ph.D. 
 
Study Physician: Christopher Holden, M.D. 
Clinical Consultant: Aneet Ahluwalia, M.D. 
 
 
Sponsor:  
National Institute on Drug Abuse 
Grant K08DA040006 
PO: Will Aklin 
 
NCT02773212 
IND/IDE: 131221 
Version: 7 
Date: 12/16/2021 


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1.0 
Project Summary/Abstract 
Cocaine Use Disorder (CUD) creates high health burdens and is resistant to treatment 
[1]. Success rates for CUD treatments are <50%, and there are no FDA-approved 
medications. One way to improve the success rate of CUD treatments may be to target 
specific neurobehavioral dysfunctions thought to underlie treatment failure. Anhedonia, 
i.e. lack of interest or pleasure in non-drug rewards, is one such target. Anhedonia is 
common in CUD, and individuals who present with anhedonia tend to have worse 
treatment outcomes. Pre-clinical studies suggest anhedonia may be produced by 
impairments in any of several reward-related functions, including the ability to 
experience pleasure, motivation for rewards, or the ability to learn and adapt behavior 
based on previous rewards. Most of these functions depend critically on dopaminergic 
brain circuits, and consistent with this, dopaminergic drugs modestly improve CUD 
outcomes. However, it is unknown which reward-related functions are most important 
to CUD outcomes, and further, whether improvements in reward functioning are the 
mechanism by which dopaminergic drugs enhance outcomes. This knowledge gap 
makes it difficult to target treatments to those who could benefit most, or refine 
treatments to more effectively engage key mechanisms. The current study tests: 1. 
How several reward-related functions relate to CUD severity at baseline, 2. Which of 
these reward-related functions are most important to treatment outcomes, using brief 
intensive Contingency Management as a model treatment. 3. Whether treatment with a 
dopaminergic stimulant improves Contingency Management outcomes, and if so, 
whether restoration of reward-related functioning is key to this effect. To address these 
questions, 80 individuals with CUD will complete an efficient proof-of-concept clinical 
trial, consisting of baseline measures of addiction severity followed by four weeks of 
treatment. Participants will be randomized to one of three treatment groups: One group 
will receive 4 weeks of intensive Contingency Management with placebo (CM/PL, 
n=30); one will receive 4 weeks of intensive Contingency Management with 60mg 
extended-release dextroamphetamine (CM/ER-AMP; n=30), a stimulant that increases 
dopamine levels, positively affects reward functioning, and has modest stand-alone 
efficacy for CUD; a third medication-only control group (n=20) will receive 60mg 
extended-release dextroamphetamine alone for 4 weeks, to answer secondary 
questions about importance of anhedonia when rewards are not part of treatment, and 
estimate effects of extended-release dextroamphetamine alone on anhedonia and 
clinical outcomes. Initial attainment of abstinence is the primary clinical outcome, and 
multi-modal measures of reward functioning will be taken at baseline and once each 
treatment week.  


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2.0 
Background/Scientific Rationale  
Cocaine is the third most abused drug in the U.S. [2], and the drug most often involved 
in ER visits [3]. Around one-fourth of cocaine users have Cocaine Use Disorder (CUD), 
and these individuals disproportionately account for cocaine-associated health burdens 
[3,4]. Yet success rates for CUD treatments are below 50% [5], and unlike nicotine, 
alcohol and opiate disorders, there are no FDA-approved medications for CUD. Thus, 
CUD is a critical public health problem that has been relatively intractable to standard 
treatment development approaches [1]. 
 
Limitations of Current Approaches. One major limitation in treatment development for 
CUD, and all psychiatric disorders, has been a reliance on traditional efficacy testing, in 
which main effects on clinical outcomes (e.g. abstinence) are the focus. Often clinical 
trials do not target or even measure putative underlying neurobehavioral mechanisms. 
This makes trial failures costly and uninformative, as it is unclear whether a mechanism 
was not engaged, was unrelated to clinical outcomes, or was only active in a sub-set of 
patients. This has been likened to attempting to treat “stomach pain disorder”, which 
could be an ulcer, food poisoning, or cancer [6]. Indeed, CUD clinical trials have 
generally targeted drug use, rather than possible neurobehavioral mechanisms, and 
only secondarily, if at all, examined which mechanisms are engaged in which patients. 
 
An Alternate Approach: Target Neurobehavioral Dysfunction. An alternative approach, 
promoted by the NIMH’s Research Domain Criteria (RDoC) project, is to use our 
knowledge of the brain’s functions to “map” the basic neurobehavioral dysfunctions 
occurring in psychiatric disorders [7], and include measures of these putative underlying 
dysfunctions in treatment development from the ground up, as moderators, mediators, 
and eventually, primary outcomes. This approach could allow us to target pathologies 
that cut across disorders, with impacts beyond any one diagnosis, and to personalize 
treatment via more effective subtyping within disorders (as proposed here). The current 
proposal applies this approach to CUD in a proof-of-concept study: identifying a key 
neurobehavioral dysfunction, testing whether this dysfunction predicts treatment 
outcomes, and targeting this dysfunction directly.  
 
Anhedonia: A Key Neurobehavioral Dysfunction in CUD. Several lines of evidence 
suggest that anhedonia is a key neurobehavioral dysfunction in CUD that contributes to 
treatment outcomes. Anhedonia, defined here as lack of interest or pleasure in non-drug 
rewards, is common in CUD [8–10], as are related neural deficits [11], such as low 
striatal dopamine [12]  and deficient responses to non-drug rewards in mesocortical 
circuits [13–16]. However, not all individuals with CUD have these deficits [14]. Indeed, 
preliminary data from our previous treatment studies shows that the presence of self-
reported anhedonia predicts worse outcomes in Contingency Management [17], an 
established CUD treatment in which individuals receive monetary rewards for 
abstinence [18]. Consistent with this, low baseline dopamine also predicts failure to 
attain abstinence in Contingency Management [19]. Further, medications that enhance 
dopamine increase Contingency Management success rates [20], and our previous 


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research suggests such medications enhance responsiveness to reward [21,22]. Putting 
this evidence together, it appears that variations in anhedonia may explain 
heterogeneity in Contingency Management outcomes, and that dopaminergic drugs 
may improve Contingency Management outcomes by improving anhedonia [19]. This 
study will be the first to test this hypothesis comprehensively, using a sophisticated 
neuroscience-based approach to anhedonia.   
 
A Neuroscience-Based Approach to Anhedonia. Classically, anhedonia was 
characterized as inability to feel pleasure, and nucleus accumbens dopamine was 
thought to underlie pleasure [23]. However, a more nuanced understanding has 
emerged, identifying three major reward functions: 1. Consummatory reward, i.e. 
pleasure from rewards, mediated by opioid “hotspots” in the nucleus accumbens and 
ventral pallidum in a circuit with ventromedial prefrontal cortex and anterior cingulate 
cortex [24]. 2. Motivational reward, i.e. exertion of effort for reward, controlled by tonic 
pacemaker-like dopamine activity in the ventral tegmental area that preferentially 
activates D2 receptors in the nucleus accumbens [25] in a circuit with ventromedial 
prefrontal cortex, anterior cingulate cortex and amygdala [26]. 3. Reward learning, i.e. 
adaptation of behavior based on reward history, encoded by fast phasic dopamine 
bursts in the ventral tegmental area [27] that preferentially activate D1 nucleus 
accumbens receptors sensitive to higher dopamine concentrations [25], in a circuit with 
dorsolateral prefrontal cortex [28]. This phasic “prediction error” signal is initially evoked 
by reward, decreases as reward becomes predictable, and re-appears if reward is 
unexpected [27]. It is unlikely these functions are totally orthogonal, but they are at least 
partially independent [11,29], and given its pathology, CUD may impair any or all of 
them [30]. To target treatment, it is critical to understand the roles these distinct 
processes play in CUD outcomes. It is unlikely that self-reports alone will cleanly map 
these distinct functions [31]. Thus, the proposed approach is multi-modal, using 
subjective, behavioral, psychophysiological and neural measures of reward functioning. 
Critically, functional Magnetic Resonance Imaging (fMRI) is included to assess 
underlying neural processes.  
 
3.0 
Objectives/Aims 
The current study will test the primary hypothesis that anhedonia is a key 
neurobehavioral dysfunction in CUD that underlies variability in Contingency 
Management outcomes, and that dopaminergic drugs enhance Contingency 
Management outcomes by reducing anhedonia, through the following specific aims: 
 
Specific Aim 1. Test the contribution of anhedonia to overall Cocaine Use Disorder 
(CUD) severity. Our hypothesis is that higher anhedonia at baseline will relate to greater 
addiction severity at baseline. This will be tested using linear regression to examine the 
relationship between a composite score of CUD severity, and anhedonia, defined as 
scores on the three major reward functions at baseline (see Section 9.0, Data Analysis 
for details on derivation of scores). 
 
Specific Aim 2. Test the relationship of anhedonia to treatment outcomes in 
Contingency Management for CUD. Our hypothesis is that higher anhedonia at 


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baseline will predict lower probability of achieving abstinence, and further, will be more 
strongly predictive of outcomes in the Contingency Management groups, where external 
rewards are part of treatment, than in the dextroamphetamine-only control group. This 
will be tested using generalized linear modeling of the probability of attainment of initial 
abstinence, defined as 2 consecutive weeks of cocaine negative urine drug tests, as a 
function of reward functioning scores at baseline by treatment group.  Secondarily, we 
will use general linear modeling to examine the continuous measure of Treatment 
Effectiveness Scores, defined as number of cocaine negative urines submitted during 
the protocol, as a function of reward functioning scores at baseline by treatment group.  
 
Specific Aim 3. Test the mediating role of anhedonia in medication enhancement 
of Contingency Management for CUD. Our hypothesis is that the combination of 
Contingency Management and extended-release dextroamphetamine will be more 
effective than either Contingency Management or extended-release dextroamphetamine 
alone, and that this synergistic improvement in outcomes will be mediated by 
improvements in anhedonia. This will be tested utilizing Bayesian Structural Equation 
Modeling to model indirect effects of treatment group (CM/PL, CM/ER-AMP, ER-AMP 
only) on abstinence, defined using the same primary and secondary measures as Aim 2, 
with change in reward functioning scores over treatment as the mediator. Of note, 
change measures are sometimes ill-conditioned (e.g. large error terms, little reliable 
variability), and if this is the case here, we will use reward functioning scores at a 
specified midpoint instead.  
 
Design Overview: These aims will be accomplished within a single efficient randomized, 
controlled, double-blind trial (see Figure 1. Schematic of Study Design, below).  
 
 
Figure 1 – Schematic of Study Design for both Treatment Study and fMRI Sub-Study 
Notes: UDS = Urine Drug Screen; EKG = Electrocardiogram; fMRI = Functional 
Magnetic Resonance Imaging 
 
In the Treatment Study, 80 individuals with CUD will complete baseline measures of 
addiction severity, a 1-week dose escalation, four weeks of treatment, and a 1-week 
dose de-escalation (see Figure 1). Participants will be randomized to one of three 
groups: one receiving 4 weeks of treatment with intensive Contingency Management 
with placebo (CM/PL, n=30), one receiving 4 weeks of treatment with intensive 
Contingency Management with 60mg extended-release dextroamphetamine (CM/ER-
AMP; n=30), or an additional control group (n=20) receiving 4 weeks of treatment with 


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60mg extended-release dextroamphetamine without CM, to answer secondary 
questions about importance of anhedonia when abstinence-contingent rewards are not 
part of treatment, and estimate effects of dextroamphetamine alone on outcomes and 
anhedonia. All subjects will complete subjective, behavioral and psychophysiological 
measures of reward functioning at baseline and once each treatment week.  
 
4.0 
Eligibility 
Participant Overview: Participants in the Treatment Study will be 80 treatment-seeking 
male and female adults aged 18-60 years who meet DSM-V criteria for current CUD of 
at least moderate severity. Participants will be recruited without regard to race, religion 
or ethnicity.  
 
4.1 Inclusion Criteria 
Inclusion Criteria for Main Treatment Study: 
Inclusion Criteria:   
1. be between 18 and 60 years of age 
2. meet DSM-5 criteria for current cocaine use disorder of at least moderate 
severity (≥ 4 symptoms) 
3. have at least 1 cocaine positive urine sample during the baseline 
screening period 
4. be in acceptable health on the basis of interview, medical history and 
physical exam, per the judgment of our study physician 
5. be able to understand the consent form and provide written informed 
consent 
6. be able to provide the names of at least 2 persons who can generally 
locate their whereabouts.  
7. if female, agree to use an acceptable method of birth control during study 
(surgical sterilization, approved hormonal contraceptives, barrier methods 
with spermicide, or intrauterine device).  
 
4.2 Exclusion Criteria 
Exclusion criteria for Main Treatment Study: 
1. current DSM-5 diagnosis for substance use disorder of least moderate 
severity (≥ 4 symptoms), other than cocaine, nicotine, marijuana, or 
alcohol 
2. Physical dependence on alcohol requiring medically supervised 
detoxification, in the judgment of the study physician 
3. current amphetamine use (by self-report in past 30 days or positive urine 
drug screen), more than 50 lifetime uses of amphetamine, or history of 
DSM-5 Amphetamine Use Disorder 
4. a current DSM-5 axis I psychiatric disorder or neurological disease or 
disorder requiring ongoing treatment and/or making study participation 
unsafe, or any history of mania or a psychotic disorder 
5. significant current suicidal or homicidal ideation 


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6. medical conditions contraindicating dextroamphetamine (e.g., significant 
cardiovascular disease, liver or kidney disease, seizure disorder, 
hypotension or hypertension)  
7. taking medications known to have effects on the central nervous system 
or that could cause significant drug interactions with dextroamphetamine 
(e.g., clonidine, prazosin) 
8. having conditions of probation or parole requiring reports of drug use to 
officers of the court 
9. impending incarceration 
10. pregnant or nursing for female patients 
11. inability to read, write, or speak English 
 
4.3 Excluded or Vulnerable Populations 
Vulnerable Populations and Protections. Children will not be included in this 
research.  The incidence of CUD in individuals under the age of 18 is small, so a 
study not specifically targeting children for recruitment is unlikely to produce 
usable information about this sub-group.  Further, validated treatment 
approaches for children with substance use disorders are different than those 
used with adults (and proposed here).  Together this makes the risk/benefit ratio 
for children unacceptable for this study.  Pregnant women will not be included as 
dextroamphetamine is a Class C drug for pregnancy.  Prisoners will not be 
included, as this is an outpatient study. Based on the demographics of individuals 
with CUD in the community and our experience to date, the study is likely to 
include individuals that are socially and economically disadvantaged or 
homeless.  To reduce potentially coercive aspects of the study for these 
individuals, base compensation is not excessive.  Although rewards in 
Contingency Management can be high, research suggests that Contingency 
Management is equivalently effective across individuals of different 
socioeconomic status, suggesting these rewards are not inequitably coercive of 
behavior for disadvantaged individuals [32]. The nature of the study can place 
individuals at risk of economic, social or legal consequences, as quantifying drug 
use is key to the study and the subject are expected to be illicit substance users. 
To address these risks we have strict confidentiality controls (see Section 13.2, 
Subject Confidentiality), and we carefully inform subjects about any remaining 
risks that cannot be mitigated.  We also exclude individuals having conditions of 
probation or parole, as dextroamphetamine may produce positive drug tests that 
could be considered a violation of probation or parole, increasing the risk of legal 
consequences for these individuals.   
 
Justification of Excluded Populations. The primary exclusion criteria for this study 
are medical or psychiatric contraindications to dextroamphetamine or other study 
procedures (e.g. fMRI).  These are required to maintain safety.  Aside from 
these, as noted above we additionally exclude children and individuals on 
probation or parole, as these individuals have less favorable risk/benefit ratios. 
We also exclude individuals who cannot read, write or speak English as our 
forms and measures have not been translated and validated in other languages. 


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5.0 
Subject Enrollment 
Recruitment Strategy: Participants will be non-hospitalized, self-referred persons who 
call in response to various advertising strategies, including print media (e.g. Chicago 
Reader, RedEye, Chicago Defender, Chicago Free Press), online media, 
advertisements on public transit, flyers, posters and brochures placed in the community, 
and clinic referrals in the Chicago area. Men and women of all ethnic backgrounds will 
be recruited to participate. It is anticipated that the subject demographic profile will 
closely mirror the larger population of individuals with CUD from which they are 
recruited.  However, efforts will be made to increase the percentage of women and 
minorities in the study. These efforts will include (1) having study staff present 
educational material and referral information at women’s clinics in Chicago and the 
surrounding communities; (2) targeted advertising in newspapers which serve African-
American and Latino communities (e.g. Chicago Defender, La Raza, Hoy); (3) 
distributing flyers and notices in neighborhoods known to have a high minority 
population; and (4) having the staff contact church and community leaders in minority 
communities to provide educational material about CUD and its consequences and also 
provide contact information to aid in referrals to our clinic. 
 
Screening and Intake: Individuals responding to these recruitment strategies will be 
screened under the ART Lab General Screening Protocol, which has been separately 
submitted for approval.  Briefly, subjects will first complete a short questionnaire on the 
telephone or online via REDCap, to determine general fit with inclusionary/exclusionary 
criteria.  This screening will include a study-specific description and questions for 
individuals calling regarding the current study (see attached Study Description and 
Study Specific Questions). Potentially eligible subjects will be scheduled for screening, 
which consists of interviews, questionnaires, medical screening and feedback. This 
protocol generally takes 5-6 hours and may be completed over 3-4 sessions, depending 
on subject availability. At the initial interview session, in a socially-distanced session at 
the ART Lab in BSB, subjects will complete structured diagnostic interviews, including 
two measures that will be used to establish addiction severity for Aim 1: The Structured 
Clinical Interview for DSM-V (SCID) [33], a well-established diagnostic interview; The 
Addiction Severity Index (ASI) [34], a semi-structured interview quantifying functional 
impacts of drug use across life domains; Please note, the SCID and ASI instruments 
are separately approved as part of the ART Lab Screening Protocol, and will not be 
used again during the current study, and therefore are not attached here. Participants 
will then complete a questionnaire session, also via a socially distanced in-person 
session. Participants who appear likely to qualify based these investigations will be 
scheduled for medical screening at the Center for Clinical Research, which includes a 
physical conducted by a nurse practitioner, electrocardiogram, urine samples for drug 
tests, and blood and urine samples for basic laboratory measures (see ART Lab 
Screening Protocol for details).  Results will be reviewed by the PI, who is a licensed 
clinical psychologist, the study physician, Dr. Holden, who is an addiction medicine 
specialist, and our clinical consultant. Dr. Ahluwalia, who is dual board-certified in 
internal medicine and psychiatry and will provide consultation on ECG interpretation and 
any questionable medical conditions.  This review will establish the inclusion and 


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exclusion criteria.  At the conclusion of the screening process, subjects will receive 
feedback, including being informed of any pertinent clinical findings from the screening.  
Participants will be either provided with appropriate referrals (if ineligible) or scheduled 
for the consent process for the current study (if eligible). Data collected during the 
screening for subjects that enroll in the study becomes part of the study record, and is 
stored per study guidelines.  Data for subjects that are ineligible or do not complete the 
consent is stored per the ART Lab Screening Protocol (approved separately). 
 
Consent Session: Participants will provide consent for the standard ART Lab screening 
separately (see separate protocol).  At the conclusion of the screening protocol, eligible 
subjects will complete the informed consent for the current study. See Section 13.1, 
Informed Consent for details on consent process for the current study.  At the same 
session, immediately after consent, subjects will complete the 30-day Timeline Follow 
Back (TLFB) [35] interview (see attached), which obtains estimates of recent drug use 
using standard aids (calendars, marking memorable events), which is given to assess 
cocaine use for 30 days prior to study enrollment (see Drug Use Measures, below). This 
will be conducted using the study Timeline Follow Back and Contingency Management 
Manual, attached.  
 
 
 
6.0 
Study Design and Procedures 
Performance sites. The majority of study procedures (initial intake, consent, treatment 
visits, behavioral sessions, therapy sessions) will be performed in the Behavioral 
Sciences Building in the ART Lab and adjoining Office of Applied Psychological 
Services, the UIC Psychology Department’s outpatient psychology clinic. Medical 
screening (as approved separately under the ART Lab Screening Protocol) will be 
performed in the UIC Clinical Research Center.  
 
Major Changes for COVID-19.  Because the primary outcome for the study is 3x weekly 
urine samples, we are unable to move to telehealth visits.  Instead, we have adapted 
our in-person procedures as follows. 
1. Before each participant visit, cleaning will take place per our approved BioRaft 
registration. 
2. Participants will be required to pass a standard COVID-19 screening 
questionnaire upon arrival, to wear a mask at the session (masks will be provided 
for people who do not have one), and to pass a temperature screening upon 
arrival.  If these criteria are not met, the session will be rescheduled, and the 
participant may be withdrawn from the study, run-down from the medication, and 
provided with referrals for treatment of COVID-19 symptoms, as appropriate (e.g. 
for confirmed cases). 
3. Research assistants will wear ASTM-certified medical grade masks during any 
face-to-face interaction with participants. 
4. Any procedures that can be conducted via webcam from another room (e.g. 
therapy sessions) will be completed via webcam using HIPAA-approved UIC web 
conferencing software (WebEx). Webex rooms will be “locked” at all times when 


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participants are being given instructions or therapy sessions are happening.  
Recording of sessions will now also be done using Webex, to secure, on-
campus, UIC controlled computers, per UIC approved protocols, rather than 
using a separate audio recorder. See attached “Distanced Communication 
Procedures” for details 
5. Any procedures that must be completed via face-to-face interaction, but can 
be completed while maintaining a 6ft. distance (e.g. providing urine samples) will 
be completed using 6ft. distancing. 
6. For the minority of procedures that cannot be completed while maintaining 6ft. 
distance (e.g. blood pressure measurements) additional PPE will be required for 
the research assistant, consisting of a face shield and gloves. Face shields will 
be cleaned in-between participants.  
 
Overview of Study Design. 80 individuals with CUD who participate in the Treatment 
Study will complete a 1-week screening and study intake (described briefly above under 
Screening and submitted separately for approval as the ART Lab General Screening), a 
1-week dose escalation, four weeks of treatment, and a 1-week dose de-escalation.  All 
subjects will complete subjective, behavioral and psychophysiological measures of 
reward functioning at baseline and once each treatment week. Details on each 
procedure are provided below. 
 


 
 
 
 
Figure 2. Overview of Study Procedures by Visit 
Notes: ER-AMP = extended-release dextroamphetamine; UDS = Urine Drug Screen; TLFB = Timeline Follow Back; 
AE/SAE = Adverse Events/Serious Adverse Events Questionnaire; C-SSRS = Columbia Suicide Severity Rating Scale; 
MEMS = Medication Event Monitoring System
Procedure 
Participant 
Time  
Screening 
(1-3 visits) 
Week 1 - 
Baseline 
Week 2 – 
Run-up  
Week 3 -
Treatment 1 
Week 4 – 
Treatment 2 
Week 5- 
Treatment 3 
Week 6 -
Treatment 4 
Week 7 – 
Run-Down 
 
 
 
 
M 
W 
R* 
F 
M 
W 
F 
M 
W 
F 
M 
W 
F 
M 
W 
F 
M 
W 
R* 
F 
Addiction 
Severity 
Measures  
60min 
(part of  
3-4hr 
screening) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reward 
Functioning 
Assessments  
120min 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Medication 
Treatment 
(mg/day in 
ER-AMP 
groups) 
5min 
* take 
home 
dose 
 
 
X 
15
mg 
X 
30
mg 
* 
45
mg  
X 
60 
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
60
mg 
X 
45
mg 
X 
30
mg 
* 
15
mg 
X 
0 
mg 
Contingency 
Management 
5min 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Motivational 
Interviewing 
60min 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Drug Use 
Measures  
(UDS, TLFB) 
10min 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety 
Measures 
(vitals, 
AE/SAE 
concomitant 
medication, C-
SSRS) 
15min  
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy 
Test (for 
women) 
No 
additional 
subject 
time 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Adherence 
Measures  
(MEMS, 
riboflavin) 
No 
additional 
subject 
time 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Wrap up and 
referrals (with 
therapist) 
15-30min 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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Reward Functioning Assessment Sessions. Each Reward Functioning Assessment 
Session will take 2 hours over 1 visit to the ART Lab. These may be combined with 
treatment visits, depending on subject availability. Participants will complete 5 Reward 
Functioning Assessment Sessions in total (one at baseline, one in each week of 
treatment), so altogether these are expected to take approximately 10 hours of subject 
time. Eligibility to complete a Reward Functioning Assessment Session will be the 
absence of acute cocaine intoxication on the day of testing (based on examination of 
DSM-V symptoms). Participants not meeting this requirement will be re-scheduled. 
Current withdrawal symptoms will also be examined at each session using the Cocaine 
Selective Severity Assessment of Withdrawal [36], see attached. The anhedonia 
measures administered have been selected to tap consummatory, motivational and 
reward learning functions across subjective, behavioral and psychophysiological 
domains. See Table 1. Reward Functioning Measures for a summary. At each Reward 
Functioning Assessment Session, the following Reward Functioning Measures will be 
administered:  
1. Subjective Reward Functioning Measures.  
The Snaith-Hamilton Pleasure Scale (SHAPS) [37] is a measure of 
consummatory reward consisting of 14 hedonic capacity statements (e.g. “I 
would enjoy my favorite TV program”).  See attached.  
The Temporal Experience of Pleasure Scale (TEPS)[38] contains 18 
statements measuring motivational (e.g. “I look forward to a lot of things in my 
life”) and consummatory (e.g. “I enjoy taking a deep breath of air”) reward. See 
attached. 
2. Behavioral Reward Functioning Measures. 
The Emotional Picture Rating Task (EPRT)[21] is a measure of consummatory 
reward consisting of self-reported positive, negative and aroused feelings while 
viewing standardized emotional pictures. Positivity and arousal ratings of 
positive pictures are the primary outcomes.  
The Emotional Picture Keypress Task (EPKT) [39] is a measure of motivational 
reward in which subjects expend effort via keypressing to extend or reduce 
viewing times for emotional pictures. Keypressing to extend positive pictures is 
the primary outcome.  
The Effort Expenditure for Rewards Task (EEfRT) [40] is a measure of 
motivational reward translated from laboratory animal tasks. On each trial 
subjects choose between a “hard task” requiring many keypresses but worth 
more money and an “easy task” requiring few keypresses but worth less 
money. Percent of hard task choices is the primary outcome.  
The Probabilistic Reward Task (PRT) [41] is a measure of reward learning 
consisting of trials in which subjects must identify whether a cartoon face has a 
short or long mouth over a brief presentation. Correct identification of one 
category (short or long) is rewarded more often with a small monetary reward. 
Response bias for the rewarded category is the outcome.  
3. Psychophysiological Reward Functioning Measures. During the EPRT (see 
above) we will record activity in the corrugator (CR; frown) muscle using 
electromyography (EMG), skin conductance (SC) and heart rate (HR). Positive 
pictures suppress corrugator activity (Larsen et al. 2003) giving a measure of 


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valenced facial responses to pictures. Skin conductance is enhanced to all arousing 
pictures, positive and negative, giving a measure of sympathetic activity to pictures. 
Heart rate acceleration in the later seconds of picture viewing is also sensitive to the 
motivation properties of pictures, with greater acceleration to more positive pictures.  
Together, these will give a comprehensive assessment of consummatory responses 
to positive pictures. EMG will be recorded using two 4mm sensors, filled with 
conductive gel (Biopac System Inc.), and attached to the subject’s face over the 
corrugator using adhesive collars. Signals will be amplified and digitized using an 
EMG100C/MP150 system (Biopac Sysems, Goleta, CA), and sampled at 1000 Hz 
throughout the tasks with Acqknowledge software. Magnitude of corrugator 
responses during positive pictures are the primary outcome. SC will be recorded 
using two 8mm sensors filled with isotonic gel (Biopac System Inc.) and attached to 
the subject’s palm with an adhesive collar. Signals will be amplified and digitized 
using an EDA100C/MP150 system (Biopac Sysems, Goleta, CA), and sampled at 
1000 Hz throughout the tasks with Acqknowledge software. HR will be measured 
using electrocardiogram data collected with disposable Ag/AgCl electrodes placed 
in a standard bilateral configuration on the chest. The data will be processed through 
a 1-100Hz bandpass filter designed to maximize R-wave frequency.  
 
 
Reward Function 
Type of Measure 
Consummatory 
Reward 
Motivational 
Reward 
Reward 
Learning 
Subjective 
SHAPS; TEPS 
- 
Consummatory 
TEPS - 
Motivational 
 
Behavioral 
EPRT 
EPKT; 
EEfRT 
PRT 
Psychophysiological 
CR EMG; SC; 
HR 
 
 
fMRI – note, only 
administered in 
fMRI Sub-Study 
MID – 
Feedback; 
EPfT 
MID – 
Anticipation 
PCfT 
Table 1. Reward Functioning Measures by type and specific reward function 
 
Treatment Visits. During the 1-week medication run-up, 4-week treatment period, and 1-
week medication run-down, subjects will make thrice-weekly visits to the ART Lab 
(ideally Monday/Wednesday/Friday). Each treatment visit will take between 30 min and 
1.5 hours depending on activities scheduled for that visit (as detailed below).  All 
together, treatment visits are expected to take 13 hours over 18 visits.  Treatment visits 
may be combined with Reward Functioning Assessment Sessions, fMRI Sessions, or 
both, depending on subject availability. Treatment visits will consist of the following 
activities (see Figure 2, Overview of measures and procedures by Study Session): 
      Treatment Activities 
1. Medication. At every treatment visit (run-up, run-down and treatment weeks) 
subjects will be administered medication and given take-home doses for intervening 
days. Participants in CM/ER-AMP and ER-AMP only groups will receive extended-
release dextroamphetamine daily, while CM/PL subjects receive placebo. Drugs will 
be administered double blind in identical capsules with 50mg riboflavin total. 
Medication dispensing is expected to take 5min at each treatment visit. All 


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medication will be initiated on a gradual 1-week run-up until target dose is reached 
(60mg for ER-AMP). Individuals will then remain on the drug for 4 weeks, followed 
by a 1-week run-down, and either discharge or referral to other treatment as needed. 
Dextroamphetamine ER (Dexedrine Spansules) will be started at 15mg (day 1–2; 
15mg am, 0mg pm), increased to 30mg (day 3; 15mg, BID), 45 mg (day 4; 30mg 
am, 15mg pm), and 60 mg (day 5; 30mg BID). Participants will remain at this level 
for 4 weeks, then be titrated down with 45 mg (day 1-2; 30mg am, 15mg pm), 30 mg 
(day 3; 15mg, BID), 15mg (day 4; 15mg am, 0mg pm), and finally no dose on the 
final day of the study (see Figure 2). Participants in the placebo group will follow the 
same dosing schedule. This same titration schedule has been used previously to 
safely titrate individuals with CUD to the targeted dose, maintain them for up to 12 
weeks, and safely withdraw them from the drug [47]. In the event that a participant 
misses 3 or more days of medication (e.g. does not present for study visits despite 
all contact attempts), a brief re-run up will be conducted (Day 1 15mg, Day 2 30mg, 
Day 3 45mg, Day 4 60mg) to return them to the study dose. 
2. Contingency Management. Participants in CM/PL and CM/ER-AMP arms will 
receive Contingency Management at visits thrice-weekly during the 4 treatment 
weeks, for a total of 12 Contingency Management sessions, per Schmitz et al. [48]. 
At each session, results of urine drug screens will be communicated to subjects by a 
trained research assistant. Research assistants will be trained using the laboratory 
Timeline Followback and Contingency Management Manual (attached), observed 
during initial Contingency Management administrations by the PI and subject to spot 
checks for adherence by the PI or other trained staff. Cocaine-negative urine drug 
screens will result in rewards (vouchers), starting at $15 and increasing by $10 for 
each consecutive negative urine drug screens, with bonus vouchers worth $10 for 3 
consecutive negative urine drug screens [48]. Positive urine drug screens will result 
in voucher omission, and reset voucher value to $15. Participants can redeem 
vouchers for cash (≤$25) and gift cards. Participants in the ER-AMP only group will 
also receive feedback on urine drug screens results at each visit during the 
treatment period, with no contingencies attached, to control for research assistant 
contact and social factors. Urine drug screen feedback and Contingency 
Management at each visit during treatment is expected to take approximately 5 
minutes. 
3. Motivational Interviewing. All subjects will receive two 1-h, manual-based 
individual Motivational Interviewing sessions in the 1st and 3rd treatment weeks to 
increase treatment attendance and adherence, per previous uses of the 
Contingency Management procedure [48].  Session 1 will focus on change 
motivation, change commitment, and making an abstinence plan. Session 2 will 
focus on personalized feedback, reassessing change commitment, and reevaluating 
the change plan. There will also be a 15-30min wrap-up and referral session with the 
therapist during the run-down week. Referrals will be tailored to the subject’s needs. 
If the subject leaves the study sooner, every effort will be made to contact the 
subject and provide referrals. The PI or a graduate-level therapist will conduct the 
Motivational Interviewing and referral sessions. Graduate-level therapists will be 
trained by the PI using exercises and role-plays, and using the study Motivational 
Interviewing Manual (see attached).  All therapy sessions will be recorded locally to 


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secure, on-campus, UIC-controlled computers using HIPAA compliant WebEx 
software, with session recordings uploaded to the Psychology Department’s secure 
server and deleted after recording.  Graduate level therapists will attend weekly 
supervision with the PI, where cases and recordings will be reviewed for compliance.   
 
Treatment Measures. Efficacy and safety will also be monitored during treatment visits 
using the following measures: 
 
1. Drug Use Measures. At every treatment visit (run-up, run-down and treatment 
weeks) subjects will complete urine drug screens with a Readitest 6 Cassette urine 
drug screen (Redwood Toxicology Laboratory), and a Timeline Follow Back of drug 
use since their last visit (see attached Weekly Timeline Follow Back form). Drug Use 
measures are expected to take 10 minutes at each treatment visit.  
2. Safety Measures. At each check-in visit, a trained research assistant will take 
subject vital signs, review the Adverse Events Form (see attached) and Concomitant 
Medication Form (see attached) with the subjects, and administer the screening 
version of the Columbia-Suicide Severity Rating Scale (C-SSRS), a validated 
instrument for monitoring for suicidal ideation in clinical trials [49], see attached. 
Female subjects will also receive a pregnancy test every two weeks. 
3. Adherence Measures. Each urine sample taken as part of Drug Use Measures will 
also be tested by trained research staff for riboflavin florescence. All urine samples 
will be collected in containers coded with subject number and visit, and disposed of 
immediately after testing.  Medication Event Monitoring System caps that record 
bottle openings will be used to dispense take-home doses, with data downloaded at 
each treatment visit when the next dose is dispensed.  Additionally, self-reported 
adherence will be briefly assessed by the research assistant at each visit as part of 
the Timeline Follow Back. Adherence measures will not require any additional 
subject time at treatment visits. 
 
Total Participant Time Commitment and Compensation. Participants are compensated 
$50 for the initial 3-4 hour Screening Session, which is paid separately through the 
separately approved screening protocol.  Total subject time in study-specific procedures 
(i.e. excluding the initial screening) is expected to be approximately 26 hours in 20 visits 
to the clinic over 7 weeks for subjects in the Treatment Study. For each of the five 2 
hour Reward Functioning Assessment Sessions, subjects will receive $20, plus their 
winnings from the tasks, which can range from approximately $5.00 - $12 and are 
estimated at an average of $8.00 per session. For the consent visit and each of the 18 
treatment visits (through run-up, run-down and treatment) subjects will receive a base 
payment of $5. Thus, base subject payment for the Treatment Study (assuming 
subjects attend all visits) will be $195, plus any winnings from the tasks. Participants in 
the two Contingency Management groups will also have the opportunity to earn money 
for submission of cocaine negative urines during the 4 treatment weeks.  Possible 
earnings range from $0 to approximately $880, and based on our previous trial using 
this same procedure, we estimate average earnings will be around $180. All subjects 
will also receive either parking validation or round trip public transportation passes at 


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each visit to the clinic, and also can opt to have an Uber called for them for one session 
per week, to make it easier to attend visits.  
 
7.0 
Expected Risks/Benefits 
Although the medication treatments, behavioral treatments and assessments to be 
administered in this study have been extremely well studied, including in individuals with 
CUD, and a favorable risk/benefit profile is expected, there are still possible risks.  
Risks, protections against risks, and benefits are described below. 
 
Potential Risks and Protections Against Risks:  
1. Emotional discomfort from questionnaires or tasks: Some of the questions asked 
may be considered sensitive information, including drug use history and psychiatric 
symptoms. Answering these questions may be psychologically discomforting to 
some subjects. To reduce this risk, we make clear that we ask for sensitive 
information as part of the consent process. Similarly, some of the pictures used in 
the behavioral tests contain emotionally negative material (e.g. war scenes, 
attacks) that may be mildly upsetting to some subjects. Participants will be 
informed during the consent process that they may view such pictures, will be 
asked to report to the research assistant if they have any particular phobias or 
triggers, and told to inform the research assistant if they continue to be bothered by 
any pictures afterwards.  Any subjects expressing continued distress after viewing 
the pictures will be counseled by a trained staff member or the PI.   
Experience to date in this study: We have not had any reports of emotional 
discomfort from questionnaires or pictures.  
 
2. Confidentiality: Given the sensitive information collected as part of the study, 
there are may also be social, legal or economic risks associated with loss of 
confidentiality. Please see Section 13.2, Subject Confidentiality, for details on 
steps we take to minimize these risks. 
Experience to date in this study: We have not had any breaches of confidentiality. 
 
3. Psychophysiological monitoring: We will monitor psychophysiological responses 
using conductive electrodes attached to the skin of subjects with an adhesive. 
Approximately 50% of subjects report mild discomfort or irritation as a result of 
cleaning the sites to apply the sensors, but this should be transient, lasting 15min 
up to an hour. A few individuals experience red marks at the site of application that 
can last up to one day after the application. A very small number of subjects 
(approximately 1 in 100) with particularly sensitive skin may experience marks that 
last longer (up to a week). This risk will be minimized by asking subjects about 
sensitive skin or previous allergic reactions to skin products and by rigorous 
training in correct skin cleaning procedures for research assistants. There are also 
risks of electrical hazard, when subjects are attached to conductive equipment. To 
reduce this risk, all equipment will be appropriately grounded and shielded, and 
stimulus equipment will be optically isolated from the subject making any electrical 
hazard to the subject extremely unlikely. There are infection risks when subjects’ 
skin is in contact with equipment. To reduce this risk, all surfaces placed in contact 


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with the subjects’ skin are disposable, and all equipment will be thoroughly cleaned 
between sessions.  
Experience to date in this study: We have not had any reports of serious skin 
irritation, electrical hazard or infection. 
 
3. Study Medication. Dextroamphetamine is extremely well understood in terms of 
benefits/effects and risks and has been studied extensively over the past 60 years 
in many populations. It has been investigated in individuals with CUD and other 
stimulant use disorders in many previous protocols [47,50–53] Previous studies 
have generally used fixed doses of the extended release preparation proposed 
here. When administered in a controlled trial, dextroamphetamine carries modest 
risks overall. We have a current Investigational New Drug Protocol for this study 
(IND #131221). 
Risks During Regular Use: Serious but rare risks of dextroamphetamine include: 
1. Heart related problems, including stroke, heart attack and increased blood 
pressure and heart rate. We protect against this specific risk by requiring a full 
ECG and physical examination prior to enrollment in the study, with our study 
physician excluding individuals with contraindicating cardiovascular conditions, and 
by reviewing subject vitals at each visit. There have been no reported serious 
adverse cardiovascular events in closely monitored cocaine dependent populations 
[47,50,51,53–56]. Any individuals reporting symptoms of cardiovascular 
complications during the study will be immediately evaluated by the study 
physician to determine treatment needs.  2. Psychiatric problems, including mania, 
psychosis and aggression.  We protect against this risk by excluding individuals 
with active psychiatric disorders aside from CUD. We additionally monitor for 
suicidal ideation at every study visit using a validated screening. Psychiatric 
adverse effects are rare, even in studies of individuals with amphetamine and 
cocaine use disorders [47,50,51,53–56]. Any individual showing symptoms of 
mania, psychosis, suicidality or aggression during the study will be immediately 
evaluated by the PI, a licensed clinical psychologist, to determine treatment needs. 
3. Peripheral vasculopathy, including Raynaud’s syndrome.  Vasculopathy 
symptoms are generally intermittent and mild, and reverse with discontinuation of 
the drug.  We protect against this risk by excluding individuals with other medical 
complications that might put them at risk for vasculopathy, and reviewing reported 
AEs for potential vasculopathy at each visit. There have been no reports of serious 
vasculopathy in studies of individuals with CUD taking this drug [47,50,51,53–56]. 
Any individuals reporting symptoms of vasculopathy during the study will be 
￼immediately evaluated by the study physician to determine treatment needs.   
More common but less serious risks include: allergic reactions, blurred vision, 
fast or irregular heart beat, decreased appetite, restlessness, anxiety, tremors, 
headache, trouble sleeping, dizziness, stomach upset, weight loss, dry mouth, 
diarrhea or constipation, impotence, changes in sex drive, frequent or prolonged 
erections (see attached Package Insert). In addition to protections against specific 
risks of dextroamphetamine outlined above, our general risk protections include: 1. 
A gradual 1-week run-up under close supervision by study staff.  2. Regular 
evaluation of adverse events, side effects, vitals and suicidality at each treatment 


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visit. Our Adverse Events Form includes both open-ended questions and a 
checklist of common side-effects completed by the subject. On the open-ended 
section: If any key symptoms for heart problems, mania/psychosis or Reynaud’s 
syndrome are spontaneously endorsed, the research assistant will contact the PI 
(for psychiatric symptoms) or the study physician (for medical symptoms) 
regardless of reported severity.  For any other adverse events/side effects 
spontaneously endorsed on the open-ended questions, the research assistant will 
ask additional questions to determine date of onset, pattern, duration and any 
precipitating events, and degree of interference with life activities. Endorsement of 
any serious adverse events per FDA criteria, or events that do not meet FDA for an 
SAE criteria but are endorsed at a “severe” level (upon questioning are interfering 
with the subject’s daily activities) will result in immediate consultation with the PI 
and study physician. On the checklist section: The research assistant will overlay 
the checklist with a transparency indicating symptoms of particular concern 
(arrived at in consultation with our study physician) and when to contact the study 
physician or PI (see Adverse Events Overlay, attached). Of note, any symptom 
endorsed at a severe level will result in contacting the physician and PI. For vitals, 
if blood pressure is  > 140/90 (either systolic or diastolic is exceeded), or resting 
heart rate is above 100bpm, the RA will hold medication and immediately consult 
with the PI and study physician. The PI and study physician will make the 
determination whether to continue, temporarily hold or discontinue medication, and 
make referrals for any needed medical or psychiatric follow up. In either of these 
cases, the study physician may also consult our clinical consultant, who is dual-
board certified in internal medicine and psychiatry, in the event a second opinion is 
required. Participants requiring additional medical evaluation to make a 
determination will be transported to the study physician’s office via cab or ride 
service.  Any patient showing signs of an emergent SAE (e.g. fainting, 
hypertensive crisis) will be transported immediately to the emergency room via 
ambulance. For suicidality, subjects will also respond to the Columbia Suicide 
Severity Rating Scale (CSSR-S) at each visit.  CSSR-S evaluations will be 
conducted by staff who have completed training created by the developers of the 
scale and been certified. Any endorsement of suicidality will result in medication 
being held and the PI being immediately contacted to evaluate the subject. 
Labeling for pill bottles will include the PI’s telephone number and institutional 
information, although there has never been an event requiring emergency breaking 
of blind at the previous study site. 
Risks During Withdrawal: There are no known major medical risks to abrupt 
discontinuation of dextroamphetamine [57]. The withdrawal syndrome consists of 
dysphoria, irritability, changes in sleep, appetite and craving.  We have included a 
drug taper to avoid the possibility that these withdrawal symptoms might trigger 
relapse in individuals abstinent at study completion. All reasonable efforts will be 
made to offer dose tapering to subjects who withdraw early. If someone withdraws 
due to a positive COVID test, it would be unsafe for us to see them to provide them 
with a taper. Thus, for the duration of the pandemic, we will issue a sufficient 
amount of medication for our normal tapering schedule (135mg) to each individual 
at the start of the treatment month. This will be marked as “for emergency use 


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under the direction of the physician only”. This is similar to our current practice of 
issuing one day of emergency medication (60mg) in case of missed sessions, 
which we have been doing without major problems throughout the study. Then, in 
the even that a participant cannot be safely seen for a run-down, study staff can 
supervise the participant tapering at home via telehealth, using either phone or 
UIC-approved tools of WebEx or PHI Zoom. We are aware of the conditions for 
using these tools (https://hipaa.uillinois.edu/telehealth-uic/) and will follow best-
practices in the event this is needed.  The ART Lab has procedures in place to 
contact subjects who miss scheduled study visits.  These procedures include 
obtaining initial consent to follow up by telephone, text, e-mail or, if necessary, 
certified mail to reach the subject or an identified “locator” who can assist in 
obtaining current contact information. We update this information weekly during the 
study using our Weekly Locator Form (see attached) 
Risks During Pregnancy: Dextroamphetamine is Category C for use during 
pregnancy. There are no adequate and well-controlled trials to describe the full 
spectrum of potential toxic effects of dextroamphetamine on the fetus. No pregnant 
women will be permitted in study and women and men will be advised to use 
contraceptive measures that we provide at the clinic. Pregnancy tests will be 
performed at intake and every two weeks during the study. A positive pregnancy 
test will result in holding study medication, consultation with the study physician, 
and referral of the patient for medical follow up.  Confirmed pregnancy will result in 
discontinuation of the study medication and referral for other treatment.  
Risks in Combination with Other Recreational Drugs. Amphetamine can be safely 
co-administered with cocaine, the most likely drug combination in our subjects [55]. 
Previous dextroamphetamine trials [47,50,51,53] in over 200 patients with CUD 
have not observed hazardous interactions with recreational use of other illicit 
drugs, or major adverse events, despite the fact that many individuals in these 
studies were using cocaine and other illicit substances concurrently. Indeed, the 
dose of dextroamphetamine proposed (60mg) has been used for comorbid cocaine 
and heroin dependence in combination with methadone over 24-week period with 
no serious adverse events [51]. However, individuals with current use of 
amphetamine, >50 lifetime uses of amphetamine, or previous Amphetamine Use 
Disorder will be excluded, and use of other recreational drugs will be monitored at 
every check-in visit using breath, urine and self-report measures for potentially 
hazardous combinations. 
Experience to date in this study: We have had one SAE to date, which was 
determined to be not medication related.  A subject with a previous history of throat 
abscesses underwent an overnight hospital stay for removal of an abscess. 
Medication was temporarily held so as not to complicate treatment.  He returned to 
the study and completed the study on medication. We have had 13 AEs evaluated 
by the study physician. Common AE’s included headache and sleep disturbance 
which are expected side effects of the medication. The majority were determined to 
require no change in medication, as they resolved spontaneously. Only two 
required medication hold or discontinuation. An increase in blood pressure resulted 
in a medication hold. With reminders about importance of compliance with 
previously prescribed medications for hypertension, this subject was able to 


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complete the study on medication. New onset of possible hypomania (unusually 
increased talkativeness and sociability, markedly increased energy level and 
decreased need for sleep, inappropriate communications with staff indicating 
grandiosity) was detected in a subject with no reported history of mania.  This 
resulted in medication discontinuation.  This event was detected during the run-up 
week of the study, medication was immediately discontinued, and the subject 
completed the remainder of the study off medication.  Mania is also a possible, 
although rare, side-effect of dextroamphetamine, and is listed explicitly on the 
consent form. Thus this did not represent an unexpected adverse event. In fact, no 
negative impacts or sequelae of this event were reported by the subject.  These 
events have been reviewed by our DSMB at the most recent yearly meeting, with 
no changes required to our study protocol. 
 
4. Behavioral Treatment.  Participants in the Contingency Management groups will 
receive rewards for abstinence. Rewards will be given in the form of small cash or 
e-payments (≤ $25) or gift cards, which could potentially be used or sold to buy 
drugs. We attempt to minimize this possibility by restricting the amount of awards 
given in cash to <$25.  Previous studies using similar reward procedures have 
generally demonstrated a beneficial, rather than detrimental, effect of such 
procedures on drug use [47,58], but it is not possible to completely eliminate this 
risk.  
Experience to date in this study: We have not had reports of subjects using 
rewards to purchase drugs.  
 
5. Alternative Treatments. There is also the risk that participating in this study 
could preclude someone from obtaining alternate, more effective treatment. We 
believe that our therapeutic interventions provide treatment that is considerably 
superior to most, if not all treatment opportunities in the community.  Nevertheless, 
we will refer patients to other facilities upon request or when required by other 
circumstances. We will also conduct regular literature searches on alternative 
treatments, and in the event that an alternative treatment emerges with clearly 
superior efficacy, we would suspend the current study and provide all subjects with 
referrals for this alternative treatment. 
Experience to date in this study: We have made referrals to other treatment as 
needed (e.g. if subjects desired to withdraw from the study due to time conflicts). 
No alternative treatments with better efficacy have emerged. 
 
Potential Benefits: Cocaine use leads to devastating consequences on a personal and 
societal level. Research participation may assist subjects in abstaining from cocaine 
during treatment and beyond. This project aims to evaluate a new 
medication/behavioral treatment combination that is expected to be more effective than 
other approaches. Both the selected medication and behavioral treatment have shown 
preliminary evidence of benefit in helping patients reduce cocaine use. Further, this 
study will pilot new approaches to evaluating treatments that may lead to more 
personalized and effective treatments for CUD. Thus, by taking part in this research 
subjects will also benefit others with similar problems because this study is designed 


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identify what types of treatment work best and for whom.   
 
8.0 
Data Collection and Management Procedures 
Data sources include urine samples, paper forms containing interview and 
questionnaire responses, electronic records of responses to questionnaires and tasks 
from screening and Reward Functioning Assessment sessions, video and voice 
recordings of therapy sessions.   
All urine samples will be collected in containers coded with subject number and visit, 
and disposed of immediately after testing. Paper forms will be kept in locked cabinets in 
a locked room in the ART Lab.  Only the PI and laboratory staff will have access to 
these paper forms. Wherever possible, subjects will enter information directly into 
electronic Access databases, or data will be collected automatically by computer 
programs (e.g. during reward functioning assessment and fMRI sessions). If this is not 
possible (e.g. for safety forms that require on-the-spot inspection by study staff), trained 
research assistants will enter data into an existing, relational database. Allowable input 
values will be restricted to standardized Access entry forms so as to maintain data 
integrity. All observations will be double-entered to verify accuracy, with any problems 
detected discussed with the PI. If necessary, re-training of research assistants will be 
conducted. After the conclusion of the study, therapy session recordings will be 
transcribed by a HIPAA-compliant service under contract with UIC, and original 
recordings will be securely deleted.  Transcripts will be maintained in the same manner 
as other electronic study data for future analysis, as language used in therapy can be 
analyzed to provide insight into processes active during therapy [59]. fMRI session data 
will also be stored in the same manner on the same secure server. Paper and electronic 
records of questionnaire and task data will identify study subjects only by a study code, 
with a separate electronic file (part of our separately established screening protocol and 
data repository, see separately submitted protocol) linking study codes to identifiable 
subject information.   
 
Per our separately submitted screening and data repository protocol, we do not plan to 
delete this separate linking file when data collection is complete.  Please see Section 
13.2, Confidentiality, and our separate screening protocol for additional details and 
justification.  Thus, coded data will NOT be treated as de-identified. Data will be stored 
for a minimum of 6 years, in accordance with NIH policy, and may be stored indefinitely. 
 
9.0 
Data Analysis 
 
Primary data analysis will be conducted by the PI.  As this study is funded by a Career 
Development Award from NIDA, the PI will also consult with her designated statistics 
mentor, Dr. Charles Green, an expert in Bayesian statistics for clinical trials at the 
University of Texas Health Science Center at Houston.  In the event that Dr. Green 
needs direct access to the data set in this capacity, the PI will follow the guidelines in 
Section 13.2, Subject Confidentiality, including complete de-identification, or if this is not 
possible, implementation of a Data Use and Transfer Agreement. 
 


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Randomization: Participants will be assigned to conditions via urn randomization for 
even distribution of past 30 days cocaine use (<=15 days vs. >15 days) and baseline 
SHAPS score (above vs. below an established clinical cut point for anhedonia). 
 
Overall Data Analytic Strategy: The analytic strategy will use parallel Frequentist and 
Bayesian analyses. Together, these two complementary approaches provide a more 
accurate evaluation of hypotheses when the sample size is small [60]. In particular, 
although conventional Frequentist approaches to statistical testing testing permit 
rejection of the null hypothesis given the observed data or data more extreme, Bayesian 
analysis permits conclusions regarding the alternative hypothesis: the probability that a 
subgroup effect of a specified magnitude exists [61,62]. Thus the Bayesian evaluation is 
considered our primary statistical approach for this initial proof-of-concept study. 
 
Generalized linear modeling and mixed effects models (R v.3.2, WinBUGS v.1.4) will 
comprise the primary analytic methods. Primary Bayesian analyses will use vague, 
neutral priors: ~Normal(μ= 0, σ2 = 1 x 106) for coefficients in the log-form and ~Gamma 
(Shape = 0.001, Inverse Scale = 0.001) for the dispersion term;  sensitivity analyses 
with pessimistic priors will also be conducted to assess robustness of findings. Clinical 
outcomes will be analyzed on an intent-to-treat basis, with sensitivity analyses of 
robustness to assumptions about missing data. For each aim, parallel analyses will be 
conducted in the full study group (N = 80) and the sub-set (N = 24) with fMRI measures.  
Significance for Frequentist outcomes will be set at p = 0.05, and a Bayesian probability 
of 80% or greater that an effect exists will be considered to merit further consideration.    
 
Severity Measures: A composite score of CUD severity will be derived from the 
summed z-scores of severity from the SCID, TLFB and ASI.  
 
Anhedonia Measures: Principal components analysis will be used to determine whether 
anhedonia measures can be reduced into composites representing consummatory, 
motivational and reward learning functions, as expected. If this is inappropriate, we will 
use individual measures with pessimistic priors to address multiplicity. 
 
Potential Confounds: Per published guidelines on confounding in clinical trials [63,64], 
we will assess all major demographic and baseline variables, and those that either differ 
between treatment groups or correlate with anhedonia, and also relate to outcomes (i.e. 
severity, abstinence) will prompt two sets of analyses, one with the variable as a 
covariate and one without, to assess confounding.  
 
Hypothesis Testing: 
Specific Aim 1. Our working hypothesis that higher anhedonia at baseline will 
relate to greater addiction severity will be tested using linear regression to examine 
the relationship between the composite of CUD severity, and anhedonia composite 
scores at baseline. 
Specific Aim 2. Our working hypothesis that higher anhedonia at baseline will 
predict less chance of poorer outcomes in Contingency Management will be tested 
using generalized linear modeling. Initial abstinence, defined as two consecutive 


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weeks of cocaine-negative urines, will be the primary clinical outcome.  Treatment 
Effectiveness Scores, defined as total number of cocaine negative urines 
submitted across the four treatment weeks, will be a secondary outcome. 
 Specific Aim 3. Our working hypothesis that anhedonia will mediate the effects of 
ER-AMP on outcomes will be tested utilizing Bayesian Structural Equation 
Modeling (SEM; MPlus v.7.2) to model indirect effects of treatment group (CM/PL, 
CM/ER-AMP, ER-AMP only) on outcomes, with change in anhedonia over 
treatment as the mediator. Of note, change measures are sometimes ill-
conditioned (e.g. large error terms, little reliable variability), and if this is the case 
here, we will use anhedonia at a specified midpoint instead. Initial abstinence, 
defined as two consecutive weeks of cocaine-negative urines, will be the primary 
clinical outcome.  Treatment Effectiveness Scores, defined as total number of 
cocaine negative urines submitted across the four treatment weeks, will be a 
secondary outcome. 
 
Power Analysis: In a Bayesian framework, the goal of a proof-of concept study is to 
produce the best possible estimate of an effect’s likelihood and size, to aid decision-
making. Thus, the sample was selected to be the maximum feasible within the financial 
means available. Traditional power analysis bears on the probability of a false negative, 
not the probability the alternative hypothesis is true (the focus of our analysis). 
However, for thoroughness, we conducted Frequentist power analyses for the full 
sample (N = 80), moderate attrition (N = 64), and fMRI sub-sample (N = 24). For Aim 1, 
which focuses on the correlation between anhedonia and addiction severity, at α =0.05 
and 80% power, the full sample could detect a small r =.31, with attrition a small-to-
moderate r =.34 and in the fMRI sub-sample a moderate r =.6. For Aim 2, Preliminary 
Data and [19] suggest a range of d = 0.68-1.60 for the effect of anhedonia on 
Contingency Management outcomes, depending on measure (self-report vs. imaging). 
At α =0.05 and 80% power, the full sample could detect a moderate d=.64, with attrition 
a moderate d=.72, and the fMRI sub-sample a large d=1.04. For Aim 3 Monte-Carlo 
simulation indicated a prohibitively large sample for this award (N = 200) would be 
needed to reach a definitive Frequentist conclusion about a moderately-sized 
mediational effect. A major advantage of our Bayesian approach is that we will be able 
provide information about the likely magnitude of this effect, even in this smaller study. 
 
Trial Termination Criteria: Because this study is relatively small (group sizes from 20 – 
30), and is designed to test a potential moderator of outcomes in the context of an 
already established behavioral treatment and off-label use of an FDA-approved drug 
already suggested to be efficacious for CUD, no interim efficacy analysis is planned and 
no trial termination criteria are set. 
 
10.0 Quality Control and Quality Assurance 
Primary responsibility for quality control and assurance will rest with the PI and her 
team, and data quality will be monitored in weekly lab meetings.  Most questionnaire 
data is entered directly into the computer by the subject, reducing data entry error. All 
behavioral and psychophysiological data is collected automatically by the computer 
using professional programs designed for this purpose. All hand-entered data 


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(miscellaneous study forms) will be double-entered into an existing, relational database, 
with any inconsistencies examined and resolved. Allowable input values will be 
restricted to standardized Access entry forms so as to maintain data integrity. All 
psychophysiological data will be scored in two passes by independent raters, with the PI 
or a trained study coordinator resolving any inconsistencies.  
 
11.0 Data and Safety Monitoring 
This protocol will continue to be monitored on a yearly basis by the Data Safety 
Monitoring Board for the Center for Neurobehavioral Research on Addiction 
(CNRA) at UTHealth, an umbrella board that monitors all studies conducted in the 
CNRA, where the study is currently located. The board has agreed to maintain this 
duty after the study moves to UIC. The board is already familiar with the protocol, 
having conducted the initial review and one interim review so far, so this will assist 
with continuity in maintaining safety in this protocol. Remote monitoring by DSMBs 
is both common and highly feasible.  The PI will attend via telephone or video 
conferencing all open meetings of the DSMB, and any other sessions as 
requested by DSMB members. Please see attached sponsor-approved Data and 
Safety Monitoring Plan for further details on the DSMP. 
 
12.0 Statistical Considerations 
Not applicable – see Data Analysis Plan above. 
 
13.0 Regulatory Requirements 
13.1 Informed Consent  
Consent for the current study will be obtained by the PI or trained study staff at 
the conclusion of the screening process. Participants will be provided with a 
verbal description of the study purpose and procedures, and then allowed ample 
time to read over the consent and then discuss with the PI or staff. If at any time 
the individual states s/he is unsure about signing the consent or needs more time 
to consider, the individual is given the option to leave and call back with a 
decision when ready. After 24 hours, we contact the individual and ask for a 
decision, and schedule a time to return to sign the consent if the decision is yes.  
All subjects will be required to provide a brief accurate description of the study 
procedures in their own words before signing, to ensure comprehension. All 
subjects will be provided with a copy of the informed consent. 
 
It is expected that the PI will consent the majority of subjects.  However, study 
staff will also be trained to perform informed consent in the unlikely event that the 
PI is unavailable.  In addition to basic human subjects training, staff members 
conducting informed consent will be required to have completed study specific 
training, consisting of a discussion with the PI on the key elements of the 
informed consent, a role-play of informed consent observed by the PI, with 
feedback given to the trainee, and an accurate informed consent session with an 
actual subject observed by the PI.  In the event that informed consent is not 
obtained by the PI, subjects will be scheduled for a brief meeting with the PI to 


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discuss the study prior to first medication dose, so that the PI can ensure subject 
comprehension and to allow the subject to be familiar and comfortable with the PI 
in the event that they need to report any issues to the PI. 
 
Original informed consent documents will be stored in a separate binder, in 
order, for ease of review by regulators. A copy of the informed consent will also 
be stored in the subject’s paper file, to ensure redundancy in recordkeeping for 
this key regulatory document.  Both original and copied informed consents will be 
stored in a locked cabinet in a locked room of ART Lab.  
13.2 Subject Confidentiality  
During study performance, personally identifiable information is necessary to 
facilitate appointments, reminders, and subject tracking. We may contact 
subjects via phone, text, or e-mail with appointment reminders.  To minimize 
risks to subject confidentiality we will ascertain their contact preferences and 
obtain contact information directly from them.  Appointment reminders will not 
indicate the type of study, and will only reference an “appointment at UIC”. We 
may also contact designated subject locators, in the event that a subject does not 
arrive for a scheduled visit and is not reachable by other methods. We will obtain 
names and contact information for these individuals from subjects, and clearly 
explain when and how these locators may be contacted.  Contacts with locators 
similarly will not indicate the purpose of the study and will only reference an 
“appointment at UIC”.   
 
To reduce risks after data is collected, we have rigorous procedures in place to 
ensure confidentiality, including locked cabinets for confidential files, subject 
coding, secure computer systems, and rigorous training of personnel (please see 
Section 8.0, Data Collection and Management Procedures, for additional details). 
Computer systems are secure and strictly monitored by University IT staff. 
Laboratory staffers are trained in confidentiality of subject information. No 
information is allowed to leave the lab or to be accessed by a computer outside 
of the university’s secure computer system, and all data are further protected by 
permissions and passwords given only to necessary research personnel. As 
described in Section 8.0, Data Collection and Management Procedures, paper 
and electronic records of questionnaire and task data will identify study subjects 
only by a study code, with a separate electronic file linking study codes to 
identifiable subject information. We have already obtained a Certificate of 
Confidentiality for this study to provide additional protection for sensitive 
information (see attached).  
 
We do not plan to destroy the file that links codes to identifiers at the conclusion 
of this individual study. Our experiences have indicated that maintaining 
persistent records of previous subjects is important for safety and research 
reasons. Substance Use Disorders are relapsing health conditions, and subjects 
often call in repeatedly to complete subsequent treatment studies in the same 
laboratory (see also our separately submitted screening and data repository 


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protocol for further discussion of how we address this). Maintaining persistent 
records of which studies subjects have completed and when allows us to reduce 
subject exposure to risks by minimizing repeat medical or psychiatric screenings, 
and by using key information gathered in one treatment study to exclude the 
subject from subsequent studies (e.g. if the subject had an adverse response to 
the drug administered).  In addition to these safety reasons, there are also strong 
scientific reasons for maintaining persistent records of subject identity across 
studies.  Subsequent secondary analyses (e.g. of which characteristics predict 
subject success in therapy) often combine outcomes across trials to increase the 
accuracy of prediction.  This requires knowing which subjects are unique, and 
which have completed more than one trial. Given these reasons, we plan to 
maintain these separate code files in a separate Access database stored on the 
Psychology Department’s secure, encrypted and password protected server. 
Thus even coded data will NOT be treated as de-identified. Data will be stored 
for a minimum of 6 years, in accordance with NIH policy, and may be stored 
indefinitely. 
 
Participants will not be identified in any publications resulting from this study. We 
will share final data in accordance with NIH policy. Final data will be made 
available upon direct requests to the PI. Identifiers will be removed from the data 
before sharing. So as to fully protect the subjects, we will evaluate each data 
request to ensure that special circumstances do not exist that would permit 
anyone to deduce the identities of individuals from the shared data. If such case 
exists, we will share the data on the basis of an agreement that will provide that 
the data be used solely for research and that no individuals will be identified in 
any manner, that data will be secured by equivalent electronic safeguards, and 
that once data analysis is complete, the data will be returned or destroyed. 
13.3 Unanticipated Problems 
Unanticipated problems will be reported to the sponsor, DSMB and FDA per the 
guidelines laid out in the attached DSMP.  Unanticipated problems will be 
reported to the IRB per UIC policy, as follows (only unanticipated problems 
applicable to this single-site protocol are listed): 
 
1. Events Requiring Reporting to the IRB within 5 Business Days of the Investigator 
Becoming Aware  
1. Local, serious adverse events which are unanticipated 
2. Serious unanticipated problems 
3. Major protocol violations that are unplanned and unintentional 
4. Apparent serious noncompliance 
5. Apparent continuing noncompliance 
6. Changes to the protocol made without IRB approval to eliminate apparent 
immediate harm to subjects 
7. Incarceration of a subject  
2. Events Requiring Reporting to the IRB within 15 Business Days of the 
Investigator Becoming Aware  


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1. Local adverse events or problems that are unanticipated and, while not 
meeting the criteria of serious, indicate research is associated with a 
greater risk of harm to subjects or others than previously known. 
2. New information indicating an unexpected change to the risks or benefits 
of the research (i.e., an unanticipated problem). 
3. Administrative hold by investigator, sponsor, regulatory authorities or other 
entities. 
4. Other events requiring prompt reporting by sponsor. 
       


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