Frontal-Striatal Reward Circuit Neuromodulation and Alcohol Self-Administration
Phase: NA
Conditions: Alcohol Use Disorder
Sponsor: Indiana University

Francis, M.M. 
 
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Version Date: v06.23.2022 
 
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Frontal-Striatal Reward Circuit Neuromodulation and Alcohol Self-Administration 
 
 
 
Principal Investigator:  
Susan Conroy, MD 
Department of Psychiatry 
IU School of Medicine 
 
Co-Investigator: 
Michael Francis, MD 
Department of Psychiatry 
IU School of Medicine 
 
Co-Investigator: 
Martin Plawecki, MD, PhD 
Department of Psychiatry 
IU School of Medicine 
 
 
 
 
 
 
 
 
NCT04971681 
 
 
 
 
 
 
 

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Table of Contents: 
 
Study Schema 
1.0 
Background & Rationale 
2.0 
Objective(s) 
2.1 
Primary Objective 
2.2 
Secondary Objective 
3.0 
Outcome Measures 
3.1 
Primary Outcome Measures 
3.2 
Secondary Outcome Measures 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
4.2 
Exclusion Criteria 
5.0 
Study Design 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Reportable Events 
9.0 
Study Calendar 
10.0 Data Safety Monitoring 
11.0 Study Withdrawal/Discontinuation 
12.0 Statistical Considerations 
13.0 Data Management 
14.0 Privacy/Confidentiality Issues 
15.0 Follow-up and Record Retention 
16.0 References 
17.0 Appendix 
 

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1.0 
Background and Rationale 
 
Alcohol Use Disorders (AUDs) are among the most common and undertreated 
psychiatric conditions in developed countries1, contributing to 4% of the global burden of 
disease2. AUDs occur in over 16.6 million adults in the United States alone3. Alcohol 
consumption has been causally linked to 60 different diseases4, and is the leading 
contributor to premature death and disability among ages 15-495 via associations with 
injuries, alcoholic liver disease, heart disease and stroke, cancers, and gastrointestinal 
disease2,4. AUDs also represent an important societal concern, contributing to an 
estimated economic burden of $223.5 billion in the United States6. With fewer than 10% 
receiving treatment7 and high rates of relapse in those that do,8-11 there is a clear need 
for novel and effective therapeutic interventions.  
 
Prevailing views on addiction suggest that altered function of neural reward circuitry is a 
key mechanism underlying the development of alcohol dependence12, as abnormal 
limbic drive may result in increased impulsivity and salience to alcohol related cues13,14. 
Research has demonstrated that aberrant hyperactivation within fronto-striatal reward 
(FSR) circuitry is an important biologic correlate of AUD onset, progression, and 
severity13. The medial prefrontal cortex (mPFC) is a central component of the valuation 
and reward system of the brain15-22.  mPFC activation has been associated with 
saliency and attribution as well as enhanced motivation to use alcohol14,23,24. Research 
has consistently demonstrated that alcohol cue exposure evokes increased functional 
activation within the mPFC13,25. Furthermore, this increased activation may predict 
transition to heavy drinking and is positively correlated with AUD severity26 as well as 
craving and relapse14,25,27-29.  In light of the role that disordered mPFC function plays in 
AUD, investigators have proposed that this may represent an important target for novel 
therapeutic interventions. Recent work have demonstrated that transcranial magnetic 
stimulation (TMS) is a mechanism by which investigators can modulate function of the 
mPFC and affect AUD relevant phenomenon such as craving30.  
 
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation 
technique that received FDA clearance for use in treatment resistant major depressive 
disorder in 2008 and has become commonly used in clinical practice.  rTMS utilizes the 
application of a repetitively pulsed magnetic field over the scalp to induce an electric 
field within a discrete area of the cerebral cortex. This electric field results in altered ion 
flow across the neuronal cellular membrane and ultimately changes in neuronal 
polarization31. rTMS modulates cortical activation depending on the stimulation 
parameters used31,32. Physiological studies have provided evidence that low-frequency 
(LF) rTMS, or rTMS delivered at a frequency of 1 Hz or less, produces an inhibitory 
effect on local cortical excitability. Studies have also demonstrated that LF rTMS can 
decrease functional connectivity between separate but related cortical structures33-36. 
Work by our group and others have shown that rTMS is a viable tool for investigating 
the neural correlates of psychiatric illness as well as a potential therapeutic option for 
these same conditions30,33,37. Our group has significant experience in rTMS 
investigations utilizing the treatment paradigm in this protocol, having completed a pilot-
study investigating rTMS as a therapeutic in schizophrenia. We are currently conducting 

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two additional studies of rTMS as a probe of the role that neural circuit aberrations play 
in cognitive impairment in early-phase psychosis (EPP)37. Additionally, Dr. Colleen 
Hanlon, a consultant on this study, is a nationally recognized expert and pioneer in the 
use of rTMS in studies of substance use disorder. Dr. Hanlon’s work has focused on 
rTMS as a probe of frontal-striatal reward (FSR) circuit modulation and its effects on 
craving13,30. However, though craving is an important phenomenon in substance use 
disorders, it is neither necessary nor sufficient in treatment of the conditions. 
 
This pilot study intends to address the critical unmet need to develop novel treatments 
for AUD, such as rTMS, that directly impact drinking behavior. Binge drinking and high 
intensity drinking, or consumption meeting at least binge criteria, is a high-risk alcohol 
self-administration (ASA) pattern associated with the binge-intoxication stage of AUD 
and the rewarding effects of alcohol. We propose to quantify the impact of mPFC rTMS 
on ASA using our novel “rate-control” paradigm. The rate control paradigm allows 
subjects to determine how quickly their breath alcohol concentration (BrAC) will change 
(increase, decrease, or stay the same) over the next 3-5 minute epoch, at the end of 
which brief computer-assisted assay of craving for alcohol and subjective response 
attributed to alcohol’s effect on stimulation, sedation, liking and well-being in a manner 
comparable to the Brief BAES38,39. Each assay requires less than 20 seconds to 
complete and will be administered during the last ~0.5 minutes of alcohol delivery but 
before selection of the next rate of exposure. The ensemble provides detailed self-
administered time course of alcohol exposure and corresponding time-stamped series 
of quantified perceptions for analysis. This approach has demonstrated sensitivity in 
associating self-reported high intensity drinking and the time until a binge alcohol 
exposure of 80 mg/dL (Figure 1). 
 
Our premise is that clinically impactful 
neuromodulation should change ASA. Coupling 
rTMS to a laboratory-assessed ASA paradigm 
could document causal changes in drinking 
behavior attributable to modulation of specific 
neural circuits. The goal of this project is to 
generate preliminary data supporting our 
central hypothesis - rTMS targeting to the 
mPFC, a primary cortical input to the FSR 
circuit, will decrease the rate of alcohol self-
administration.   
 
 
2.0 
Objective(s) 
 
Primary Objective 
The primary objective of this pilot study is to determine the effect size of the 
relationship between mPFC LF rTMS and a change in the time required to self-
administer at least a binge-level alcohol exposure of 80 mg/dL. We hypothesize that, 
Figure 1: High Intensity Drinking Groups and Time 
to 80 mg/dL.  N=33 subjects completing the rate 
control ASA paradigm. Groups are defined by 
multiples of self-reported binge intensity for display. 
Time to 80 mg/dL is sensitive to drinking intensity (p 
= 0.0035). Report in preparation. 

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compared to sham stimulation, mPFC LF rTMS will slow the time to a breath alcohol 
concentration (BrAC) of 80 mg/dL. 
 
Secondary Objective 
The secondary objective is to explore the effects of mPFC rTMS on subjective 
responses to alcohol, time until a high intensity drinking exposure, and, during a 4-week 
follow-up period, self-reported alcohol consumption patterns.   
 
 
3.0 
Outcome Measures/Endpoints 
 
Primary Outcome Measures 
The primary outcome measure will be the amount of time subjects take to self-
administer enough alcohol to raise their BrAC to 80 mg/dL in the rTMS treatment 
condition compared to the rTMS sham condition during the two alcohol self-
administration sessions. 
  
Secondary Outcome Measures 
The secondary outcome measures will be the subjective responses to alcohol during 
the self-administration sessions and the amount of daily alcohol consumption as 
measured by Time Line Follow Back (TLFB) during the 4-week follow-up period. 
 
 
4.0 
Eligibility Criteria 
 
 Inclusion criteria:  
1. Overtly healthy men and women aged 21 – 35 
2. Able to give informed consent 
3. Able to understand/complete questionnaires and procedures in English 
4. Willing and able to adhere to the study schedule 
5. At least 2 binge drinking events (at least 4 or 5 drinks on a drinking day for 
women and men respectively over the last 5 weeks, unless determined by 
study physicians that drinking history meets study objectives  
6. Have venous access sufficient to allow blood sampling 
 
Exclusion criteria:  
1. Pregnant or breast-feeding  
2. Desire to be treated for any substance use disorder or court ordered to not 
drink alcohol 
3. Medical disorders or other conditions, such as lifetime history of a seizure, 
including history of ECT but excluding febrile seizures and those induced by 
substance withdrawal, that may influence study outcome or subject safety 
4. First degree relative with idiopathic epilepsy or other seizure disorder 
5. DSM 5 Disorders (non-AUD) or current/history of neurological disease of 
cerebral origin, or head injury with > 20 min loss of consciousness, if 
determined by the study physicians to affect subject safety or data integrity 

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6. Positive urine drug screen for amphetamines/ methamphetamines, 
barbiturates, benzodiazepines, cocaine, opiates, or phencyclidine if 
determined by the study physicians to adversely affect subject safety or data 
integrity 
7. Medications (past 30 days) that could influence subject data/subject safety 
(e.g. antidepressants, antipsychotics, benzodiazepines, etc.) as determined 
by study physicians 
8. Positive BrAC reading at beginning of any study session 
9. Actively suicidal (for example, any suicide attempts within the past 3 months 
or any current suicidal intent, including a plan) or are at serious suicidal risk, 
by clinical judgment of the study physicians 
10. Any condition for which the study physicians determine it is unsafe or not 
prudent to enroll a subject 
 
 
5.0 
Study Design 
 
This will be a single site randomized, 2-session, 
within-subject cross-over design pilot study 
(Figure 2). 20 enrolled (of 30 consented) subjects 
reporting varying levels of binge and high intensity 
drinking, defined as at least 2 episodes of drinking 
4 (for women) or 5 (for men) drinks on an 
occasion over the last 5 weeks, (unless determined by PI that drinking history meets 
study objectives), will be enrolled. Subjects will be randomized to undergo one session 
of rTMS or sham immediately followed by our rate control IV ASA paradigm.  Subjects 
will then return 7-14 days later and undergo the same sequence of events with the 
opposite intervention (i.e. rTMS or sham) from session 1. 
 
Duration of Treatment 
Subjects will complete two stimulation (LF and sham) and IV ASA paradigm sessions 
over two to three weeks, with one session occurring every 7-14 days. Previous work 
has demonstrated that a single session of rTMS is sufficient to modulate AUD related 
behavior30.  
 
Clinical Research Sites  
rTMS treatments and alcohol challenge sessions and lab visits will take place at the 
Indiana Clinical Research Center, in either Goodman Hall at the Neuroscience Center 
and/or in the Neural Systems Laboratory at Indiana University Hospital.  
 
Dr. Conroy is the Medical Director of the IU Neurostimulation Program and is a 
psychiatrist in the IU Department of Psychiatry. Dr. Conroy and associated research 
personnel will conduct TMS procedures, help with subject transportation and 
monitoring, and assist with gathering demographic data. The program has 1 research 
psychiatrist and 1 research coordinator. 
 
Figure 2: Study Design for rTMS Modulation of ASA 

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Dr. Francis is the Research Medical Director of the IU Psychotic Disorders Program 
(IUPDP). The IUPDP is located in Indianapolis, IN. and is part of the IU Department of 
Psychiatry. IUPDP research personnel will conduct TMS procedures, help with subject 
transportation and monitoring, and assist with gathering demographic data. The IUPDP 
has 2 research psychiatrists, a fully dedicated study manager, a fully dedicated study 
coordinator, one dedicated subject recruiter, and two raters (1 PhD, 1 Masters level) 
who have been trained and have extensive experience in conducting the assessments 
and cognitive tests used as outcome measures. 
 
Dr. Plawecki is the Director of the Neural Systems Lab (NSL) in Indianapolis and is also 
a psychiatrist with the IU Department of Psychiatry. Dr. Plawecki and the NSL will 
manage the day-to-day activities of conducting the trial, consenting and screening 
subjects, the alcohol self-administration portion of the study, and subject monitoring (in 
conjunction with the CRC). The NSL has 1 research psychiatrist, 1 research scientist, 
and four technicians with extensive training and experience conducting alcohol 
challenge experiments.  
 
 
6.0 
Enrollment/Randomization 
 
Subjects will be recruited through the NSL registry, and self-referrals through 
advertisement and word-of-mouth.  Subjects that meet inclusion/exclusion criteria will 
be enrolled at the discretion of the Principle investigator and randomly assigned to one 
of the two schedules (rTMS first, or Sham first). 
 
 
7.0 
Study Procedures 
 
Recruitment and Screening 
Subjects from the NSL registry will be contacted by phone or email, while other 
subjects will contact the study phone line or email after learning about the study from 
print, electronic advertising, or word of mouth. Subjects who meet basic criteria will 
either 1) be invited for an in-person interview when they will consent to participate in the 
study, or 2) arrange for a remote interview where they will consent to participate and 
complete interview measures electronically and converse with study staff via IU Zoom 
Health or similar secure platform. Subjects will complete some or all of the following 
measures, at the discretion of the principal investigators: 
 
Self-Report Measures: 
• 
The Alcohol Use Disorders Identification Test (AUDIT) 
• 
The Family History of Alcoholism Module of the SSAGA 
• 
The UPPS-P Impulsive Behaviors Scale measures impulsivity traits 
• 
Self-Rating of Effect of Alcohol assessing retrospective sensitivity to the 
subjective response to alcohol (SRE). 
• 
Short Inventory of Problems – Revised (SIP-r) 
• 
Medical History (including menstrual phase for women) 

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• 
Nicotine History Measure 
• 
Penn Alcohol Craving Scale (PACS) 
• 
Subjective Response Questions 
•          Five Factor Model Form 
• 
Drinking Refusal Self-Efficacy Questionnaire-Revised (DRSEQ-R) 
• 
Alcohol Expectancy Questionnaire (Full and Brief versions) 
• 
Drinking Motives Questionnaire (Full and Brief versions) 
• 
COVID-19 Questionnaire 
 
Interviews: 
• 
The Semi-structured Assessment for the Genetics of Alcoholism – II, Alcohol 
Diary Measures:  
• 
Timeline Follow-back (TLFB) modified to assess for one-month recall of alcohol, 
tobacco, drug, and cannabis use 
Screening tools:  
• 
Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA) 
• 
GAD-7 and GAD-2 Generalized Anxiety Disorder Assessment, 7 and 2 item 
scales assessing anxiety symptoms over the last 2 weeks 
• 
PHQ-9 and PHQ-2 Patient Health Questionnaire, 9 and 2 item scales assessing 
depressive symptoms over the last 2 weeks 
• 
Urine pregnancy and drug screen (UPS, UDS, including EtG urine screen at 
discretion of study physicians) 
• 
Breath Alcohol Concentration Measurement 
• 
Liver function assessment 
• 
TMS Screening Checklist 
 
Miscellaneous: 
• 
Contact Form and Follow-up questionnaires  
 
Note: Screening tool score above the cutoff or concerning patterns as determined by 
the study technician may prompt additional testing from the set of measures completed 
at the interview (For example, PHQ-2 score greater than or equal to the cutoff of 3 will 
prompt completion of the PHQ-9.). 
 
Subjects that complete part of the interview remotely and appear to meet study 
criteria will be asked to visit the ICRC for a short visit where they will provide a blood 
sample, urine, and be paid the interview fee of $25.  Blood samples may be stored 
indefinitely in a secure location for future genetic research. There is not a plan to submit 
to the NIH genomic database. At this time, there is no planned analysis for these 
samples and due to our sample size, we do not meet the requirements for inclusion in 
the NIH genomic database. Subjects who complete part of the interview remotely and 
do not meet study criteria will be informed of the decision and mailed a check or gift 
card in the amount of $25.  
 
Based on the information collected at the screening interview, the investigators will 
decide whether or not to enroll the subject in the study. If the subject is enrolled in the 

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study, they will be either randomly assigned to one of the two schedules, or assigned to 
one of the two schedules based on group enrollment balance or subject safety at the 
discretion of the study physicians, and contacted to schedule their experimental 
sessions. If the subject agrees to enroll in the study and schedules their study visits, 
they will be sent an email with pertinent information. 
 
 
Procedures on the testing day 
Orientation to Laboratory:  On the days of testing, the subject will arrive at the ICRC 
between 7:00 and 9:00 am and undergo a brief physical exam by ICRC Nurses, testing 
of urine for hCG in females and a drug screen for all subjects, and documentation of 
zero BrAC before a 550 cal breakfast is served. Study protocol will be reviewed and car 
keys, if the subject drove themselves, taken for safekeeping or confirmed that the keys 
are held by the hospital valet service. Age, sex, blood pressure, heart rate, temperature, 
height, and weight will be measured. 
 
rTMS Treatment 
Immediately before rTMS administration, subjects will be prompted to recall their most 
recent experience using alcohol through a standardized series of cue-induced 
questions. During the rTMS/sham sessions, subjects will be instructed to imagine 
themselves in that scenario. These mental priming techniques have been previously 
employed by study collaborator Dr. Hanlon30. 
 
rTMS will be delivered using the Magventure MagPro X100 Magnetic Stimulator 
(Magventure Inc., Alpharetta, Georgia). Motor threshold (MT) will be determined using 
single pulse stimulation over the left primary motor cortex, assessed as the lowest 
intensity producing five visible movements of the right abductor pollicis brevis out of ten 
stimulations. The Magventure MagPro X100 is equipped with a research-dedicated coil 
with combined active and sham stimulation capabilities, with both functions sharing the 
same acoustic properties. The sham condition additionally mimics cutaneous 
stimulation, facilitating subject blinding. Study conditions (1 Hz, sham) will be assigned 
a label, such as A or B, by a non-blinded staff member who is not directly involved with 
the research team. Subjects will be assigned a sequence of blinded study conditions in 
randomized and counterbalanced fashion. 
 
The rTMS coil is held in place by a movable arm attached to the chair in which the 
subject sits. The coil is placed, by the PI, over the intended target and rests gently on 
the subject’s head. The movable arm is then locked in place by the PI, who is present 
during the entire stimulation session to assess for subject comfort. 
 
Low frequency rTMS: Low frequency rTMS, or rTMS at 1 Hz or less, is able to produce 
an inhibitory effect on local brain activity. This has been observed in healthy subject 
motor corticospinal output40. Previous studies have demonstrated that a single session 
of 1 Hz rTMS is capable of inhibiting local brain activity and modulating distal but related 
circuitry33. This work is in-line with the use of 1 Hz stimulation proposed in this study. 
Low Frequency rTMS Protocol: Subjects will receive one session of low frequency rTMS 

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targeting the mPFC, delivered over FP1 per the 10-20 international scalp electrode 
location system (an approach taken by our consultant41,42), within the following 
stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 110% of MT, for a 
total of 1200 pulses. This protocol was shown by Chen et al. (2013) to produce an 
inhibitory effect on local cortical excitability as well as effects on connectivity of related 
circuitry33. The stimulation design is within safety limits for rTMS32,40,43. If needed for 
tolerability, stimulation intensity (% MT) may be decreased, down to but not beyond the 
subjects resting MT, during the course of the study section. 
 
rTMS administration monitoring 
All subjects will be instructed to wear earplugs during each rTMS session and will be 
monitored by medically trained research staff throughout the entirety of each rTMS 
session. 
 
Subjects will complete the rate control IV alcohol self-administration session as soon as 
feasible after rTMS administration. Upon completion of the alcohol self-administration 
session, subjects be taken to the ICRC for post-session monitoring until the time for 
discharge. 
 
Alcohol Administration 
Laboratory Testing:  Each subject will be tested during each of two outpatient visits 
spanning Goodman Hall and University Hospital. After testing is complete, subjects will 
remain at the ICRC until at least 7 pm or their BrAC reaches 35 mg/dL, whichever is 
later. 
 
Preparation for Testing: Using sterile technique, a 20 gauge (or 22 gauge if necessary) 
indwelling venous catheter will be placed in an antecubital vein by an ICRC nurse, then 
flushed with saline and capped with a heparin lock.  The subject will be instructed in the 
use of the Draeger® BrAC meter and familiarized with the subjective response 
procedures under NSL technician supervision. 
 
Preparation for Infusion: After the subject is prompted for a bathroom break, the venous 
catheter will be Y-connected to 2 parallel infusion pumps, each capable of delivering up 
to 999 ml/hr and set to deliver 4 ml/hr to keep the vein open. Subject concerns of any 
kind will be addressed, and the start of the infusion, marking the beginning of 
experimental time, Txp = 0, will be announced. Subjects will be unaware of BrAC 
readings and infusion rates at all times. The subject will be able to talk to the technician 
at any time without manual effort. 
  
Infusion rate profile computation: 
Using individualized PBPK parameters44, the Computer-assisted Alcohol Infusion 
Software45-48 will deliver an approximately 6.0 % (v/v) alcohol solution prepared by the 
Research Pharmacy. The infusion rate profile is based on individualized physiologically-
based pharmacokinetic model parameters to achieve specified incremental alcohol 
exposure rates independent of the subject’s age, height weight and gender. The safety 
limit will be set to 170 mg/dL, but subject inputs that would exceed 165 mg/dL are 

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disabled, allowing subjects to self-administer to a high-intensity drinking threshold of 
160 mg/dL if they so choose and accommodating potential deviance from our 
pharmacokinetic modelling or measurement error.   
 
We will use the rate control paradigm during the 90-minute alcohol self-administration 
session to allow the subject to determine their alcohol exposure trajectory (Figure 3). 
For the first self-administration epoch and at the end of each subsequent 3-5 min self-
administration interval, the subject will specify the next alcohol exposure rate. Alcohol 
delivery raises the subject’s BrAC by the specified rate over 3-5 minutes. During the last 
~0.5 minutes of the exposure, the subject may complete the brief computer-assisted 
assay of craving for alcohol and subjective response and then select the next exposure 
rate, all while the current exposure rate is maintained.  
 
 
Subjects approaching the functional exposure limit of 165 mg/dL will have their range of 
BrAC choices limited in a corresponding way. An alcohol self-administration session 
may be terminated early at the discretion of the study investigators if the outcome 
measures have been obtained (for example, the safety limit has been reached and thus 
binge and high intensity drinking alcohol exposures achieved with corresponding 
subjective responses). Subject payment will not change and they will not be informed of 
the reason for early termination to preclude change in behavior at any subsequent 
sessions.  
 
Except for ad-libitum bathroom breaks, participants remain in the testing environment 
for the duration of the experiment; technician interaction is limited to occasional BrAC 
samples and dependent-measure data collection. 
 
Upon completion of the infusion and return to the ICRC, participants are served a meal 
from the ICRC kitchen and remain in a room until at least 7:00 pm, or until BrAC < 35 
mg/dL. Subjects may discharge earlier at the discretion of the principal investigator and 
if transportation has been arranged for them, however subjects are not informed of this 
Figure 31: : Exposure Rate Selection and Subjective Response Determination Sequence. The task begins 
with an initial exposure rate selection, with the display indicating no past rate of change (baseline). After 2.5 
minutes, a set of subjective responses are collected over approximately 20 sec after which time the next 
exposure rate selection prompt is displayed, now indicating the prior selection in the left hand (shaded) 
portion of the display. The choice and subjective response sequence is repeated throughout the experiment. 
The next exposure rate is then selected by rotation of the CAIS response button (Griffin Technologies 
Powermate®, inset) to a position within the available range depicted in gray. The arrow position follows 
button rotation in real time, and rate chosen by single button press. Text instructions are for illustrative 
purposes. 

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option as it is exercised only in emergencies or urgent situations.  If the BrAC is 40 
mg/dL or higher at 5:30pm, the participant will be offered a dinner from the ICRC 
kitchen, gratis. Participants will be paid in cash upon discharge from each session, with 
an escalating payment schedule used to encourage retention. Subjects will be 
compensated $25 for the screening interview, $125 for the first rTMS/Alcohol session, 
and $175 for the second rTMS/Alcohol session. Subjects that complete only a portion of 
any study procedure will be compensated at a rate of $15 per hour at the discretion of 
the study physicians. 
 
Alcohol consumption follow-up 
Subjects will be contacted and compensated $25 four weeks after Session 2 for a 
timeline follow-back assessment of drinking49. 
 
 
8.0 
Reportable Events 
 
Serious adverse events resulting in any physical harm associated with testing will be 
reported to the IRB within 24 hours; minor adverse events (e.g. nausea, infusate 
infiltration, discomfort associated with infusion) will be reported to the Alcohol Studies 
DSMB meeting at least annually. 
 
Adverse events (AEs), especially those for which the relationship to study treatment is 
not “unrelated,” will be followed up until they have returned to baseline status or 
stabilized at the discretion of the PI. If after the follow-up period, return to baseline or 
stabilization cannot be established an explanation will be recorded in the source 
documentation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9.0 
Study Calendar 

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rTMS Study 
Screening 
Experimental Visits 
Follow-up 
Procedure 
Phone Interview 
Usual 1 
Usual 2 
1 
Phone Screen 
X 
 
 
 
 
Informed Consent 
 
X 
 
 
 
Audit 
 
X 
 
 
 
SSAGA 
 
X 
 
 
 
SKID V 
 
X 
 
 
 
UPPS-P 
 
X 
 
 
 
SRE 
 
X 
 
 
 
PHQ-9 
 
X 
 
 
 
SIP-r 
 
X 
 
 
 
Medical History 
 
X 
 
 
 
Nicotine History 
Measure 
 
X 
 
 
 
Five Factor Model 
Form 
 
X 
 
 
 
APT 
 
X 
 
 
 
PACS 
 
X 
 
 
 
TLFB 
 
X 
X 
X 
X 
CIWA 
 
X 
 
 
 
GAD-7 
 
X 
 
 
 
UDS 
 
X 
X 
X 
 
UPS 
 
X 
X 
X 
 
BrAC 
 
 
X 
X 
 
Liver Function 
 
X 
 
 
 
Genotype Sampling 
 
X 
 
 
 
rTMS 
 
 
X 
X 
 
Alcohol Exposure 
 
 
X 
X 
 
Subjective 
Measures 
 
 
X 
X 
X 
CAGE 
 
X 
 
 
 
General Self-
Efficacy Scale 
 
X 
 
 
 
DRSEQ-R 
 
X 
 
 
 
AEQ 
 
X 
 
 
 
DMQ 
 
X 
 
 
 
TMS Screening 
Checklist 
 
X 
 
 
 

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10.0 Data Safety Monitoring 
 
The Data Safety and Monitoring Board (DSMB) that monitors virtually all the alcohol 
studies at IUSM, chaired by Dr. Laura Tormoehlen, who is independent of the sponsor 
and investigators, and comprised of other faculty with like status, will review this study 
at six-month intervals. The following will be monitored as part of the Data Safety 
Monitoring Plan (DSMP): data quality, subject recruitment, accrual, retention, outcome 
and adverse event data, assessment of scientific reports or therapeutic development, 
results of related studies that may impact subject safety, and procedures designed to 
protect the privacy of subjects. 
 
The IRB is notified of significant findings by way of the DSMB meeting minutes at the 
time of continuing review. Due to the small sample size and single site design of this 
protocol, there is not sufficient justification for conducting interim analyses to examine 
trends. Data on the number of subjects enrolled and the number of adverse events will 
be reviewed by the DSMB every six months and more frequently if needed. The 
resultant report will be issued to the Indiana University IRB at least at the time of 
continuing review or more frequently by request. Any unanticipated events will be 
immediately directed to the PI who will follow the Indiana University IRB reporting 
procedures. 
 
 
11.0 Study Withdrawal/Discontinuation 
 
The participant may withdraw from the study at any time for any reason, and will be 
paid an amount pro-rated to the duration of their participation on the testing day, 
including time to recover to a BrAC < 35 mg/dL.  The PI may choose to terminate any 
subject’s participation at any time if it is deemed that s/he cannot participate or 
cooperate in testing procedures safely, with the same pro-rated compensation to the 
subject. 
 
 
12.0 Statistical Considerations 
 
Analyses 
 
Sample Size 
 
We plan to consent and screen 30 subjects, enroll 20 subjects and anticipate a 30% 
drop out rate, yielding 14 completers. This is consistent with our previous clinical trial 
efforts, including a study of adjunct rTMS for cognitive impairment in first-episode 
psychosis37.  
 
Statistical and Power Analyses 
 

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We will conduct a Cox proportional hazards survival analysis, which will control for 
drinking intensity, to determine effect sizes for a subsequent, properly powered formal 
study of the effect of rTMS on rate control alcohol self-administration. A recent review 
reported Cohen’s d from 0.05 to 4.42 of rTMS on craving and other substance use 
disorder related outcomes50. Our previous alcohol self-administration work showed 
effect sizes from 0.49 to 1.31 depending on the phenotype. Thus, overall, we hope for 
an effect size of at least 0.5 across SA1 and SA2. 
 
Finally, with consent, we are collecting blood samples to allow for the combination of 
data from this project with previously collected human samples; enabling future analysis 
of polygenetic risk in the combined sample. 
 
 
 
13.0 Statistical Data Management 
 
Primary data will be collected via paper source documents, phone interviews, and direct 
data capture from clinical and symptom measurements. Data will be stored electronically 
on a department server and paper source documents will be stored in a double locked 
and access-controlled research records room. The storage location will be backed up 
automatically on a daily basis.  Other data sources include pathology lab data and Scram 
systems data that will be stored in separate electronic files and merged with the primary 
data as needed. The following data quality control methods will be used: single entry with 
random checks of accuracy, range checks, testing of database by study team prior to 
moving to data analysis, and regular, periodic extraction and cleaning of data. 
 
 
 
14.0 Privacy/Confidentiality Issues 
 
Confidentiality will be protected by ensuring all research staff have been properly 
trained in confidentiality and human subject research procedures, coding all subject 
information when possible, and by securing subject files in a locked filing cabinet or on 
secured databases with access available only to the study physicians and research 
staff. Furthermore, data entered into a computer database will only use subject codes 
on secured computers that will be password protected with access available only to the 
study physicians and research staff. Limited screening information (first name, phone 
number) obtained from potential research subjects who subsequently do not participate 
in the research study will be held for 6 months and then destroyed.  
 
 
15.0 Follow-up and Record Retention 
 
Paper copies of medical records and source documentation will be kept for seven years 
after the study is closed with the IRB. One year after study closure, the documents will 

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be shipped to the Indiana University Department of Psychiatry long-term storage facility 
until destruction. 
 
 
 

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32. 
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17.0 
Appendix 
Attachment 1:  Concomitant Medication Table 
Medication 
Allowed 
Notes 
Amitriptyline 
No 
 
Amphetamines et., 
methylphenidate, 
dextroamphetamine)  
No 
 
Antiemetics (eg., 
metoclopramide, 
domperidone, others with 
dopamine blocking 
properties) 
No 
 
Antiepileptic mood 
stabilizers 
Yes 
Stable dose, no changes 
or additions 
Antihistamines, 
nonsedating (eg., loratidine, 
fexofenadine, cetirizine) 
Yes 
 
Antihistamines, sedating 
(eg., diphenhydramine, 
hydroxyzine, meclizine, 
benztropine) 
Yes-Episodic Use 
Only 
No use within 24 hours of 
cognitive assessments 
Antipsychotic medications 
Yes 
Stable dose over four 
weeks prior to 
randomization, no 
changes or additions 
during duration of trial 
Barbiturates 
No 
 
Benzodiazepines 
Yes-Episodic Use 
Only 
No use within 24 hours of 
cognitive assessments 
Chlorpromazine 
No 
 
Bupriopion 
No 
 
Clozapine 
No 
 
Decongestants (eg., 
pseudophedrine) 
Yes-episodic use 
only 
No use within 24 hours of 
cognitive assessments 
Doxepine 
No 
 
Dicyclomine 
No 
 
Herbal medications or Over 
the Counter Medications w/ 
primary CNS activity 
No 
 
Lithium 
Yes 
 
MAOIs 
Yes 
 
Methadone 
No 
 
Mirtazepine 
Yes 
Stable dose, no changes 
or additions 

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Muscle Relaxants 
Yes-Episodic Use 
Only 
No use within 24 hours of 
cognitive assessments 
Nicotine Replacement 
Yes 
 
Nortriptyline 
No 
 
Opiates 
No 
 
Benzodiazepine derivative 
sleep agents (eg., 
Zolpidem) 
Yes-Episodic Use 
Only 
No use within 24 hours of 
cognitive assessments 
SNRIs 
Yes 
 
SSRIs 
Yes 
 
Tricyclic antidepressants 
Yes 
 
Trazodone 
Yes-Episodic Use 
Only