Conditions: Alcohol Drinking
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
The proposed project will utilize perfusion functional magnetic resonance imaging (fMRI) to examine the effects of topiramate on brain and behavioral responses in heavy drinkers to appetitive alcohol reminders (cues that motivate continued alcohol use and relapse). This project will yield novel findings on brain and behavioral responses to alcohol cues, the effects of topiramate on alcohol cue reactivity, and the mechanisms underlying topiramate's ability to blunt alcohol cue reactivity and heavy drinking.

Detailed description:
This project is a double-blind, randomized, placebo-controlled study of topiramate's effects on brain and behavior responses in heavy drinkers. Eligible volunteers who meet study criteria will be randomized to receive either topiramate or placebo with weekly visits and medication management sessions. Participants will complete two magnetic resonance imaging sessions. The first scan session will occur prior to starting study drug, and the second scan will occur following six weeks of study drug. This project will yield novel findings on brain and behavioral responses to alcohol cues, the effects of topiramate on alcohol cue reactivity, and the mechanisms underlying topiramate's ability to blunt alcohol cue reactivity and heavy drinking.

Arms:
arm 1: up to 200mg/day orally (over 8 weeks during which the dosage is gradually increased up to 200 mg orally and then maintained, and 1 week of medication taper) arm 2: placebo

Interventions: intervention 1: Topiramate intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
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sponsor 
   HUMAN RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
BRAIN MECHANISMS OF TOPIRAMATE’S EFFECTS ON 
HEAVY DRINKING  
 
 
 
Regulatory Sponsor: 
Reagan Wetherill, Ph.D. 
Psychiatry 
3900 Chestnut Street 
Philadelphia, PA  19104 
(215) 222-3200 ext. 141 
 
Funding Sponsor: 
Departmental Funds (Kranzler) 
Contact Person: Linda L. Mangino 
Manager of Administration & Finance 
CSA/Psychiatry 
University of Pennsylvania 
3440 Market Street, Ste. 370 
Philadelphia, PA  19104 
(484) 802-4375 
 
Study Product: 
Topiramate 
Protocol Number: 
818988 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 9: 
[10/10/2014] 
 
 
 
 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 3 
1.3 
PRECLINICAL DATA ........................................................................................................................ 3 
1.4 
CLINICAL DATA TO DATE................................................................................................................. 4 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 4 
2 
STUDY OBJECTIVES ......................................................................................................................... 5 
3 
STUDY DESIGN ................................................................................................................................... 5 
3.1 
GENERAL DESIGN .......................................................................................................................... 5 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 6 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 6 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 6 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 6 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 7 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 7 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 7 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 7 
5 
STUDY DRUG ...................................................................................................................................... 8 
5.1 
DESCRIPTION ................................................................................................................................. 8 
5.2 
TREATMENT REGIMEN .................................................................................................................... 8 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................... 8 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................................... 9 
5.5 
SUBJECT COMPLIANCE AND MONITORING ........................................................................................ 9 
5.6 
PRIOR AND CONCOMITANT THERAPY  .............................................................................................. 9 
5.7 
PACKAGING ................................................................................................................................... 9 
5.8 
BLINDING OF STUDY DRUG ............................................................................................................. 9 
6 
STUDY PROCEDURES ....................................................................................................................... 9 
6.1 
INITIAL TELEPHONE SCREEN .......................................................................................................... 9 
6.2 
INFORMED CONSENT & SCREENING VISIT ...................................................................................... 10 
6.3 
LABORATORY/MRI SESSION 1 VISIT .............................................................................................. 11 
6.4 
WEEKLY VISITS ............................................................................................................................ 13 
6.5 
LABORATORY/MRI SESSION 2 VISIT .............................................................................................. 14 
6.6 
ENDPOINT VISIT ........................................................................................................................... 14 
7 
STATISTICAL PLAN ......................................................................................................................... 15 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 15 
7.2 
STATISTICAL METHODS ................................................................................................................ 15 
7.2.1 
Imaging Data Processing ...................................................................................................... 15 
7.2.2 
Imaging Data Analyses ......................................................................................................... 15 
7.2.3 
Behavioral Analyses .............................................................................................................. 16 
7.2.4 
Genetic Analyses .................................................................................................................. 16 
7.3 
SUBJECT POPULATION FOR ANALYSIS ........................................................................................... 16 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 16 
8.1 
DEFINITIONS ................................................................................................................................ 16 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 18 


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8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 18 
8.3.1 
IRB Notification by Investigator ............................................................................................. 18 
8.4 
UNBLINDING PROCEDURES ........................................................................................................... 18 
8.5 
MEDICAL MONITORING ................................................................................................................. 18 
8.6 
PROTECTION OF SUBJECTS .......................................................................................................... 19 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 19 
9.1 
CONFIDENTIALITY ......................................................................................................................... 19 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 20 
9.3 
CASE REPORT FORMS.................................................................................................................. 20 
9.4 
RECORDS RETENTION .................................................................................................................. 20 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 20 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 20 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 22 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 23 
11.1 
CONSENT PROCEDURES ............................................................................................................... 23 
12 
STUDY FINANCES ............................................................................................................................ 23 
12.1 
FUNDING SOURCE ........................................................................................................................ 23 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 23 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 23 
13 
REFERENCES ................................................................................................................................... 24 
14 
APPENDIX 1 (PILOT TEST CUE SETS) ........................................................................................... 26 
 


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sponsor 
Study Summary 
Title 
BRAIN MECHANISMS OF TOPIRAMATE’S EFFECTS ON HEAVY DRINKING 
Short Title 
Brain Mechanisms of Topiramate 
Protocol Number 
818988 
Phase 
N/A 
Methodology 
Pilot study/Basic Research 
Study Duration 
Approximately 24 months 
Study Center(s) 
Single Center, Center for Studies of Addiction 
Objectives 
1.  Pilot test cue sets and confirm brain and behavioral responses to alcohol 
cues using pseudo-continuous arterial spin labeling functional magnetic 
resonance imaging 
2a. Demonstrate neuromodulatory effects of a GABA/glutamate modulator, 
topiramate, on resting baseline and alcohol cue reactivity 
2b. Examine the mechanism underlying topiramate’s ability to blunt alcohol cue 
reactivity and reduce heavy drinking days 
Number of Subjects 
100 enrolled for a target of 40 for main study, up to 10 for the pilot sub-study  
Diagnosis and Main 
Inclusion Criteria 
DSM-5 diagnosis of Alcohol Use Disorder 
Study Product, Dose, 
Route, Regimen 
Topiramate tablets encapsulate for blinding.  Maximum daily dosage is 200 mg 
by mouth.  Six-week titration to maximal dosage. 
Duration of 
administration 
8 weeks 
Reference therapy 
placebo 
Statistical 
Methodology 
Frequencies and descriptives; Voxel-wise analyses of cerebral blood flow 
(CBF) data using a general linear model on absolute and relative CBF 
 


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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference 
on Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures.  
1.1 Background 
Alcohol is the third leading risk factor for premature death and disability [1], as well as a leading cause of 
preventable cancers [2]. Alcohol dependence affects 18-20 million Americans (i.e. 1 in 12), and alcohol 
problems cost our society nearly $225 billion annually [1]. Alcohol dependence is a chronic disorder marked 
by high rates of relapse. Relapses to drinking are often preceded by a strong desire or craving for alcohol 
when exposed to alcohol-related stimuli. Knowledge of the mechanisms underlying stimuli- or alcohol cue-
induced craving may aid in the search for additional viable pharmacotherapies to help alcohol dependent 
individuals remain abstinent for life.   
Currently, there are three FDA-approved medications to treat alcohol use disorders (AUD): naltrexone, 
acamprosate, and disulfiram [3]. Empirical evidence suggests that naltrexone reduces the reward 
properties of and cravings for alcohol [4] and acamprosate supports abstinence [5]; however, their effect 
sizes compared to placebo are small [6-8]. Disulfiram differs from naltrexone and acamprosate in that it 
blocks the metabolism of alcohol’s primary metabolite, acetylaldehyde, which accumulates in the blood 
causing unpleasant effects when alcohol is ingested [9]. There is limited evidence of the efficacy of 
disulfiram, and its potential for toxicity limits it use [10]. These concerns about safety and limited efficacy 
likely contribute to the fact that FDA-approved medications for AUD are not widely prescribed [7, 11]. 
Indeed, only 2.8% of patients treated in the Veterans Health Administration who were diagnosed with an 
AUD received pharmacotherapy [6]. Given these issues and concerns, several medications, other than the 
currently approved medications for AUD, have been prescribed off label and have shown promise in 
reducing alcohol consumption.  
One promising medication for the treatment of AUD is the GABA/glutamate modulator, topiramate. Although 
topiramate is FDA-approved as an anticonvulsant, prophylactic treatment for migraine, and for weight loss, 
both preclinical [12, 13] and clinical studies [14-17] show that topiramate is effective in reducing heavy 
drinking. Specifically, topiramate reduced alcohol craving [17]; had a moderate treatment effect in reducing 
heavy drinking in three published placebo-controlled trials [14-16], and appears to have a larger effect size 
than naltrexone [18, 19] and acamprosate [20]. Kranzler et al. (in press) found that 200 mg/day of topiramate 
was well tolerated, reduced the number of heavy drinking days and increased the number of abstinent days 
more than placebo. In fact, during the last week of the 12-week study, the odds of the placebo group having 
at least one heavy drinking day was 5.33 times that of the topiramate group. Although these robust findings 
support the use of topiramate to reduce heavy drinking, the mechanisms underlying its therapeutic effects 
are not well understood. Thus, the present study aims to elucidate the brain and behavioral mechanisms 
that mediate topiramate’s reduction of heavy drinking. 
Functional neuroimaging provides a powerful, non-invasive method to study addictive processes. For 
example, we, and others, have identified a consistent neural substrate for reactivity to cocaine-, heroin-, 
cigarette-, marijuana- and alcohol-related cues using a variety of imaging modalities [21-26]. In general, 
chronic, heavy substance users show greater neural activity in reward-related brain regions, such as the 
orbitofrontal cortex (OFC), striatum, and anterior cingulate cortex, during drug cue exposure than during 
non-drug cues. Neuroimaging techniques have also been used to determine how some pharmacotherapies 
influence factors contributing to substance use. For example, naltrexone has been shown to reduce alcohol 
cue-induced activation in the ventral striatum (VS) and OFC in non-treatment-seeking alcoholics [27], 
suggesting that naltrexone’s effects are mediated through its reduction of reward-related cue reactivity. To 
date, there are no published studies examining the effects of topiramate on neural activity or how such 
effects could be associated with changes in heavy drinking. Based on our own recent finding that topiramate 
decreased heavy drinking days and increased abstinent days and other research indicating that topiramate 
reduces heavy drinking days [14-16] and self-reported craving [17], we hypothesize that topiramate may 
be an effective tool in reducing the reward-related neural activity commonly associated with heavy drinking 
(i.e., alcohol cue reactivity). Further, our longitudinal, quantitative perfusion fMRI approach, which provides 


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for the acquisition of resting brain cerebral blood flow (CBF: ml of blood/100 g of tissue/minute) will provide 
invaluable information on the mechanisms underlying the ability of a GABA/glutamate modulator to blunt 
alcohol cue reactivity and heavy drinking. 
 
Neurogenetics is a promising and novel addition to neuroimaging studies. Twin, family and adoption studies 
indicate that vulnerability to substance abuse is partially inherited. Individual response to medications will 
most likely be related to genetic phenotypes. Genetics studies, on their own, require huge sample sizes 
and are expensive; however, when combined with neuroimaging, which offers a ‘picture’ of individual brains, 
we can learn why some individuals are vulnerable to alcohol and substance use disorders and why others 
do not. For example, evidence suggests that the rewarding properties of alcohol involve GABA-ergic, 
glutamatergic, opiodergic, and dopaminergic neurotransmitter systems. As such, we will focus on genes 
associated with these systems, such as DRD4 (D4 dopamine receptor gene), GABRA2 (GABAA receptor 
alpha-2 subunit gene), OPRM1 (mu-opioid receptor gene), and GRIK1 (glutamate receptor, ionotropic, 
kainate 1 gene) [28]. Further, based on our previous research showing that the C-to-A single nucleotide 
polymorphism (SNP), rs2832407, in intron 9 of the GRIK1 gene is associated with alcohol dependence 
[29], this variant in GRIK1 will be our primary focus. Thus, those who have the A allele will likely show the 
strongest alcohol cue responses.  
 
In summary, the data reviewed above provide strong support for the need to identify the brain and 
behavioral mechanisms underlying the effects of one of the most prescribed [30], yet poorly understood, 
medications to treat AUD, topiramate, on key factors contributing to heavy drinking. Given that topiramate 
1) has been shown to be effective in reducing heavy drinking [14-17], 2) appears to have a larger effect 
size than naltrexone [18, 19] and acamprosate [20], and 3) has dual GABAA-mediated inhibitory impulses 
and AMPA and kainate antagonist effects [31] that likely suppress reward-related mesocorticolimbic 
dopamine release, we hypothesize that topiramate ameliorates neurophysiological vulnerabilities to heavy 
drinking by dampening neural activity in the brain at rest and during alcohol cue exposure in reward-related 
brain regions. The current study will elucidate the brain and behavioral mechanisms underlying topiramate’s 
effects and test our hypotheses using a randomized, double-blind placebo-controlled design, pseudo-
continuous arterial spin labeling (pCASL) perfusion functional magnetic resonance imaging (fMRI), and 
other relevant assessments described below. This project will yield novel findings on brain and behavioral 
responses to alcohol cues, the neuromodulatory effects of topiramate on alcohol cue reactivity, and the 
mechanisms [resting baseline (RB) modulation] underlying the ability of this GABA/glutamate modulator to 
blunt alcohol cue reactivity and heavy drinking. Thus, the proposed research, although not a treatment trial, 
will examine the effects of topiramate on brain and behavior and thereby contribute to medications 
development and the treatment of AUD.   
1.2 Investigational Agent 
Topiramate is an anticonvulsant medication for oral administration approved in the United States for the 
treatment of seizures and to prevent migraine headaches in adults. The molecular formula is C 12 H 21 NO 
8 S and the molecular weight is 339.35. It is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-
fructopyranose sulfamate. Preclinical studies indicate that topiramate blocks voltage-dependent sodium 
channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the 
GABA-A receptor, antagonizes the AMPA/kainite subtype of the glutamate receptor, and inhibits the 
carbonic anhydrase enzyme, particularly isozymes II and IV. Topiramate absorption is rapid, with peak 
plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The bioavailability 
of topiramate from the table formulation is about 80% compared to a solution and is not affected by food. 
The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady-state is reached in 
about 4 days. 
According to the FDA-approved labeling, topiramate has been found to be safe at doses of 200mg and 
400mg per day in adults. 
1.3 Preclinical Data 
Drug-Drug Interactions and Precautions 


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Topiramate may have interactions with some antiepileptic drugs and oral contraceptives. Specifically, 
concomitant use of topiramate with standard antiepileptic drugs (i.e., Phenytoin, Carbamazapine, Valproic 
acid, and Lamotrigine) has been shown to decrease plasma levels of topiramate. Topiramate may also 
reduce the efficacy of some hormonal contraceptives (birth control pills, hormonal implants, or hormonal 
injections). Topiramate does not produce clinically significant additive central nervous system depressant 
effects in combination with ethanol. Concomitant use of topiramate with other carbonic anhydrase inhibitors 
(e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase severity of metabolic acidosis and 
may also increase the risk of kidney stone formation. There is no evidence that topiramate has carcinogenic, 
teratogenic, or mutagenic potential. Further, topiramate is not reinforcing and is therefore not a drug of 
abuse. 
1.4 Clinical Data to Date 
Topiramate has been evaluated for safety in over 3000 adults, and there are few serious adverse effects 
associated with topiramate. The most common adverse effect of topiramate compared to placebo is 
numbness and tingling (49% vs. 6%). The other most common side effects (experienced by 10-31% of 
patients) in clinical trials include: change in sense of taste, tiredness/sleepiness, fatigue, dizziness, loss of 
appetite, nausea, diarrhea, weight decrease, difficulty concentrating and difficulty with memory. Cognitive 
dysfunction adverse effects (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, 
difficulty with memory, speech or language problems, particularly word-finding difficulties) that were 
reported during 6-month migraine prophylaxis studies (28% vs. 10% for placebo) were of mild-to-moderate 
severity.  Other adverse effects (experienced by 5-9% of patients) in some clinical trials include: 
nervousness, slow thinking, abnormal vision, confusion, decreased sensitivity (hypesthesia), anxiety, 
abdominal pain, dry mouth, involuntary muscle contractions, and language problems.  Depression and 
mood problems have also been reported (experienced by 5-9% of patients).  Severe metabolic acidosis 
(decreased bicarbonate levels) is associated with topiramate treatment in 3-7% of individuals taking the 
medication. 
1.5 Dose Rationale and Risk/Benefits 
Dose Rationale 
The dosage of topiramate selected for this study (200 mg/day) is based on previous research indicating 
that 200 mg/day is the dosage at which heavy drinkers begin to show therapeutic effects [14-16]. Further, 
one study of 138 heavy drinkers who sought to reduce their drinking received a 12-week treatment with 
topiramate (N=67) 200 mg/day or matching placebo and showed that topiramate was well tolerated, with 
no serious side effects, and was efficacious at reducing heavy drinking days and increasing abstinent days 
[32]. 
 
Potential Risks 
The potential risks of this study include adverse reactions to topiramate, adverse reactions attributable to 
the combination of topiramate and alcohol, and the small risk incurred by venipuncture. Individuals will be 
advised to drink adequate amounts of liquid to avoid renal calculi (experienced by 2% of individuals taking 
the medication). Individuals who are taking carbonic anhydrase inhibitors will be excluded from the study, 
due to the added risk of metabolic acidosis (decreased bicarbonate levels), which has been reported in 3-
7% of individuals taking the medication.  
 
Topiramate is not reinforcing and therefore there is no abuse potential; however, access to topiramate will 
be strictly limited by the study design and use will be carefully monitored.  
 
Potential Benefits 
Individuals receiving study medication may experience a reduction in or discontinuation of their alcohol 
consumption, which may improve their health and well-being. Subjects will also receive close psychiatric 
and medical attention, including careful evaluation of their medical and psychiatric status. The potential 
benefits to society include a potential improvement in the effectiveness of treatment for problem drinking, 
which may reduce the personal and societal costs associated with the problem.  
 


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Risk Benefit Ratio 
The potential benefits of this study far outweigh the potential risks. Alcohol use disorders are serious 
disorders with mildly effective pharmacotherapy. Even in the best programs, relapse rates are high. 
Individuals accepted into this study will receive close medical and psychiatric monitoring. Subjects will be 
screened prior to admission into the study and those at risk for adverse reactions will be excluded. Subjects 
selected for participation will be monitored closely for adverse effects of topiramate. 
2 Study Objectives 
Objective 1 Pilot cue sets (see Appendix 1) and confirm brain and behavioral responses to alcohol cues in 
individuals with AUD using pCASL fMRI 
Hypothesis 1: Similar to our other pCASL fMRI cue-reactivity studies in drug-dependent 
individuals, subjects will exhibit greater brain activity in the interconnected VS and medial 
orbitofrontal cortex (mOFC) during alcohol cue exposure compared to non-alcohol cue exposure. 
Objective 2a Demonstrate neuromodulatory effects of a GABA/glutamate modulator, topiramate, on RB 
and alcohol cue reactivity 
Hypothesis 2a: We hypothesize that topiramate will ameliorate neurophysiological vulnerabilities 
by dampening neural activity in the brain ‘at rest’ and during alcohol cue exposure in reward-
related regions, such as the amygdala, mOFC, VS, and the insula. In contrast, neural activity in 
placebo-treated individuals at rest and in alcohol cue reactivity will not differ from pre- to post-
treatment. 
Objective 2b Examine the mechanism underlying topiramate’s ability to blunt alcohol cue reactivity and 
reduce heavy drinking days 
Hypothesis 2b: We hypothesize that there will be a direct relationship between RB in the VS and 
mOFC and its effects on alcohol cue reactivity. Although overall effects are expected, reductions 
in heavy drinking days will correlate with topiramate’s ability to modulate reward circuitry 
responses. 
Exploratory Objective Examine the moderating effects of rs2832407 on topiramate’s effects on brain and 
behavioral responses 
Exploratory hypothesis: C-allele homozygotes at this locus will show the most robust effects of 
topiramate. 
3 Study Design 
3.1 General Design 
 
Phase IV Study - This is a phase IV research study aimed at identifying the brain and behavioral 
mechanisms underlying the GABA/glutamate modulator, topiramate. 
 
Design – Heavy drinkers who meet DSM-5 criteria for AUD and express an interest in reducing or 
stopping drinking will be recruited, screened, consented, and if eligible, will complete a randomized 
double-blind, placebo-controlled study of topiramate (N=40; topiramate 200 mg/day: n=20 or 
placebo: n=20). Topiramate or placebo will be initiated after Scan 1 and continued with weekly 
visits and medical management [33]. During the 7th week, participants will complete Scan 2 followed 
by medication taper and an endpoint visit. We will use perfusion fMRI during alcohol cue exposure 
to acquire brain and behavioral responses to alcohol cues. The goals of this study are to pilot test 
the validity of our alcohol cues and to identify brain and behavioral mechanisms of topiramate in 
reducing heavy drinking in alcohol dependent individuals.  
 
Study Duration – The duration of this study will be approximately 9 weeks, including screening, 
Scan 1, 8 weeks of medication and medical management (including medication taper), Scan 2 
during week 7, medication taper, and an endpoint visit. The entire study will run for approximately 
24 months. 
 
 


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3.2 Primary Study Endpoints 
The primary endpoints to be measured include: 
 
Self-report ratings of cues, subjective ratings of craving during/following cue exposure, and 
neuroimaging data on cerebral blood flow when the brain is at rest and when exposed to alcohol 
cues. 
3.3 Secondary Study Endpoints 
The effects of rs2832407 on topiramate’s neural mechanisms 
4 Subject Selection Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1) 
Physically healthy, as determined by a comprehensive physical examination and approval 
of the study physician males or females who drink alcohol, ages 18-60. 
2) 
Have an average weekly ethanol consumption of >24 standard drinks for men, or >18 
standard drinks for women [34]. 
3) 
Females must be non-pregnant, non-lactating and either be of non-childbearing potential 
(i.e. sterilized via hysterectomy or bilateral tubal ligation or at least 2 years post-
menopausal) or of child bearing potential but practicing a medically acceptable method of 
birth control. Examples of medically acceptable methods for this protocol include: the birth 
control pill, intrauterine device, injection of Depo-Provera, Norplant, contraceptive patch, 
contraceptive ring, double-barrier methods (such as condoms and diaphragm/spermicide), 
male partner sterilization, abstinence (and agreement to continue abstinence or to use an 
acceptable method of contraception, as listed above, should sexual activity commence), 
and tubal ligation.  
4) 
Provide voluntary informed consent. 
5) 
Must be able to read. [Subjects are required to be able to read because there are several 
self-administered measures that they must read, understand and provide written answers.] 
6) 
Intelligence quotient of ≥ 80, as estimated by the 2-subtest score of the Wechsler 
Abbreviated Scale of Intelligence (WASI) [35].  
4.2 Exclusion Criteria 
1) 
A current, clinically significant physical disease or abnormality on the basis of medical 
history, physical examination, or routine laboratory evaluation. 
2) 
History of head trauma or injury causing loss of consciousness, lasting more than five (5) 
minutes or associated with skull fracture or inter-cranial bleeding or abnormal MRI. 
3)      Current major DSM-IV Axis I diagnoses other than alcohol, nicotine, and cannabis use 
disorders.  
4) 
Presence of magnetically active irremovable prosthetics, plates, pins, permanent retainer, 
bullets, etc. (unless a radiologist confirms that it’s presence is unproblematic).   
5) 
History of a serious psychiatric illness including psychosis, bipolar disorder, or suicidal or 
homicidal intent.  
6) 
Current treatment with carbonic anhydrase inhibitors, due to the added risk of metabolic 
acidosis. 
7) 
Claustrophobia or other medical condition preventing subject from lying in the MRI for 
approximately one (1) hour. 
8) 
Current regular treatment with psychotropic medications (e.g., benzodiazepines, 
antidepressants), which affect neurotransmitter systems or a medication being used to 
treat alcohol use disorders (e.g., naltrexone, acamprosate). 
9)  
Vision problems that cannot be corrected with glasses.   
10)  
Body Mass Index (BMI) greater than or equal to 34, body girth greater than 52 inches and 
a head girth greater than 25 inches [Imaging data acquisition is impaired with high weight 
individuals]. 


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11) 
Individuals suffering from or with a history of stroke and/or stroke related spasticity. 
12) 
History of glaucoma or kidney stones. 
13) 
Individuals who are HIV positive, as the human immunodeficiency virus affects the brain. 
14) 
Individuals with a history of seizures. 
15) 
Individuals who have taken topiramate for alcohol use disorder and report no treatment 
response. 
16) 
Current DSM-5 diagnosis of alcohol use disorder that is clinically too severe to permit them 
to participate in a research trial in which the goal is to stop or reduce drinking  [Because 
there is no clear empirical basis for choosing a cutoff with respect to AUD criteria, we will 
exclude patients who, on clinical examination by a physician, are deemed to be too 
severely alcohol dependent to permit them to participate in a research trial. This 
determination will be based on evidence of adverse medical (e.g., gastritis) or psychiatric 
effects (e.g., depression with suicidal ideation). In addition, individuals with no recent 
evidence of the capacity to reduce drinking from very high levels of intake or a history or 
present evidence of significant alcohol withdrawal symptomatology will be excluded.  
(Significant withdrawal will be considered to be present when there is a history of 
substantial tremor, autonomic changes, perceptual distortions, seizures, delirium, or 
hallucinations or a report of drinking to avoid withdrawal symptoms or of prior treatment of 
withdrawal). 
4.3 Subject Recruitment and Screening 
Subjects will be recruited from those who respond to IRB-approved advertisements. Advertisements will be 
in the form of IRB-approved radio ads, flyers, billboards, e-lists, and word of mouth. Individuals who have 
completed prior studies and meet study criteria will also be invited to participate if subject participation 
ended at least 30 days before the current study starts (i.e., no pharmacotherapy or psychotherapy for 30 
days). An initial telephone interview covering recent medical status, substance use, treatment history, 
medication, and general psychiatric history will be conducted.  The potential subject will be provided with 
an overview of the study and will be informed that all information obtained will be used to determine his/her 
eligibility for study participation. If the individual satisfies preliminary criteria and shows continued interest 
in participating in the study, an appointment will be made for further screening at the Center for Studies of 
Addiction (CSA).  The CSA initial screening process will be described, and the individual will also be 
informed that s/he must be available for at least two separate appointments during the screening week 
(unless the two appointments are combined). For details on Screening, see 6.2 Informed Consent and 
Screening Visit below. 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects with severe psychological symptoms (e.g., suicidal thoughts), those who fail to adhere to protocol 
requirements, and those withdraw consent will be withdrawn from the study and if applicable, referred for 
appropriate clinical care. If a subject is found to be pregnant during screening or during study, she will 
immediately be withdrawn from the study, referred for obstetric evaluation, and advised to discontinue all 
drinking.  
 
Any subject experiencing a serious adverse event felt to be related to study drug should be withdrawn from 
the study. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
We will make a strong effort (via phone calls and alternative contact information) to obtain follow-up 
information on all subjects who are prematurely withdrawn from the project. 


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5 Study Drug  
Topiramate is an anticonvulsant medication for oral administration approved in the United States for the 
treatment of seizures and to prevent migraine headaches in adults. According to the FDA-approved 
labeling, topiramate has been found to be safe at doses of 200mg and 400mg per day in adults. 
For more detailed information, see section 1.2 (Investigational Agent). 
5.1 Description 
Topiramate for this study is supplied in opaque capsules. The placebo formulation is a table that appears 
identical to the topiramate capsules. 
5.2 Treatment Regimen 
Subjects will be randomized to receive topiramate or placebo, to begin after completing the first 
Laboratory/MRI visit according to the following regimen: 
 
Table 1. Medication Dosing Schedule for Topiramate 
 
Medication 
Dispensed 
Morning Dose 
Evening Dose 
Total Daily Dose 
Screening Visit -0 
Week 0 
No medication 
No medication 
0 mg 
Scan 1/ Visit 1 
Week 1 
No medication 
25 mg 
25 mg 
Visit 2 
Week 2 
25 mg 
25 mg 
50 mg 
Visit 3 
Week 3 
25 mg 
50 mg 
75 mg 
Visit 4 
Week 4 
50 mg 
50 mg 
100 mg 
Visit 5 
Week 5 
50 mg 
100 mg 
150 mg 
Visit 6 
Week 6 
100 mg 
100 mg 
200 mg 
Scan 2/Visit 7 
Week 7 
100 mg 
100 mg 
200 mg 
Taper Visit 8 
Week 8 
Reduce dose by 50 mg every 2 days (150 mg for 2 days, 
100 mg for 2 days, 50 mg for 2 days, then D/C 
Final visit/Visit 9 
Week 9 
No medication 
No medication 
0 mg 
 
If subjects experience significant side effects from the study drug (topiramate or placebo), the investigators 
will have the option to reduce the dose (number of pills) during the study, based on consultation with the 
research staff, or as clinically indicated, by interviewing the subject directly. All dosing is on a double blind 
basis, thus, the physician can vary the number of capsules of placebo or topiramate in response to adverse 
effects reported by the subject. Upward titration following a dose reduction will be allowed once during the 
trial. Dose titration, if necessary, will be carefully documented in the study chart along with the clinical 
rationale. 
5.3 Method for Assigning Subjects to Treatment Groups 
Subjects will be randomly assigned to one of two treatment conditions: topiramate 200 mg/day (n = 20) or 
placebo (n = 20). Study staff and the Investigational Drug Service (IDS) staff will be responsible for 
medication randomization.  The process for randomization is: 1) Research coordinator will complete an 
“randomization form,” which includes the variables to be entered into the block randomization program by 
study staff (i.e., sex, number of heavy drinking days in the past month( >12 heavy drinking days and =<12 
heavy drinking days)); 2) study staff will enter variables into the block randomization program, 3) study staff 
will fax randomization group to IDS, who will assign a kit number to subject and fax kit assignment to 
research coordinator; 4) the research nurse or Physician will dispense medication to subject and complete 
and sign IDS Rx prescription form included in starter kit. 5) Research coordinator will fax completed form 
to IDS. The medication will be dispensed using the above dosing schedule. To maintain double-blind 
conditions, study staff responsible for randomization will not be involved in subject participation, study visits, 
or data collection. 
 
Study drug for subsequent visits will be ordered by the research coordinator using the “Research Pharmacy 
Schedule” form, a copy of which will be retained in the subject’s research file.  At each visit, a supply of 


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study drug will be dispensed by the research nurse. Subjects with severe psychological symptoms or 
determined to be inappropriate for the study by an investigator will be withdrawn from the study.  Subjects 
who are withdrawn completely will be referred for appropriate clinical care.   
5.4 Preparation and Administration of Study Drug 
Topiramate will be purchased commercially and formulated in opaque capsules by IDS. Placebo will be 
formulated to match the active medication, such that inspection of the capsules will not permit the two to 
be differentiated.  The study medication will be shipped to the Research Pharmacy where, it will be stored 
at room temperature (59-86º F) until dispensed to nursing staff for distribution to subjects. The IDS will 
supply study staff with starter kits for week 1 doses. Study medication will be stored at room temperature 
(59-86º F) in a locked drawer until dispensed by nursing staff for distribution to subjects.  
5.5   Subject Compliance Monitoring 
We will conduct pill counts at the weekly visit of all study subjects. Unused amounts will be documented. 
Proper drug dosing will be reviewed with subjects at each visit with clear instructions to take all study drug, 
as directed. In addition, subjects in both medication groups will receive Medical Management (MM) [33]. 
This provides a basic clinical intervention that was designed to be used in conjunction with prescribed 
medication, and to be easily implemented by medically trained practitioners in non-specialty settings. The 
treatment will support subjects’ efforts to reduce their drinking, with the study nurse making direct 
recommendations for reducing drinking to sensible levels (see below).   
5.6 Prior and Concomitant Therapy 
Individuals who have completed prior alcohol treatment studies and meet study criteria will also be invited 
to participate if subject participation ended at least 30 days before the current study starts (i.e., no 
pharmacotherapy or empirically supported treatment for 30 days). Subjects currently in treatment program 
for alcohol use disorders. See exclusion criteria, section 4.2. 
5.7   Packaging 
The Investigational Drug Service of the University (IDS) of Pennsylvania will package bulk drug on-site, as 
containing 8 days of medication in child-safe prescription bottles. Subjects will be provided with an extra 
day of medication to ensure that subjects have enough medication if a weekly visit needs to be rescheduled. 
5.8   Blinding of Study Drug 
All subjects and research staff will be blinded as to whether the subject is in the topiramate or placebo 
group until the end of the study once the decision to break the study blind is determined (after study 
database lock). Codes linking randomization number for each subject to actual treatment will be secured in 
a sealed, opaque envelope and maintained in a locked drawer in the research pharmacy and the hospital 
pharmacy. Research subjects will be given the emergency contact number for the study during the 
consenting process. 
See section 8.4 (Unblinding Procedures) for a description of the process for unblinding a study subject. 
6 Study Procedures 
6.1 Initial Telephone Screen (approximately 20 minutes)  
Subjects will be recruited from the Center for Studies of Addiction at 3900 Chestnut St. through local 
advertisements. Subjects who express interest by responding to advertising are contacted by phone and 
participate in a telephone screening interview. The nature of the study, including the number of visits to the 
center and a description of fMRI procedures, subject protections and confidentiality, are described. If the 
caller is still interested, questions on general health are asked. If the applicant is determined to be eligible 
based on this screening, s/he is asked whether they accept or decline to participate.  If the caller is still 
interested, s/he will be scheduled for an initial consenting appointment.  


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6.2 Informed Consent and Screening Visit (approximately 4 hours) 
Upon arriving to the Informed Consent and Screening Visit, subjects will be asked to show legal 
identification and to complete a breathalyzer test to ensure a breath alcohol concentration (BrAC) of 0.00 
g%. Reading ability will be evaluated followed by a review of HIPAA privacy laws and the informed consent. 
Specifically, subjects will be provided a standard HIPAA form that contains privacy laws, and a study staff 
member will review the consent form with the subject, including an explanation of the study protocol, its 
risks, potential benefits, and alternative treatment. Following resolution of any questions, subjects who 
appear to understand the nature of the study and consent will be asked to sign the study consent form.  An 
entire copy of the informed consent form will be given to each subject. S/he is also reminded that the 
consent expresses willingness to participate but that the subsequent screening process will determine final 
eligibility. Further, s/he is reminded that participation is voluntary, and at any time, s/he may withdraw from 
the study. 
 
Following consent, subjects will watch an fMRI video that simulates the experience of undergoing an MRI, 
meet with the study nurse to complete physical examination and laboratory evaluation, and meet with study 
staff to complete additional assessments. Baseline laboratory measures include: 1) CBC, 2) Blood 
chemistries (i.e., standard blood work and lipids), 3) gamma glutamyltransferase (GGTP) to assess the 
validity of self-reported drinking, 4) HIV test (blood), 5) Electrocardiogram, 6) Urine Toxicology (presence 
of psychoactive drugs) and 7) for females: a urine pregnancy test and an additional blood sample for 
biochemical measurement of progesterone and estradiol levels for determination of menstrual cycle phase. 
A total of approximately 3 tablespoons of blood will be taken. A portion (approximately 2 tablespoons) of 
this blood sample will also be used to acquire DNA samples from each subject. This portion will be stored 
for later extraction and analyses. In cases where blood samples are drawn and potential lab errors or 
abnormal findings occur, subjects will be asked to provide an additional blood sample to repeat the test(s). 
If the HIV test is positive, the subject will be referred to their primary care provider. 
 
Measures obtained: 
 
a. Sociodemographic/subject information: General demographic information, marital status, 
educational, and occupational information will be obtained. 
b. The Timeline Follow-back (TLFB) [36] will be used to estimate past 30-day drinking. This 
interview procedure will provide quantity/frequency of alcohol consumption data for each day during the 
period prior to the interview. The TLFB is reliable and valid when used by trained interviewers. We will 
also measure tobacco and other substance use patterns using the TLFB. 
c. The Short Index of Problems (SIP) is a 15-item instrument, derived from the 50-item DrInC 
[37], measures alcohol dependence symptoms and medical, psychological, social, occupational, and 
legal problems. We have chosen to use the shorter SIP because we [38] found that, like the DrInC, the 
SIP measures a single factor of alcohol-related problems. 
d. The Alcohol Urge Questionnaire (AUQ) [39] is an 8-item, self-administered state measure 
assessing the urge for an alcoholic drink at the time the questionnaire is completed and provides an index 
of acute craving. The AUQ contains four items pertaining to the desire for a drink: two items regarding 
expectations of positive effects from drinking, and two items relating to the inability to avoid drinking if 
alcohol were present. This measure has strong correlations with measures of alcohol dependence and 
severity. 
e.  The Fagerstrom Test for Nicotine Dependence (FTND) [40] is a 6-item, self-report measure 
of nicotine dependence derived from the Fagerstrom Tolerance Questionnaire.   
 
f.  The Obsessive Compulsive Drinking Scale (OCDS) [41] is a 14-item, self-report measure that 
assesses aspects of alcohol craving, including obsessive thoughts about alcohol use and compulsive 
behaviors toward drinking. 
 
g. The Clinical Institute Withdrawal Assessment for Alcohol Scale – revised (CIWA-Ar) [42] 
is a  10-item scale for clinical quantification of the severity of alcohol withdrawal. 
 
h. Structured Clinical Interview for DSM (SCID) will be administered to obtain DSM-5 diagnosis 
of alcohol use disorder and, using DSM-IV criteria, to rule out other psychiatric disorders (except nicotine 
and cannabis use disorders).   
 
i. Wechsler Abbreviated Scale of Intelligence (WASI) [35] is a brief and reliable measure of 
intelligence that provides an estimate of an individual’s IQ scores. We will use the two-subtest form 


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(vocabulary and matrix reasoning) that offers an estimate of an individual’s cognitive functioning. Individuals 
with an intelligence quotient of ≤ 80 are excluded because they do not have the cognitive skills necessary 
to participate in several of the study components. 
j. Beck Depression Inventory (BDI), a 21-item self-report measure of depressive symptoms, 
yields a total score that ranges from 0 to 63 (Beck et al. 1961). The BDI is generally regarded as a sensitive 
self-report measure of depressive symptoms and suicidal ideation. 
k. Menstrual Cycle Questionnaire (MCQ) is a questionnaire administered by the Nursing Staff to 
all prospective female subjects that elicits information on menses status, menstrual cycle length, and 
premenstrual symptoms (PMS). This measure is acquired because hormone levels vary and cortical GABA 
levels decline from follicular to luteal phase of the menstrual cycle [43], and these changes influence CBF 
[44] and behavior [45]. Thus, this questionnaire (and progesterone/estrogen levels) will help us determine 
if females are pre-, peri- or post-menopausal. 
 
ALL screening assessments will be performed to determine subject eligibility criteria, which will be 
documented. All subjects will also complete a practice round of cognitive testing with the CogState battery 
(described in detail below). The PI will confirm and sign off on the inclusion and exclusion criteria on a case 
report form (CRF) prior to the subject formally included in the study. Prospective subjects will be notified of 
their eligibility by telephone within 5 business days. This waiting period is necessary to examine results 
from the screening visit to determine whether the subject meets eligibility requirements. 
6.3  Laboratory/MRI Session 1 Visit (approximately 3.5 hours) 
Interested, eligible, consented subjects will attend the first of two laboratory/MRI session visits. Prior to 
each scan visit, subjects will be instructed not to drink alcohol for 24 hours before the scheduled scan 
session. Upon arrival, subjects will be breathalyzed to ensure that they have not recently consumed alcohol 
(BrAC = 0.00 g%). During this visit, subjects will complete: 1) brief questionnaires (see Table of 
Assessments), 2) CogState and CogBias computerized tasks (described below), 3) females will take a urine 
pregnancy test and provide a blood sample (approximately 2 tablespoons) for biochemical verification of 
menstrual cycle phase, 4) an MRI scan, and 5) following the scan, a brief medical management session 
with a nurse to receive medication.  
 
Prior to MRI scanning, subjects will meet with study staff who will conduct the CIWA-Ar and prepare the 
subject for the MRI session. Subjects will also be asked to drink to satiety prior to starting the scan session 
to avoid potential confounding effects of thirst on neural responses to cues. During the scanning session, 
subjects will be asked to lie still with their eyes open for a 5 minute resting baseline scan, followed by two 
10-minute audio-visual clips consisting of either alcohol-related cues: individuals differing in race, age and 
sex who are drinking alcohol and using explicit language designed to induce appetitive desire for alcohol; 
or non-alcohol-related cues that are similar in content, but individuals relate interesting short stories that do 
not portray alcohol consumption or alcohol reminders. Subjects will also be asked their level of alcohol 
craving (on a scale from 0-10) before and after each audio-video clip. Following the scan session, subjects 
will meet with a nurse to receive their first week of medication and the initial medical management session 
(see below). 
 
MRI scanning will be conducted on a Siemens 3.0 Tesla Trio whole-body scanner (Siemens AG, Erlangen, 
Germany), using a standard Transmit/Receive head coil. A 30-second localizer scan and a 5-minute T1-
weighted high-resolution scan are acquired before the functional scanning. These scans are used for 
subsequent normalization and anatomical co-registration of the images, and they provide subjects with a 
habituation period to the MRI environment. The 3-plane localizer scan (sagittal, axial and coronal) is 
acquired with FOV = 280 mm, TR/TE = 20/5ms, 192x144 matrix, and slice thickness 5mm. Acquisition 
parameters for the 3D High-Resolution MPRAGE structural in the axial plane are: FOV = 250 mm, TR/TE 
= 1620/3ms, 192x256 matrix, slice thickness 1 mm. The CASL technique will be used to acquire images 
during functional MRI (RB and SC exposure).  Interleaved images with and without labeling will be acquired 
using a gradient echo echo-planar imaging sequence. A delay of 1000 ms will be inserted between the end 
of the labeling pulse and image acquisition to reduce transit artifact. Acquisition parameters are: 
FOV=22cm, matrix=64x64, TR/TE = 3000/17ms, flip angle=90°. Fourteen slices (8mm thickness with 


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1.5mm gap) will be acquired from inferior to superior in a sequential order. Each cue CASL scan with 200 
acquisitions will be 10 minutes in length. The RB CASL scan will be 5 minutes with 100 acquisitions.   
 
Double Booking Option 
Subjects may be offered the option to “double-book” a scanning appointment for the first scan. In this case, 
they would be scheduled for a scan as a backup to a participant from other studies conducted by our lab. 
If the participant from the other study does not arrive for their scheduled scan, our subject will fill that MRI 
time slot. If our subject is not scanned, they will be compensated for their time and travel and re-scheduled 
for another scan session. If a subject does opt for double-booking, they would only be double-booked once 
and only for their first scan. 
 
Assessments on Scan Visits: 
CogState computerized battery, which is a 20-minute assessment to examine the cognitive 
effects of changes in drinking behavior and of topiramate treatment, will be administered at Laboratory/MRI 
session 1, 2, and endpoint visits.  It consists of: 
     - Detection Task (Psychomotor Speed) [2 minutes].  For this test, subjects must press a response key 
as soon as they detect an event. The software measures the response time to detect each event.    
 
- Identification Task (Attention) [3 minutes].  In this task an event occurs in the center of the computer 
screen and the subject must decide whether the event meets a predefined and unchanging criterion.  The 
software measures the speed and accuracy of each response.  
 
- One Card Learning Task (Visual Learning) [5 minutes].  In this task a pre-determined set of six cards 
is shown repeatedly four times. Each time the set of six cards is presented the six cards are intermixed with 
eight distracter stimuli. Each distracter stimulus is shown only once in a task. Each time subjects see a 
stimulus presented in the center of the computer monitor they must decide whether they have seen this 
card in the task before. The software measures the speed and accuracy of each response.     
 
- One Back Memory Task (Working Memory) [1 minute]:  On this task the subject is shown a single 
stimulus in the centre of the computer screen (a card turns face up). They must decide whether the current 
card matches the card they had seen on the immediately previous trial. The software measures the speed 
and accuracy of each response. 
 
- Shopping List Task (Verbal Learning and Memory) [5 minutes]: The test administrator reads the subject 
a brief list of words at the rate of one word every 2 seconds. After the list is complete, the subject is asked 
to recall as many of the words as possible. This process is repeated for a second and a third trial. After a 
delay, the subject is asked again to recall as many words as possible, without being read the list again. The 
total number of words recalled at initial recall and delayed recall are the outcome scores for this task.  
 
- Groton Maze Learning Test (GMLT) (Reasoning and Problem Solving) [5 minutes]:  The task begins 
with a chase task to familiarize the subject with the task context. The subject is shown a 10 x 10 grid of tiles 
on a computer touch screen and is instructed to “chase” a moving tile around the grid. This is followed by 
the timed chase test, where they must chase the target for 30 sec. The subject is then shown the same 10 
x 10 grid of tiles on a computer touch screen.  A 28-step pathway is hidden among the 100 possible 
locations, with the start and finish locations in the top left and bottom right of the grid, respectively. The 
subject is instructed to move one step from the start location and to continue, one tile at a time, toward the 
end. The subject moves by touching a tile next to the current location with the stylus. After each move, the 
computer indicates whether it is correct or incorrect.  If a choice is incorrect, the subject must touch the last 
correct location and then make a different tile choice to advance toward the end.  While moving through the 
hidden maze, the subject is required to adhere to two rules: no diagonal moves or touching the same tile 
twice in succession and no moving backwards along the pathway. The subject learns the 28-step pathway 
though the maze on the basis of this trial and error feedback.  Once completed, the subject is returned to 
the start location and repeats the task, usually 4 more times, trying to remember the pathway just 
completed. There are 20 well-matched alternate forms for this task, and these are selected in pseudo-
random order to ensure that no subject completes the same hidden path until all 20 have been completed.  
The software measures the total number of errors. 
 
Cognitive Bias Computer Tasks: It is documented that individuals with emotional or dependence 
disorders exhibit biased attention toward stimuli associated with their disorder. This bias appears to diminish 
following successful treatment. Several tasks will be administered: the dot-probe attention task, the primed 
attention task, the implicit association task, and a go/nogo inhibition task. Generally, subjects will be told 


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that the purpose of the task is to see how quickly and accurately they can detect targets presented on a 
display terminal.  During the tasks, the subject will be seated in front of an eye level computer screen. 
Alcohol, nonalcohol, pleasant and unpleasant pictures will be presented on the screen. Subjects will be 
given specific instructions for each task and will be asked to respond appropriately by pressing a button.  
 
Controlled Oral Word Association Test (COWA) is a verbal fluency test that takes approximately 5 
minutes to administer and measures spontaneous production of words beginning with a designated letter 
[46]. This measure will be used to examine the effects of topiramate on verbal fluency. 
 
Wechsler Adult Intelligence Scale-Third Edition Digit Span subtest [47] will be used to assess verbal 
working memory and explore the potential effects of topiramate on verbal working memory. 
6.4 Weekly Visits (approximately 50 minutes) 
At each weekly visit, subjects in both medication groups will receive medical management (MM) [33].  This 
provides a basic clinical intervention that was designed to be used in conjunction with prescribed 
medication, and to be easily implemented by medically trained practitioners in non-specialty settings.  The 
treatment will support subjects’ efforts to reduce their drinking.   
 
The first session (conducted right after the first MRI scan) will consist of a review of the results of the initial 
evaluation, identifying any medical concerns. This session will also use the brochure A Guide to Sensible 
Drinking, developed for use in the World Health Organization Brief Intervention Study project. The subject 
is then provided with a rationale and information about pharmacotherapy and the importance of adherence. 
At each visit, assessment and counseling (lasting approximately 15 minutes) are conducted. During these 
sessions, the nurse will perform a medical check on the subject’s general functioning, obtain vital signs and 
weight, ask about medication side effects and concurrent medications, monitor the subject’s medication 
adherence, and as appropriate, make recommendations on strategies for medication adherence for the 
subject to follow until the next visit. Men will be advised to consume no more than 4 standard drinks per 
day and 12 standard drinks per week and women will be advised to consume no more than 3 drinks per 
day and 8 drinks per week. Because subjects will not be physically dependent on alcohol, reduction of 
heavy drinking is a safe and ethical goal. The research technician or coordinator will measure the subject’s 
breath alcohol concentration, perform a brief assessment of the subject’s drinking, review the self-
administered BDI to assess suicidal thoughts/ideation (and discuss with the nurse and/or physician, if there 
is endorsement of suicidal thoughts). For patient safety during travel, subjects will be instructed not to drink 
prior to study visits. At each visit, the subject’s BrAC, weight, and vital signs will be measured. Subjects 
must have a breath alcohol level of 0.00 g% to complete the screening visit, 2 lab MRI scan visits, and 
endpoint visit, and below 0.05 g% to complete the weekly study visits. Study staff will follow TRC standard 
operating procedures for all subjects that present with a breath alcohol level above 0.00 g% at study visits.  
 
Throughout the study, if a subject misses a study visit due to a vacation or an unforeseen event, the study 
nurse will provide the subject with enough study medication to ensure that he or she will be able to maintain 
the daily dosage of study medication until the next scheduled visit. The nurse will also provide instructions 
on how to take the study medication as per the dosing schedule. Study nurses will instruct subjects to call 
the TRC at any time to discuss any problems or concerns they may have while taking the study medication. 
All subjects will be provided phone numbers to contact the study staff during office hours and the beeper 
number for off-hours contact 24 hours a day. Subjects will be asked to come in for their next study visit as 
soon as possible.    
If a subject calls to cancel a scheduled study visit due to an unforeseen event, study personnel will 
reschedule the study visit for as soon thereafter as possible. Study staff will mail the study medication to 
the subject via registered mail under the supervision of a study nurse. Staff will mail the study medication 
with the intent to reach the subject, before he or she runs out of study medication. The subjects will only 
be provided with enough study medication to ensure that they will be able to maintain their daily dosage 
of study medication until their next scheduled visit. The nurse will provide instructions over the phone on 
how to take the study medication as per the dosing schedule and record any adverse events that have 
occurred since the last study visit. Study nurses will instruct subjects to call the TRC at any time to 


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discuss any problems or concerns they may have while taking the study medication. Study staff will make 
efforts to reschedule missed study visits as soon as possible. An investigator will determine how many 
additional weeks of study medication a subject will be allowed to receive without attending a study visit.  
6.5 Laboratory/MRI Session 2 Visit (approximately 3.5 hours) 
During week 7, subjects will complete the 2nd scanning session. Procedures for the Laboratory/MRI Session 
2 visit are the same as the 1st Laboratory/MRI Session procedures.  
 
Early Termination Visit: 
 
All patients (including those who discontinue treatment prematurely) will be asked to complete an end-of-
treatment evaluation and to complete all scheduled assessments to facilitate intention-to-treat (ITT) 
analyses. All patients will be informed of these procedures prior to study enrollment. Patients will be 
compensated $50 for completing the end-of-treatment visit. Patients who decide to terminate the study prior 
to week 8 will also receive $50 upon completion of the end-of-treatment procedures. For patients who 
withdraw early and do not wish to continue with study visits/procedures, all end-of-treatment procedures 
will be administered at the time of withdrawal.   Such patients will also be asked to undergo in-person or 
telephone follow-up at end-of-treatment for collection of the remaining treatment-phase Timeline Follow-
back data.  
6.6 Endpoint Visit (approximately 2 hours) 
Following study drug taper, subjects will complete the Endpoint visit. During this visit, subjects will complete: 
1) a breathalyzer to ensure a BrAC of 0.00 g%, 2) a blood draw (GGTP only), 3) brief questionnaires 
(including BDI for suicidal ideation,, and Endpoint visit), 4) Cogstate battery, and 5) Medication 
Questionnaire. Subjects will be eligible to request and receive de-briefing after completing the Endpoint 
Visit. The procedure for debriefing subjects involves the following: (1) study staff informs subjects at the 
Endpoint Visit that they are eligible to learn from the pharmacy whether they received active medication or 
placebo during the study, (2) if the subject wishes to receive this information, study staff will provide UPENN 
IDS an envelope with postage and the subject’s address, along with the “Pharmacy Debriefing” sheet, which 
notes the subject’s name & ID#, (3) the pharmacy technician will mail the subject the appropriate letter 
indicating the medication assignment, (4) study staff  will remain blinded to study medication assignment. 
 
Schedule of Assessments 
 
Instrument 
Visit 0 
Screening 
Visit 1 MRI 
Visits 2-6 
Visit 7 
MRI 
Visit 8 
Visit 9 
Endpoint 
Breath Alcohol Concentration 
& Vital signs 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Study Overview & Informed 
Consent 
 
X 
 
 
 
 
 
Medical History & Physical 
Exam 
 
X 
 
 
 
 
 
Laboratory tests (Blood for 
CBC, GGTP, HIV and DNA) 
 
 
X 
 
 
 
 
X (GGTP 
only) 
MRI video 
X 
 
 
 
 
 
MRI safety sheet (metal) 
X 
X 
 
X 
 
 
Urine pregnancy test 
Females 
Females 
 
Females 
 
 
Urine drug toxic screen 
X 
X 
 
X 
 
 
Blood sample (2 Tbsp) 
Females 
Females 
 
Females 
 
 
Demographic interview 
X 
 
 
 
 
 
Structured Clinical Interview 
for DSM 
 
X 
 
 
 
 
Alcohol 
Module Only 
Wechsler Abbreviated Scale of 
Intelligence 
 
X 
 
 
 
 
 
 
Timeline Follow-Back 
Interview 
X 
X(brief) 
X(brief) 
X(brief) 
X(brief) 
X(brief) 
Beck Depression Inventory 
X 
X 
X 
X 
X 
X 
Short Index of Problems 
X 
 
 
X 
 
X 


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Fagerstrom Test of Nicotine 
Dependence 
X 
 
 
 
 
X 
Obsessive Compulsive 
Drinking Scale 
X 
X 
 
X 
 
X 
Alcohol Urge Questionnaire 
X 
X 
 
X 
 
X 
Within Session Rating Scale 
 
X 
 
X 
 
 
Clinical Institute Withdrawal 
Assessment for Alcohol Scale 
X 
X 
 
X 
 
 
 
CogBias Tasks 
 
X 
 
X 
 
 
Cogstate Battery 
 
X 
 
X 
 
X 
Controlled Oral Word 
Association test 
 
X 
 
X 
 
 
Digit Span 
 
X 
 
X 
 
 
Medical Management 
 
X 
X 
X 
X 
X 
Endpoint/ 
Termination Form 
 
 
 
 
 
 
X 
Medication Questionnaire 
 
 
 
 
 
X 
Measures of Treatment 
 
X 
X 
X 
X 
X 
 
7 Statistical Plan 
7.1 Sample Size Determination 
The current sample size is based on the need to pilot our alcohol and non-alcohol audio-visual videos both 
on- and off-magnet through computerized tasks and during pCASL perfusion fMRI scanning.  
7.2 Statistical Methods 
7.2.1 Imaging Data Processing 
Prior to performing analyses, brain data are examined for gross movement and full image acquisition. A 
Statistical Parametric Mapping (SPM)-based ASL data processing toolbox is used for data analyses. ASL 
image pairs are realigned to the mean of all control images and spatially smoothed with a 3D isotropic 
Gaussian kernel with full width at half maximum of 10mm. CBF image series are generated using a 
simplified two-compartment model with the sinc interpolation method for CBF calculations. The mean 
control image of each subject’s data is co-registered to a high-resolution 3D T1 structural image using the 
mutual information based co-registration algorithm provided by SPM8. The same co-registration 
parameters are used to co-register the CBF maps to the structural image. The structural image is then 
spatially normalized to the Montreal Neurological Institute (MNI) standard brain. The same parameters are 
used to normalize the CBF images to the MNI standard space. Each subject’s normalized mean control 
images are segmented using SPM8. The segmented gray matter masks are averaged and the overlap of 
subject’s gray matter is extracted. This final mask is used for calculating global CBF for each session. 
7.2.2 Imaging Data Analyses 
Global CBF time course will be included in the model as a covariate to examine the effects of topiramate 
on regional CBF. No temporal smoothing will be applied. Contrasts between conditions (alcohol cue vs non-
alcohol cue; scan 1 vs scan 2) will be defined in the general linear model to assess the voxel by voxel CBF 
difference. Using the corresponding parametric maps of this contrast ( maps), random effects analysis will 
be employed to test for a significant main effect of condition with a statistical parametric map of the T 
statistic at each voxel for population inference for each session for the placebo and topiramate groups 
(second-level analysis). A 2x2 factorial design matrix will be used to assess the effects of the 
pharmacological manipulation by including the group (topiramate vs placebo) and condition (scan 1 vs scan 
2) as the two factors.  An associated contrast will be defined in this model to examine administration effects. 
This two-stage analysis is theoretically equivalent to a 2-way analysis of variance (ANOVA). Simple 
regression analyses will be conducted on CBF with the change in craving scores [post-alcohol cue minus 
pre-alcohol cue craving scores, number of heavy drinking days during the past 30 days, and age] as 
covariates of interest to test for prognostic brain/behavioral correlations. For the exploratory aim, subjects 
will be grouped by genotype (CC vs A-allele carrier) to examine the moderating effects of rs2832407 in 


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GRIK1 on topiramate effects using the same simple regression analyses described above.  We will limit 
this analysis to European Americans, as that is the population in which the preliminary findings were 
obtained and allele frequencies differ significantly by population. 
7.2.3 Behavioral Analyses 
Statistical significance tests use an alpha of .05 unless otherwise noted.  Continuous demographic variables 
(e.g., age, education, quantity/frequency of alcohol use) are checked for normality, transformed if 
necessary, and summarized by calculating means, standard deviations and ranges. Scores on each factor 
will be included as covariates of interest with respect to perfusion fMRI data and genetic variance. Analysis 
of variance will be used to assess demographic differences across groups. Nominal demographic variables 
(e.g., race, sex, genotype) are summarized by calculating proportions and compared across groups using 
chi square analyses. Demographic (age, years education, monthly income) and clinical (depression, 
anxiety) will also be summarized. 
7.2.4 Genetic Analyses 
Genotyping will be carried out by Dr. Joel Gelernter at Yale University.  Blood will be coded and shipped to 
Dr. Joel Gelernter’s lab at Yale University. Samples will be shipped without identifiers, on dry ice following 
University of Pennsylvania and international shipping procedures. Staff will send blood shipments in 
batches and verify that shipments arrived at the lab maintaining tracking logs of all samples sent. DNA will 
be purified from whole blood using the PureGene kit (GentraSystems, Minneapolis, MN).  We typically 
obtain ~30mg of high-quality DNA per ml of blood extracted.  TaqMan alleleic discrimination assays have 
been designed (for the SNPs already examined) or will be designed (for SNPs still to be examined, e.g., in 
GRIK1) using Primer Express 3.0 software (Applied Biosystems Inc.).  Genotyping will be performed using 
the 5’-nuclease TaqMan closed-tube fluorescence method and an ABI 7500 Sequence Detector System 
for post-PCR plate reads. 
7.3 Subject Population for Analysis 
Protocol-compliant subjects’ data will be used for analysis. 
8 Safety and Adverse Events 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 


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other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in inpatient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the laboratory/scan session (approximately 2 weeks from 
informed consent).  
 
Pre-existing Condition 
A pre-existing condition is one that is present at the start of the study.  A pre-existing condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse 
event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the subject 
is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the investigator 
should instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.  The investigator should notify 
the IRB of any adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The IRB will  also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly in a subsequently conceived 
offspring of a subject that has participated in this study.  
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for 
and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, an investigator or staff member must seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Information on all adverse events should be 
recorded immediately in the source document, and also in the appropriate adverse event module of the 
case report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results 
should recorded in the source document, though should be grouped under one diagnosis. 
 


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All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
8.3.1 IRB Notification by Investigator 
A Serious Adverse Event (SAE) must be reported to the IRB within 72 hours of the event. The 
investigator will keep a copy of this SAE form in the study binder.  
At the time of the initial report, the following information will be provided: 
Study identifier 
 
Whether study participation was 
discontinued 
Study Center 
Subject number 
  
The reason why the event is classified as 
serious 
A description of the event 
 
Date of onset 
 
Investigator assessment of the association 
between the event and study participation 
 
Current status 
Significant new information on ongoing serious adverse events should be provided promptly to the IRB. 
8.4   Unblinding Procedures 
In the event that subjects are prematurely discontinued, it will be necessary to avoid breaking the blind 
whenever possible, in order to protect the integrity of the study. If an emergency necessitates that the blind 
be broken, only the pharmacist will have access to the unblinding codes and will be given the names of the 
staff with authority to request that the blind be broken. If the IDS or hospital pharmacy is contacted by other 
persons in requesting the study blind be broken for a subject, and Drs. Wetherill and Kranzler are not 
reachable, the pharmacist will act according to his/her best judgment in deciding whether or not to break 
the study blind for that subject. The hospital pharmacist can be reached 24 hours a day by beeper to rapidly 
access subject unblinding codes. 
The pharmacy emergency beeper number is: 215-555-1212. 
8.5   Medical Monitoring 
It is the responsibility of the physician investigator to oversee the safety of the study at his/her site. This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see 
Section 10 Auditing, Monitoring and Inspecting). Medical monitoring will include a regular assessment of 
the number and type of serious adverse events. 
8.6   Protection of Subjects 
Complementing the safety measures noted above, additional procedures will be followed to protect the 
safety of the research subjects. Potential Subjects will be screened for medical illnesses that would preclude 
the use of topiramate. Subjects selected for the study will be evaluated weekly while receiving study drug 
treatments. AEs will be monitored weekly and a study physician will be available at all times to evaluate 
and treat adverse effects of the medication. On a weekly basis weights and vital signs will be obtained. 


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Significant AEs will result in exclusion from the study. Venipuncture will be carried out with good aseptic 
technique by an experienced phlebotomist, nurse, or physician. Venipuncture sites will be monitored 
carefully for signs of infection. At the conclusion of randomized medications, a physical examination, 
STUDY LABORATORY TESTS, and a urine pregnancy test (if female of childbearing capability) will be 
performed. Subjects will be given a 24-hour emergency number they can call if necessary. The PI or study 
psychiatrist will clinically follow all subjects who are discontinued due to a serious AEs until the AE resolves 
and becomes completely stable, unless a referral to another physician (i.e. specialist) is clinically indicated 
or requested by the subject.  
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts will be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
Records, filed in the IRB office, verify that all research project personnel have completed training in the 
protection of human research subjects in accordance with the guidelines of the U.S. Department of Health 
and Human Services (DHHS) and the Office for Human Research Protection (OHRP).  The study staff (PI, 
Clinical research coordinator, etc.) will keep all study medical records (including any codes to de-identified 
data) under lock and key in a secure location, as required by law. Only date and time of the research visit 
and lab specimen data will be placed in the client’s existing electronic medical record. All electronic data 
and files (e.g., database, spreadsheet, etc.) containing identifiable subject information shall be password 
protected.  Any computer hosting such files shall have a BIOS password to prevent access by un-authorized 
users.  If subject data are to be exchanged with others, the data will be coded. If identification is necessary, 
then the data will be encrypted while en route to the recipient with strong encryption levels (≥ 128 bits for 
symmetric encryption (DES) and ≥ 1024 bits for asymmetric encryption (RSA).    
 
All data and blood specimens will be stored without direct identifiable information, but will be identifiable via 
a linking code. The secured research records are labeled with code numbers only (names and other 
identifying information are kept separate from research records). Access to hard copy data is only given to 
staff members working on the study. Only staff members designated to handle or analyze study samples 
will have access to the samples and their storage. Coded blood samples are stored in clinic-specific 
refrigerators and freezers, which are located in secure rooms. As per routine in the CSA, all electronic files 
(e.g., database, spreadsheet) will be password protected. Any computer hosting such files will have a BIOS 
password to prevent access by un-authorized users.  
 
Blood will be collected for DNA analysis. The information derived from analysis of the subjects’ DNA will 
not be provided to the subject, since at the present time the existing preliminary genetic data for predicting 
response to topiramate do not provide a basis for genetic counseling. Should that situation change over the 
course of the study, procedures will be developed in conjunction with the UPenn IRB, to provide subjects 
with relevant information on genotype and to counsel them in relation to that information. While the study 
is open, DNA samples will be coded with a number that provides an indirect link to the subject’s identity 
(samples will be accessible only by the researchers and staff involved with this study). Upon completion of 
the study, the sample will be kept in storage indefinitely. However, the sample will forever be separated 
from all identifiers. These de-identified samples may be shared with other researchers and used in other 


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projects. The lab procedures for storage include a passcode-protected locked room, and secure storage 
freezers.  All samples will be retained securely as per lab protocols.  
9.2 Source Documents 
Source data is all information, original records, observations, or other activities during participation in the 
study.  Source data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, evaluation 
checklists, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the laboratories. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the item is not applicable 
to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated. 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 3 years after the closure 
of the study with the IRB.  
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan described below. The Principal Investigator 
will allocate adequate time for such monitoring activities. The Investigator will also ensure that the monitor 
or other compliance or quality assurance reviewer is given access to all the above noted study-related 
documents and study related facilities (e.g., diagnostic laboratory, etc.), and has adequate space to conduct 
the monitoring visit. 
 
The Principal Investigator and research staff will monitor the study. Written monitoring procedures for 
monitoring clinical investigations, proposed by the OHR and previously established at the CSA will be 
implemented to assure the quality of the study and to assure that each person involved in the monitoring 
process carries out his or her duties.  
 
The Principal Investigator will maintain a record of the findings, conclusions, and action taken to correct 
errors noted by the monitor for each visit.  
 
Monitoring Responsibilities: The monitor, in accordance with local and NIH requirements, should ensure 
that the study is conducted and documented properly by carrying out the following activities:  
a. Verifying that the investigator has adequate qualification and resources and these remain adequate 
throughout the study period, and that the staff and facilities, including laboratories and equipment, are 
adequate to safely and properly conduct the study and these remain adequate throughout the study 
period.  
b. Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.  
c. Verifying that written informed consent was obtained before each subject's participation in the study.  
d. Verifying that the investigator is enrolling only eligible subjects.  
e. Reporting the subject recruitment rate.  
f. Verifying that source data/documents and other study records are accurate, complete, kept up to 
date, and maintained.  


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g. Verifying that the investigator provides all the required reports, notifications, applications, and 
submissions, and that these documents are accurate, complete, timely, legible, dated and identify the 
study.  
h. Checking the accuracy and completeness of the CRF entries, source data/documents, and other 
study related records against each other.  
i. Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure 
that appropriate corrections, additions, or deletions are made, dated, explained, and initialed by the 
investigator or by a member of the study staff who is authorized to initial CRF changes for the 
investigator. This authorization should be documented.  
j. Determining whether all adverse events (AE's) are appropriately reported within the time periods 
required by GCP, the protocol, the IRB/IEC, the applicable regulatory requirement(s).  
k. Determining whether the investigator is maintaining the essential documents.  
l. Communicating deviations from the protocol, SOP's, GCP, and the applicable regulatory 
requirements to the investigator and taking appropriate action designed to prevent recurrence of the 
detected deviations.  
m. Follow the University SOP's, GCP, and the applicable regulatory requirements.  
 
Study Monitoring  
The study Principal Investigator and research staff have prepared a case record form (CRF) that is designed 
to reduce coding errors and promote data quality. Each page of the CRF will contain a header that includes 
the title of the protocol, the protocol number, the subject randomization number, subject screening number, 
and visit number. The technicians are responsible for data entry. The research charts will be maintained 
separately from the CRF and will contain subject information that is not entered in the study CRF database.  
 
Regulatory Binder:  A detailed Regulatory Binder will be assembled.  Any changes to procedures are 
documented in this section. This binder is the backbone of quality assurance.  We use this binder to train 
any new study personnel and for reference so that our policies and procedures are standard throughout all 
phases of the protocol. The ‘Measures’ section of the binder addresses, specifically all forms and 
instruments that comprise the CRF. A Table of Contents has been prepared that contains all the forms used 
in the study.  
The study manual will include 
· 
study protocol research team names, titles, roles and responsibilities, work and home phone 
numbers  
· 
purpose of study, study intent and rationale 
· 
all study procedures for each team member (PIs, technicians, study coordinator, pharmacists, 
nurses, physicians, etc.)  
· 
recruitment and screening procedures 
· 
intake procedures 
· 
study phase procedures  
· 
completion/discontinuation procedures 
 
Data Collection Training  
The CSA provides comprehensive data collection training for all research technicians (RTs).  RTs receive 
training on how to proceed with problematic subjects.  RTs are extensively trained on all MRI procedures. 
RTs are trained to follow the general data collection guidelines listed below.   
· 
RTs should be present when subject is completing instruments. 
· 
Research interviews and evaluations should be administered in a private, quiet office or area. 
· 
Instruments are introduced and explained the same way each time to each subject. 
· 
Order of research assessments should be maintained, as much as possible. 
· 
Order of specimens obtained should be maintained as much as possible. 
· 
RTs should show an interested, polite, appropriate, and helpful demeanor. 
 
Quality assurance (QA) procedures  
Changes to the CRF and the study database are strictly monitored.  After a single line is drawn through the 
corrected data point, the RT documents the change by placing his or her initials and the date of the change 
adjacent to the correction. Typical QA responsibilities of the RT include: 


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· 
Checking all data during or immediately after study visits. 
· 
Checking charts at predetermined points during the study (initials and date of checker are required 
on each form checked). 
· 
Performing the initial data check after a few charts have been entered. 
· 
Performing a 10% data check when all data have been entered. 
 
Typical responsibilities of the PI include: 
· 
Monitoring and reporting on RT interviewing and data collection proficiency at subject study visits. 
· 
Checking charts at predetermined points during the study (initials and date of PI are required on 
each form checked). 
· 
Supervising study database checks. 
· 
When databases, in Filemaker Pro or other applications, are developed by the research staff, only 
the data checked by the RT are entered.  Data sets are double checked in pairs by technicians.  
The PI supervises any corrections to the data set and reviews the completed database before the 
information is used in any reports or analyses. 
· 
The PI holds meetings with the RTs to report and review the project and data entry status.  
· 
PI reviews lab results and screening information  for potential subjects.  
· 
PI reviews adverse events on at least a weekly basis. 
 
 
Study Logs and Reports  
Study logs are routinely maintained in order to keep computerized back up records of identifying and socio-
demographic characteristics and experimental group status.  The study subject log usually includes 
subjects’ initials, study number, CRF number, date of birth, race, medication start dates, subject status 
(active, drop-out, completer, follow-up) and relevant dates and comments. 
 
Data Storage on Site   
The CRFs and research charts are stored in file rooms specifically designed for data storage.  All study 
data are housed in locked file cabinets.  Only designated members of the research team have access to 
the file cabinets containing research data.  Data are kept on site for not less than three years after the 
subject has completed the final assessment.  Data are then eligible for archiving. 
10.2 Auditing and Inspection 
The investigator will permit study-related monitoring, audits, and inspections by the IRB and University 
compliance and quality assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
11.1 Consent Procedures 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study (See Subject 
Informed Consent Form).  This consent form will be submitted with the protocol for review and approval by 
the EC/IRB for the study.  The formal consent of a subject, using the EC/IRB-approved consent form, must 
be obtained before that subject undergoes any study procedure.  The form must be signed by the subject 
or legally acceptable surrogate, and the investigator-designated research professional obtaining the 
consent.  
 


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The investigator or designee will obtain informed consent before any study procedures occur, explaining 
all procedures in detail in an individual session. The consent form and explanation will include; detailed 
information about functional magnetic resonance imaging, the rationale for why it is being used, length of 
participation, as well as safeguards and emergency procedures. The collection of all lab specimens will be 
described in detail, as will the number and frequency of the research interviews and self-assessments. 
Subjects will be assured that their participation is voluntary and that withdrawal from the study would not 
jeopardize current or future participation in research studies. All subjects will be informed of potential risks 
and benefits involved in the study. 
12 Study Finances 
12.1 Funding Source 
This study will be financed by the Department of Psychiatry. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan.  All 
University of Pennsylvania investigators will follow the University conflict of interest policy. 
12.3 Subject Stipends or Payments 
Subjects will receive 2 SEPTA tokens (valued at $4.50) for travel for each scheduled appointment (all visits, 
even if subject does not pass the consent/screening), $75 for completing the initial laboratory/MRI session 
visit, $5 for returning medication bottles during weekly visits, $20 for completing Week 6 visit, $75 for 
completing the second MRI scan visit 7, and $25 for completing the Endpoint Visit. The total amount that 
subjects can receive for full participation in the research study is $235.00 plus 20 SEPTA tokens for a total 
of $280.00. Subjects who choose the double-booking option have the possibility of receiving $305.00, if the 
subject attends the scan session but is not scanned at double-booking appointment. 
 
Table 3. Schedule for Study Payments 
Visit  
Payment 
SEPTA 
tokens  
 
Cost 
($2.25/token) 
Screening 
$0 
2 tokens  
$4.50 
Week 1 (Baseline & MRI 1) 
$75 
2 tokens  
$4.50 
Week 2 
$5 returning med bottles 
2 tokens  
$4.50 
Week 3 
$5 returning med bottles 
2 tokens  
$4.50 
Week 4 
$5 returning med bottles 
2 tokens 
$4.50 
Week 5 
$5 returning med bottles 
2 tokens  
$4.50 
Week 6  
$20 + $5 returning med 
bottles 
2 tokens  
$4.50 
Week 7 (MRI 2) 
$75+5 returning med 
bottles 
2 tokens  
$4.50 
Visit 8 (Taper started)  
$5 returning med bottles 
2 tokens  
$4.50 
Visit 9 (Endpoint) 
$25 + $5 returning med 
bottles 
2 tokens 
$4.50 
Totals 
Up to $235 
20 tokens  
$45.00 
 
*Subjects will receive a portion of the payment based on completion of study visit and returning both 
medication containers (i.e., $2.50 for returning only one of 2 bottles).   


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13 References 
 
1. 
Alcoholism, N.I.o.A.A.a. NIAAA recognizes alcohol awareness month.  2013  [cited April 1, 2013 
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Psychological Corporation. 
 
 
14 Appendix 1: Pilot Test Cue Sets (COMPLETED) 
14.1 Background 
The primary goal of this study is to elucidate the brain and behavioral mechanisms that mediate 
topiramate’s reduction of heavy drinking, and one way that we propose to reach this goal is to examine the 
effects of topiramate on alcohol cue reactivity. As such, we need to ensure that our alcohol cues are 
effective in eliciting reward-related neural responses and that our non-alcohol cues do not. As part of 
Objective 1, we aim to pilot test our cue sets; therefore, this small substudy will acquire pilot data on up to 
10 subjects to ensure that our cue sets are effective and will be useful for the study’s other objectives. 
14.2 Objective 
Pilot test alcohol and non-alcohol cues in individuals with AUD to ensure brain and behavioral responses 
for remaining study objectives. 
14.3 Design 
Heavy drinkers who meet DSM-5 criteria for AUD will be recruited, screened, and consented, and if eligible 
will complete an MRI scan session. We will use perfusion fMRI during alcohol cue exposure to acquire brain 
and behavioral responses to alcohol and non-alcohol cues to pilot test the validity of our cue sets. Study 
duration for subjects is approximately one week and includes a consent visit and one scan session. Up to 
10 individuals will complete the sub-study with the goal of obtaining 6 usable imaging data sets.. 
14.3.1 Primary Study Endpoints 
The primary endpoints to be measured include: 
 
Self-report ratings of cues, subjective ratings of craving during/following cue exposure, and 
neuroimaging data on cerebral blood flow when the brain is at rest and when exposed to alcohol 
cues. 
14.4 Subject Selection and Withdrawal 
14.4.1 Inclusion Criteria 
1) 
Physically healthy, as determined by a comprehensive medical history and approval of the 
study physician males or females who drink alcohol, ages 18-60. 
2) 
Have an average weekly ethanol consumption of >24 standard drinks for men, or >18 
standard drinks for women [34]. 
3) 
Females must be non-pregnant, non-lactating and either be of non-childbearing potential 
(i.e. sterilized via hysterectomy or bilateral tubal ligation or at least 2 years post-
menopausal) or of child bearing potential but practicing a medically acceptable method of 
birth control. Examples of medically acceptable methods for this protocol include: the birth 
control pill, intrauterine device, injection of Depo-Provera, Norplant, contraceptive patch, 
contraceptive ring, double-barrier methods (such as condoms and diaphragm/spermicide), 
male partner sterilization, abstinence (and agreement to continue abstinence or to use an 
acceptable method of contraception, as listed above, should sexual activity commence), 
and tubal ligation.  
4) 
Provide voluntary informed consent. 


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14.4.2 Exclusion Criteria 
1) 
A current, clinically significant physical disease or abnormality on the basis of medical 
history. 
2) 
History of head trauma or injury causing loss of consciousness, lasting more than five (5) 
minutes or associated with skull fracture or inter-cranial bleeding or abnormal MRI. 
3)        History of major DSM-IV Axis I diagnoses other than alcohol use disorder (except nicotine 
use disorder) 
4) 
Presence of magnetically active irremovable prosthetics, plates, pins, permanent retainer, 
bullets, etc. (unless a radiologist confirms that it’s presence is unproblematic).  An x-ray 
may be obtained to determine eligibility given the possibility of a foreign body. 
5) 
History of a serious psychiatric illness including psychosis, bipolar disorder, or suicidal or 
homicidal intent.  
6) 
Claustrophobia or other medical condition preventing subject from lying in the MRI for 
approximately one (1) hour. 
7) 
Current regular treatment with psychotropic medications (e.g., benzodiazepines, 
antidepressants), which affect neurotransmitter systems or a medication being used to 
treat alcohol use disorders (e.g., naltrexone, acamprosate). 
8)  
Vision problems that cannot be corrected with glasses.   
9)  
Body Mass Index (BMI) greater than or equal to 34, body girth greater than 52 inches and 
a head girth greater than 25 inches [Imaging data acquisition is impaired with high weight 
individuals]. 
10) 
Individuals suffering from or with a history of stroke and/or stroke related spasticity. 
11) 
Individuals with a history of seizures. 
14.5 Subject Recruitment and Screening 
Subjects will be recruited from those who respond to IRB-approved advertisements. Advertisements will be 
in the form of IRB-approved radio ads, flyers, billboards, e-lists, and word of mouth. Individuals who have 
completed prior studies and meet study criteria will also be invited to participate if subject participation 
ended at least 30 days before the current study starts (i.e., no pharmacotherapy or psychotherapy for 30 
days). An initial telephone interview covering recent medical status, substance use, treatment history, 
medication, and general psychiatric history will be conducted.  The potential subject will be provided with 
an overview of the study and will be informed that all information obtained will be used to determine his/her 
eligibility for study participation. If the individual satisfies preliminary criteria and shows continued interest 
in participating in the study, an appointment will be made for further screening and the CSA. The screening 
process will be described, and the individual will also be informed that s/he must be available for at least 
two separate appointments during the screening week (unless the two appointment are combined). For 
details on Screening, see 14.7.2 Informed Consent and Screening Visit below.   
14.6 Early Withdrawal of Subjects 
14.6.1 When and How to Withdraw Subjects 
Subjects with severe psychological symptoms (e.g., suicidal thoughts), those who fail to adhere to protocol 
requirements, and those withdraw consent will be withdrawn from the study and if applicable, referred for 
appropriate clinical care. If a subject is found to be pregnant during the study, she will immediately be 
withdrawn from the study, referred for obstetric evaluation, and advised to discontinue all drinking.  
14.6.2 Data Collection and Follow-up for Withdrawn Subjects 
We will make a strong effort (via phone calls and alternative contact information) to obtain follow-up 
information on all subjects who are prematurely withdrawn from the project. 


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14.7 Study Procedures 
14.7.1 Initial Telephone Screen (approximately 20 minutes)  
Subjects will be recruited from the Center for Studies of Addiction at 3900 Chestnut St. through local 
advertisements. Individuals who have completed prior studies or expressed interest in other research 
studies at the CSA, but were deemed ineligible due to AUD (e.g., nicotine studies), and meet study criteria 
will also be invited to participate if subject participation ended at least 30 days before the current study 
starts (i.e., no pharmacotherapy or psychotherapy for 30 days). Subjects who express interest are 
contacted by phone and participate in a telephone screening interview. The nature of the study, including 
the number of visits to the center and a description of fMRI procedures, subject protections and 
confidentiality, are described. If the caller is still interested, questions on general health are asked. If the 
applicant is determined to be eligible based on this screening, s/he is asked whether they accept or decline 
to participate.  If the caller is still interested, s/he will be scheduled for an initial consenting appointment.  
14.7.2 Informed Consent and Screening Visit (approximately 2 hours)  
Upon arriving to the Informed Consent and Screening Visit, subjects will be asked to show legal 
identification and to complete a breathalyzer test to ensure a breath alcohol concentration (BrAC) of 0.000. 
Reading ability will be evaluated followed by a review of HIPAA privacy laws and the informed consent. 
Specifically, subjects will be provided a standard HIPAA form that contains privacy laws, and a study staff 
member will review the consent form with the subject, including an explanation of the study protocol, its 
risks, and potential benefits. Following resolution of any questions, subjects who appear to understand the 
nature of the study and consent will be asked to sign the study consent form.  An entire copy of the informed 
consent form will be given to each subject. S/he is also reminded that the consent expresses willingness to 
participate but that the subsequent screening process will determine final eligibility. Further, s/he is 
reminded that participation is voluntary, and at any time, s/he may withdraw from the study. 
 
Following consent, subjects will watch an fMRI video that simulates the experience of undergoing an MRI, 
and meet with the study nurse to complete a medical history, urine toxicology, and females will complete a 
urine pregnancy test. Subjects will also meet with study staff to complete additional assessments. 
 
Measures obtained: 
 
a. Sociodemographic/subject information: General demographic information, marital status, 
educational, and occupational information will be obtained. 
b. The Alcohol Urge Questionnaire (AUQ) [39] is an 8-item, self-administered state measure 
assessing the urge for an alcoholic drink at the time the questionnaire is completed and provides an index 
of acute craving. The AUQ contains four items pertaining to the desire for a drink: two items regarding 
expectations of positive effects from drinking, and two items relating to the inability to avoid drinking if 
alcohol were present. This measure has strong correlations with measures of alcohol dependence and 
severity. 
c. The Timeline Follow-back (TLFB) [36] will be used to estimate past 30-day drinking. This 
interview procedure will provide quantity/frequency of alcohol consumption data for each day during the 
period prior to the interview. The TLFB is reliable and valid when used by trained interviewers. We will 
also measure tobacco and other substance use patterns using the TLFB. 
d. Structured Clinical Interview for DSM (SCID) will be administered to obtain DSM-5 diagnosis 
of alcohol use disorder and, using DSM-IV criteria, to rule out other psychiatric disorders (except nicotine 
dependence).   
14.7.3 Laboratory/MRI Visit (approximately 2 hours)  
Interested, eligible, consented subjects will attend a laboratory/MRI session visit. During this visit, subjects 
will complete: 1) a breathalyzer to ensure a BrAC of 0.000, 2) a urine pregnancy test, 3) urine toxicology, 
4) an MRI scan, and 5) brief questionnaires. 
 
Prior to MRI scanning, subjects will meet with study staff who will prepare the subject for the MRI session. 
Subjects will also be asked to drink to satiety prior to starting the scan session to avoid potential confounding 


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effects of thirst on neural responses to cues. During the scanning session, subjects will be asked to lie still 
with their eyes open for a 5 minute resting baseline scan, followed by two 10-minute audio-visual clips 
consisting of either alcohol-related cues: individuals differing in race, age and sex who are drinking alcohol 
and using explicit language designed to induce appetitive desire for alcohol; or non-alcohol-related cues 
that are similar in content, but individuals relate interesting short stories that do not portray alcohol 
consumption or alcohol reminders. Subjects will also be asked their level of alcohol craving (on a scale from 
0-10) before and after each audio-video clip. For MRI acquisition details, see 6.3 Study Procedures above. 
 
Table 4. Schedule of Assessments for Pilot 
Instrument 
Visit 0 (Screening) 
Visit 1 (MRI Scan) 
Breath Alcohol Concentration 
X 
X 
Study Overview & Informed Consent 
X 
 
Medical History 
X 
 
MRI video 
X 
 
Urine toxicology 
X 
X 
Urine female pregnancy test 
X 
X 
Demographic interview 
X 
 
Structured Clinical Interview for DSM 
X 
 
Timeline Follow-Back Interview 
X 
 
Alcohol Urge Questionnaire 
X 
X 
Within Session Rating Scale 
 
X 
 
14.8 Statistical Plan 
14.8.1 Sample Size Determination 
The current sample size is based on the need to pilot our alcohol and non-alcohol audio-visual videos both 
on- and off-magnet through computerized tasks and during pCASL perfusion fMRI scanning.  
14.9 Statistical Methods 
14.9.1 Imaging Data Processing 
Prior to performing analyses, brain data are examined for gross movement and full image acquisition. A 
Statistical Parametric Mapping (SPM)-based ASL data processing toolbox is used for data analyses. ASL 
image pairs are realigned to the mean of all control images and spatially smoothed with a 3D isotropic 
Gaussian kernel with full width at half maximum of 10mm. CBF image series are generated using a 
simplified two-compartment model with the sinc interpolation method for CBF calculations. The mean 
control image of each subject’s data is co-registered to a high-resolution 3D T1 structural image using the 
mutual information based co-registration algorithm provided by SPM8. The same co-registration 
parameters are used to co-register the CBF maps to the structural image. The structural image is then 
spatially normalized to the Montreal Neurological Institute (MNI) standard brain. The same parameters are 
used to normalize the CBF images to the MNI standard space. Each subject’s normalized mean control 
images are segmented using SPM8. The segmented gray matter masks are averaged and the overlap of 
subject’s gray matter is extracted. This final mask is used for calculating global CBF for each session. 
14.9.2 Imaging Data Analyses 
Global CBF time course will be included in the model as a covariate to examine regional CBF. No temporal 
smoothing will be applied. Contrasts between conditions (alcohol cue vs non-alcohol cue) will be defined in 
the general linear model to assess the voxel by voxel CBF difference. Using the corresponding parametric 
maps of this contrast ( maps), random effects analysis will be employed to test for a significant main effect 
of condition with a statistical parametric map of the T statistic at each voxel for population inference. Simple 
regression analyses will be conducted on CBF with the change in craving scores [post-alcohol cue minus 
pre-alcohol cue craving scores] as covariates of interest to test for prognostic brain/behavioral correlations.  


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14.9.3 Behavioral Analyses 
Statistical significance tests use an alpha of .05 unless otherwise noted.  Continuous demographic variables 
(e.g., age, education, quantity/frequency of alcohol use) are checked for normality, transformed if 
necessary, and summarized by calculating means, standard deviations and ranges. Scores on each factor 
will be included as covariates of interest with respect to perfusion fMRI data. 
14.10 Subject Stipends or Payments 
Subjects will receive 2 SEPTA tokens (value of $4.50) and $10.00 for completing the screening visit with a 
negative urine toxicology screen. If the subject has a positive urine drug screen, they will be excluded from 
the study and only receive 2 SEPTA tokens for transportation to and from the TRC. Subjects will receive 
$75 for completing the MRI visit of this pilot substudy. The total amount that subjects can receive for full 
participation in the research study is $85.00 plus 2 SEPTA tokens for a total of $89.50. 
 
*All remaining aspects of the substudy are described in Sections 8-13 above.