Conditions: Alcoholism Alcohol Use Disorder (AUD)
Keywords: Topiramate Pharmacogenetics Personalized Medicine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 320
Healthy volunteers: no

Brief summary:
The purpose of this study is to advance the effort to develop personalized pharmacotherapy for alcohol use disorders (AUDs). The investigators propose to conduct a 12-week, prospective, randomized clinical trial of the moderating effect of rs2832407 on the efficacy of TOP in reducing heavy drinking (HD) in 200 individuals of European descent with DSM-5 AUD. The investigators will stratify the randomization on genotype and oversample rs2832407\*C homozygotes, the most TOP-responsive genotype, to ensure comparable numbers of patients in the four medication x genotype groups. The investigators will use daily data collection to examine changes in relevant process variables (e.g., alcohol expectancies) and their interaction with genotype and medication group as predictors of HD. The proposed study is innovative in that it will be the first prospective test of a pharmacogenetic hypothesis involving TOP; it will use daily reports to examine expectancies and how they interact with medication and genotype to predict HD; and it will enroll DSM-5 AUD patients whose goal is either to reduce or stop drinking, which will increase the study's external validity.

Detailed description:
This is a 12-week, prospective, randomized clinical trial of the moderating effect of rs2832407 on the efficacy of topiramate in reducing HD in 200 individuals of European descent with DSM-5 AUD. The investigators will stratify the randomization on genotype and oversample rs2832407\*C homozygotes, the most topiramate-responsive genotype, to ensure comparable numbers of subjects in the four medication x genotype groups. The investigators will compare the efficacy of topiramate to placebo in reducing the frequency of HDDs in subjects with AUD using a two-arm, parallel-groups design. Subjects will either have a goal of reducing their drinking to safe levels or abstinence.

The investigators will use daily data collection to examine changes in relevant process variables and their interaction with genotype and medication group as predictors of HD. At each visit, all subjects will receive Medication Management (Pettinati, Weiss et al. 2004), which was developed for the COMBINE Trial and which the investigators modified to be relevant for both reducing heavy drinking and promoting abstinence. Random assignment to treatment group and double-blind conditions will be maintained throughout the study. Raters will be trained in the reliable use of all assessments. The investigators will use serum GGTP and percent disialotransferrin (%dCDT), an improved assay for carbohydrate deficient transferrin, to validate subject reports. Following a one-week pre-treatment assessment period, subjects will receive 12 weeks of treatment, after which there will be a 6-day taper period, during which subjects will reduce their dosage of topiramate gradually and then discontinue it completely. Daily reports during the treatment period will be obtained using interactive voice response (IVR) to identify subjective correlates of medication effects and to monitor medication use. Following the 12-week treatment period, subjects will be asked to return to the clinic for 3-month and 6-month post-treatment follow-up visits to evaluate the durability of treatment effects.

Two hundred men and women of European descent will be randomized to study medication. Subjects will be recruited using referrals from treatment programs throughout Philadelphia; IRB-approved advertisements on mass transit, on local radio and television stations and in newspapers, social media, and broadcast email messages at institutions that offer such a service and by posting/distributing recruitment materials in community and college settings. Respondents will initially be evaluated by telephone prior to an in-person visit to the Treatment Research Center of the University of Pennsylvania Perelman School of Medicine. The investigators will select subjects based on their genotype to ensure comparable numbers of individuals who are rs2832407\*C-allele homozygotes and A-allele carriers. The investigators will block randomize subjects to balance the groups on treatment goal (i.e., reduced drinking or abstinence).

Arms:
arm 1: Topiramate 200 mg/day orally in two divided doses. Dose will be titrated upward over a six-week period, maintained for 6 weeks, then tapered over 6 days + Medical Management sessions for 15-25 minutes per study visit arm 2: Inactive placebo with dosing schedule matched to intervention group + Medical Management sessions for 15-25 minutes per study visit

Interventions: intervention 1: Topiramate intervention 2: Medical Management intervention 3: Inactive Placebo
Intervention descriptions: intervention 1: Max therapeutic dose of 200mg/day intervention 2: Medical Management (MM; Pettinati, 2004) will support subjects' efforts to reduce or stop their drinking. The study nurse makes direct recommendations for reducing drinking to sensible levels. The first session will use the brochure A Guide to Sensible Drinking (WHO 1996). The subject is provided with information about pharmacotherapy and the importance of adherence to topiramate/placebo. Subsequent treatment sessions (15-25 minutes) will be conducted at each study visit, during which the nurse will perform an assessment of the subject's drinking, monitor his/her medication adherence, and make recommendations to follow until the next visit. Men will be advised to consume no more than 3 drinks 4 times per week; women will be advised to consume no more than 2 drinks 4 times per week. intervention 3: In capsules indistinguishable from topiramate capsules and gradually increased to a maximum equivalent of 200 mg of topiramate/day

Protocol document:
Prot_SAP_002.pdf: 
 
CONFIDENTIAL 
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sponsor 
NCT02371889   Unique Protocol ID: 821035   Secondary IDs: 821035, 
R01AA023192
Study Title: A Randomized, Double-blind Placebo-Controlled 
Pharmacogenetic Study of Topiramate in European-American Heavy 
Drinkers (TOPG) Protocol with Statistical Analysis Plan 
Feburary 19, 2019 


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CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
 
A Randomized, Double-blind Placebo-Controlled 
Pharmacogenetic Study of Topiramate in European-American 
Heavy Drinkers 
 
 
 
Regulatory Sponsor: 
Henry Kranzler, M.D.  
Psychiatry  
3535 Market St., Fifth Floor, Suite 500 
Philadelphia, PA 19104 
(215) 386-6662 
 
Funding Sponsor: 
National Institute on Alcohol Abuse and Alcoholism 
National Institutes of Health 
Study Product: 
Topiramate 
Protocol Number: 
821035 
IND Number: 
 NA 
 
 
 
 
 
 
 
 
 
 
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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 6 
1 
INTRODUCTION .................................................................................................................................. 7 
1.1  BACKGROUND ...................................................................................................................................... 7 
1.1.1  Personalized Treatment of AUD Using Pharmacogenetics ....................................................... 8 
1.1.2  Innovative Aspects ..................................................................................................................... 8 
1.2  INVESTIGATIONAL AGENT ...................................................................................................................... 9 
1.3  PRECLINICAL DATA ............................................................................................................................... 9 
1.4.  CLINICAL DATA .................................................................................................................................... 9 
1.5  DOSAGE RATIONALE AND RISK/BENEFITS ............................................................................................ 11 
2 
STUDY OBJECTIVES ....................................................................................................................... 13 
2.1  PRIMARY OBJECTIVE .......................................................................................................................... 12 
2.2  SECONDARY OBJECTIVE ..................................................................................................................... 13 
2.3  OPTIONAL MRI SUB-STUDY OBJECTIVE............................................................................................... 13 
3 
STUDY DESIGN ................................................................................................................................. 13 
3.1 GENERAL DESIGN ............................................................................................................................... 13 
3.2  PRIMARY STUDY ENDPOINTS .............................................................................................................. 15 
3.2.1  To exaine the moderating effects of GRIK1 SP rs2832407 on the response to topiramate .... 14 
3.2.2  To examine the relations among daily process measures, medication use, and drinking level
 ............................................................................................................................................................ 14 
3.3  SECONDARY STUDY ENDPOINTS ......................................................................................................... 14 
3.4  PRIMARY SAFETY ENDPOINTS ............................................................................................................. 15 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 15 
4.1  INCLUSION CRITERIA ........................................................................................................................... 15 
4.1.1  Inclusion of Women, Children, and Minorities .......................................................................... 15 
4.2  EXCLUSION CRITERIA ......................................................................................................................... 16 
4.3  SUBJECT RECRUITMENT AND SCREENING ............................................................................................ 17 
4.4  EARLY WITHDRAWAL OF SUBJECTS ..................................................................................................... 18 
4.4.1  When and How to Withdraw Subjects ...................................................................................... 18 
4.4.2  Data Collection and Follow-up for Withdrawn Subjects ........................................................... 19 
5 
STUDY DRUG .................................................................................................................................... 19 
5.1  DESCRIPTION ..................................................................................................................................... 19 
5.2  TREATMENT REGIMEN ........................................................................................................................ 19 
5.3  METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS .............................................................. 20 
5.4  PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 21 
5.5  SUBJECT COMPLIANCE MONITORING AND ENHANCEMENT .................................................................... 21 
5.6  PRIOR AND CONCOMITANT THERAPY ................................................................................................... 21 
5.7  PACKAGING ........................................................................................................................................ 21 
5.8  BLINDING OF STUDY DRUG ................................................................................................................. 21 
5.9  RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................ 21 
5.9.1    Receipt of Drug Supplies ........................................................................................................ 21 
5.9.2   Storage .................................................................................................................................... 22 
5.9.3   Dispensing of Study Drug ........................................................................................................ 22 
5.9.4   Return or Destruction of Study Drug ....................................................................................... 22 
6  STUDY PROCEDURES .......................................................................................................................... 24 
6.1  INITIAL TELEPHONE SCREEN (APPROXIMATELY 20 MINUTES) ................................................................. 23 
6.2  INFORMED CONSENT AND SCREENING VISIT (WEEK 0) ......................................................................... 23 
6.3  VISIT 1 (WEEK 1; BASELINE AND FIRST TREATMENT VISITS) ................................................................. 25 


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6.4  VISITS 2-8 (WEEKS 2-11; TREATMENT VISITS) ..................................................................................... 27 
6.5  VISIT 9 (WEEK 12; ENDPOINT VISIT) .................................................................................................... 28 
6.6  MISSED VISIT ..................................................................................................................................... 29 
6.7  VISIT 10 (WEEK 13) ............................................................................................................................ 30 
6.8  VISITS 11 AND 12 (WEEKS 24 AND 36; POST-TREATMENT FOLLOW-UP VISITS) ...................................... 30 
6.9  DESCRIPTION OF STUDY TREATMENTS ................................................................................................ 30 
6.9.1  Pharmacotherapy: .................................................................................................................... 30 
6.9.2  Medical Management Counseling: ........................................................................................... 31 
6.10  DESCRIPTION OF LABORATORY/MEDICAL ASSESSMENTS: ................................................................... 31 
6.11  STUDY TIMELINE: ............................................................................................................................. 32 
7 
STATISTICAL PLAN ......................................................................................................................... 32 
7.1  SAMPLE SIZE DETERMINATION ............................................................................................................ 32 
7.2  STATISTICAL METHODS ....................................................................................................................... 32 
7.3  SUBJECT POPULATION FOR ANALYSIS ................................................................................................. 34 
7.4 Genetic Analyses…………………………………………………………………………………………...34 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 34 
8.1  DEFINITIONS ....................................................................................................................................... 34 
8.2  RECORDING OF ADVERSE EVENTS ...................................................................................................... 36 
8.3  REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ....................................... 36 
8.3.1  Investigator reporting: Notifying the Penn IRB ......................................................................... 42 
8.3.2   Sponsor reporting: Notifying the FDA ..................................................................................... 38 
8.4  UNBLINDING PROCEDURES ................................................................................................................. 39 
8.5  MEDICAL MONITORING ........................................................................................................................ 39 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 51 
9.1  CONFIDENTIALITY ............................................................................................................................... 51 
9.2  SOURCE DOCUMENTS ......................................................................................................................... 53 
9.3  CASE REPORT FORMS ........................................................................................................................ 53 
9.4  RECORDS RETENTION ........................................................................................................................ 41 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 41 
10.1  STUDY MONITORING PLAN ................................................................................................................ 41 
10.2  AUDITING AND INSPECTING ............................................................................................................... 57 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 58 
12 
STUDY FINANCES ............................................................................................................................ 44 
12.1  FUNDING SOURCE ............................................................................................................................ 44 
12.2  CONFLICT OF INTEREST .................................................................................................................... 44 
12.3  SUBJECT STIPENDS OR PAYMENTS .................................................................................................... 58 
13 
APPENDIX I:  (SUB-STUDY) BRAIN MECHANISMS OF TOPIRAMATE’S EFFECTS ON HEAVY 
DRINKING................................................................................................................................................... 45 
13.1  BACKGROUND .................................................................................................................................. 45 
13.2  RISK/BENEFITS ................................................................................................................................ 47 
14 
SUB-STUDY OBJECTIVES ............................................................................................................... 61 
15 
SUB-STUDY DESIGN ........................................................................................................................ 48 
15.1  GENERAL DESIGN ............................................................................................................................. 48 
15.2  PRIMARY STUDY ENDPOINTS ............................................................................................................ 62 
15.3  SECONDARY STUDY ENDPOINTS ....................................................................................................... 62 
16 
SUB-STUDY SUBJECT SELECTION AND WITHDRAWAL ............................................................ 62 
16.1  INCLUSION CRITERIA ......................................................................................................................... 62 
16.2  EXCLUSION CRITERIA ....................................................................................................................... 62 


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16.3  SUBJECT RECRUITMENT AND SCREENING .......................................................................................... 49 
16.4  EARLY WITHDRAWAL OF SUBJECTS ................................................................................................... 64 
16.4.1  When and How to Withdraw Subjects .................................................................................... 64 
16.4.2  Data Collection and Follow-up for Withdrawn Subjects ......................................................... 64 
16.5  INFORMED CONSENT AND SCANNING VISIT 1 (APPROXIMATELY 3 HOURS) ............................................ 50 
16.6  LABORATORY/MRI SESSION 2 VISIT (APPROXIMATELY 2 HOURS) ........................................................ 68 
 
17     SUB-STUDY STATISTICAL PLAN .................................................................................................... 53 
 
17.1  SAMPLE SIZE DETERMINATION .......................................................................................................... 53 
17.2  STATISTICAL METHODS ..................................................................................................................... 53 
17.2.1  Imaging Data Processing ....................................................................................................... 53 
17.2.2  Imaging Data Analyses .......................................................................................................... 68 
17.2.3  Behavioral Analyses ............................................................................................................... 54 
17.3  SUBJECT STIPENDS OR PAYMENTS .................................................................................................... 54 
 
18       CONFIDENTIALITY .......................................................................................................................... 58 
 
19    APPENDIX II: CLINCARD PROGRAM: DATA SECURITY & PRIVACY STATEMENT…………….60 
20     REFERENCES .................................................................................................................................... 61 
 


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List of Abbreviations 
 
AD: Alcohol dependence 
AUD: Alcohol use disorder 
CDT: carbohydrate-deficient transferrin 
%dCDT: percent disialotransferrin 
DSM: Diagnostic and Statistical Manual of Mental Disorders 
GGTP: gamma glutamyl transpeptidase 
HDD: Heavy drinking day 
SNP: single nucleotide polymorphism  
TLFB: Timeline Follow-back Method 
 


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Study Summary 
Title 
A randomized, double-blind placebo-controlled pharmacogenetic study 
of topiramate in European-American heavy drinkers 
Short Title 
Topiramate by Genotype (TOP-G) 
Protocol Number 
 
Phase 
2 
Methodology 
Randomized, double-blind, placebo-controlled, parallel-groups  
Study Duration 
5 years 
Study Center(s) 
University of Pennsylvania and Corporal Michael J. Crescenz VA 
Medical Center (CMCVAMC) 
Objectives 
1) To examine the moderating effect of rs2832407 in GRIK1 on the 
efficacy of topiramate 200 mg/day in reducing the frequency of heavy 
drinking; 2) To examine daily processes, including expectancies 
regarding the positive effects of drinking and confidence in resisting 
heavy drinking, and their interaction with genotype and medication 
group to predict nighttime drinking; 3) To conduct 3- and 6-month post-
treatment follow-up assessments to examine the persistence of 
treatment effects; 4) To conduct an optional sub-study to examine the 
effects of topiramate on resting baseline cerebral blood flow and 
alcohol cue reactivity using functional magnetic resonance imaging. 
Number of Subjects 
A total of 200 subjects will be randomized (up to 100 at the CMCVAMC 
site) 
Diagnosis and Main 
Inclusion Criteria 
Heavy drinkers who self-identify as European-American and who have 
an average weekly ethanol consumption of >24 standard drinks for men 
or >18 standard drinks for women, with a weekly average of > 2 heavy 
drinking days (HDDs) during the month before screening 
Study Product, 
Dose, Route, 
Regimen 
Topiramate 200 mg/day for 12 weeks. Dosage will be 200 mg/day, 
initiated at 25 mg/day and gradually increased such that the maximal 
dosage will be reached in the sixth week of treatment.  The dosage will 
be altered to minimize adverse effects and after 12 weeks will be 
tapered off completely. 
Duration of 
administration 
12 weeks (plus a one-week taper) 
Reference therapy 
Placebo 
Statistical 
Methodology 
The four medication by genotype groups will be compared on weekly 
number of HDDs using mixed effects models for count responses.  
Estimates of effects over the final six weeks of treatment, with 
associated standard errors and confidence intervals, will be used to test 
the primary hypothesis.  Similar models will be used to examine data 
from 3- and 6-month follow-up visits to evaluate the persistence of 
treatment effects.  Regression analyses will also examine the effects of 
topiramate and rs2832407 and their interaction on resting baseline 
cerebral blood flow and alcohol cue reactivity. 
 


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1 Introduction 
This document is a protocol for a human research study. The 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 
In the United States, the estimated 12-month prevalence of a DSM-IV alcohol use disorder 
(AUD) is 8.5%; this includes 4.7% of individuals with alcohol abuse and 3.8% with alcohol 
dependence (AD) (Grant, Dawson et al. 2004).  Although AUDs are associated with a range of 
problems and are a leading cause of preventable death in the United States (Mokdad, Marks et 
al. 2004), their treatment is generally not evidence based (McGlynn, Asch et al. 2003).  Thus, 
despite the fact that, since 2005, NIAAA has recommended that medications with demonstrated 
efficacy be considered as a first-line treatment for AD, in practice, few people receive such 
treatment (Mark, Kranzler et al. 2003; Mark, Kranzler et al. 2003; Mark, Kassed et al. 2009).  In 
part, the reluctance of physicians to prescribe alcohol treatment medications and of patients to 
take them stems from their limited efficacy (Mark, Kranzler et al. 2003; Mark, Kranzler et al. 
2003).  Further, although some studies have included subjects who are heavy drinkers, without 
necessarily meeting a diagnosis of AD (Kranzler, Armeli et al. 2003; Karhuvaara, Simojoki et al. 
2007; Kranzler, Tennen et al. 2009), most medication trials have been limited to individuals with 
AD, reducing their applicability to heavy drinkers and others who want to reduce their drinking.  
Recently, DSM-5 replaced the abuse/dependence distinction with the diagnosis of AUD, which 
requires that only two of 11 criteria be met for the diagnosis.  This will increase the identification 
of individuals needing an intervention (Agrawal, Heath et al. 2011; Peer, Rennert et al. 2013).  
This study will help to address that need by testing topiramate in individuals with DSM-5 AUD 
who are regular heavy drinkers. 
 
Currently, three medications are FDA-approved to treat AUD: naltrexone, acamprosate, and 
disulfiram (Harris, Kivlahan et al. 2010). Empirical evidence suggests that naltrexone reduces 
the reward properties of and cravings for alcohol (Sinclair 2001) and acamprosate supports 
abstinence (Mason, Goodman et al. 2006); however, their effect sizes compared to placebo are 
small (Mark, Kranzler et al. 2003; Rosner, Hackl-Herrwerth et al. 2010; Oliva, Maisel et al. 
2011). 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 (Franck and Jayaram-Lindstrom 2013). There is 
limited evidence of the efficacy of disulfiram, and its potential for toxicity limits it use (2009). 
These concerns about safety and limited efficacy likely contribute to the fact that FDA-approved 
medications for AUD are not widely prescribed (Mark, Kranzler et al. 2003; Mark, Kranzler et al. 
2003). Indeed, only 2.8% of patients treated in the Veterans Health Administration who were 
diagnosed with an AUD received pharmacotherapy (Oliva, Maisel et al. 2011). 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.  
The anticonvulsant topiramate, though not approved to treat AD, substantially reduced the 
frequency of heavy drinking in four placebo-controlled trials and two open-label studies.  Based 
on these findings, topiramate is increasingly being prescribed off-label to treat AD (e.g., in the 
VA Healthcare System).  Recently, we found that the ability of topiramate to reduce heavy 
drinking was limited to individuals with the CC genotype of rs2832407, a single nucleotide 
polymorphism (SNP) in GRIK1, the gene encoding the kainate receptor GluK1 subunit.  This 
finding for topiramate adds to similar pharmacogenetic findings for two other medications to 


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treat AD, the beneficial effects of which are substantially enhanced by genetic moderators: 
naltrexone (which is moderated by a SNP in the mu-opioid receptor gene, OPRM1) and 
ondansetron (which is moderated by two genotypes in SLC6A4, the serotonin transporter gene).  
Consistent with the goal of personalized treatment for AD, these findings would allow clinicians 
to identify, in advance, which patients are likely to respond to each of these medications and 
which should be spared the unnecessary adverse effects that may accompany treatment in a 
likely non-responder.  Of note, together, these three pharmacogenetic findings would make it 
possible to select the best medication to reduce heavy drinking in ~75% of European 
Americans. 
1.1.1  Personalized Treatment of AUD Using Pharmacogenetics 
Topiramate Pharmacogenetics:  Topiramate’s effects, as mentioned above, are moderated by 
kainate receptors, tetrameric assemblies that respond to glutamate.  The GluK1 and GluK2 
kainate subunits (encoded by GRIK1 and GRIK2, respectively) are the ones for which 
topiramate’s effects on AMPA/kainate receptors are most potent and selective (Gryder and 
Rogawski 2003; Kaminski, Banerjee et al. 2004).  Kranzler, Gelernter et al. (2009) examined 
variation in GRIK1, on the hypothesis that evidence of association to AD could identify a 
moderator of the effects of topiramate in individuals with AD.  The study focused on variation in 
the 3’-half of the gene, including the differentially spliced exons 9, 17, and 18.  The C allele of 
rs2832407 in intron 9 was significantly overrepresented in AD (Kranzler, Gelernter et al. 2009).  
GRIK1 was also nominally associated with successful attempts to quit smoking in pooled 
genomewide association analyses (Uhl, Liu et al. 2008), suggesting that it may serve more 
generally as a moderator of treatment response in addictive disorders.  Ray et al. (Ray, Miranda 
Jr et al. 2009) examined the moderating effect of rs2832407 on topiramate treatment outcome 
in 51 individuals from a placebo-controlled study of topiramate in heavy drinkers (Miranda Jr, 
MacKillop et al. 2008).  Although they found that the SNP did not moderate the therapeutic 
effects of topiramate, carriers of the A allele reported more severe topiramate-induced adverse 
events.  In our recently completed topiramate study (Kranzler, Covault et al. 2014) we did not 
find a moderating effect of rs2832407 on adverse events.  However, we found that the SNP 
robustly moderated the therapeutic response to topiramate.  Further, in that trial, use of a micro-
longitudinal approach, which previously supported the pharmacogenetics of naltrexone 
response (Kranzler, Armeli et al. 2013), helped to clarify the associated subjective effects of 
topiramate, rs2832407, and their interaction. Although there are no known coding SNPs in 
GRIK1, rs2832407 is in a region of differential splicing and is upstream of a GRIK1 antisense 
RNA.  Thus, rs2832407 or other SNPs with which it is in linkage disequilibrium may act by 
influencing RNA processing or the regulation of gene expression.  We are currently examining 
the SNP’s functional effects using expression assays in neural cultures derived from induced 
pluripotent stem cells (Lieberman, Levine et al. 2012). 
1.1.2  Innovative Aspects 
This is the first prospective study of a genetic moderator of topiramate with adequate statistical 
power to guide the personalized treatment of AD.  Currently, approximately 10% of FDA-
approved medications contain pharmacogenetic labeling, which allows the prescriber to 
personalize treatment based on a genetic test, representing a paradigm shift in medical care 
(Hamburg and Collins 2010).  The public health implications of tailoring treatments to those with 
an AUD based on likely treatment response are considerable.  Pharmacogenetics offers the 
potential to do that with topiramate.  Additionally, topiramate is a generic medication for which 
there is no incentive for further commercial development.  However, combining a genetic marker 
with the medication offers the potential to develop a commercially viable entity that could lead a 
company to develop topiramate specifically to treat AUD. 


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The dosage of topiramate used in this study is lower than that used in most previous studies.  In 
our recently completed trial (Kranzler, Covault et al. 2014), use of a 200 mg/day dosage 
enhanced treatment retention and provided additional information on the optimal dosage of 
topiramate to be used in clinical care (i.e., taking into account both its efficacy and tolerability). 
Subject selection is also an important aspect of this study, and will be more inclusive than in 
previous studies. It will include both individuals whose goal is to reduce drinking and individuals 
whose goal is to become abstinent, allowing us to generalize the findings regarding the utility of 
topiramate and the moderating effects of rs2832407 to a more diverse population than prior 
studies, which were limited to people with a goal of abstinence (Johnson, Ait-Daoud et al. 2003; 
Johnson, Rosenthal et al. 2007) or a goal of reducing drinking (Kranzler, Covault et al. 2014).  
This will increase the external validity of the study. Selected subjects will also include individuals 
with DSM-5 AUD, a more inclusive diagnostic group than DSM-IV AD.  Given the shift to DSM-
5, this will increase the external validity and applicability of the study’s findings. Our use of daily 
data collection (i.e., a micro-longitudinal study design) to monitor daily processes and drinking 
behavior will provide insight into the subjective dimension of topiramate’s effects in reducing 
heavy drinking, both overall and as a function of genotype.  Finally, the use of functional 
magnetic resonance imaging to examine the effects of topiramate and its moderation by 
rs2832407 has not previously been done, and it may provide insights into the mechanism of the 
pharmacogenetic effect. 
1.2  Investigational Agent 
Topiramate is an anticonvulsant medication for oral administration approved in the United 
States for the treatment of seizures, the prevention of migraine headaches, and for the 
promotion of weight loss (in combination with phentermine). 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 tablet 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 dosages of 
200 mg and 400 mg per day in adults.  
1.3  Preclinical Data 
Topiramate is a sulfate-substituted monosaccharide with multiple pharmacological effects.  It 
facilitates GABAergic function by interacting with a non-benzodiazepine site on the GABAA 
receptor (White, Brown et al. 2000), antagonizes glutamate activity at AMPA and kainate 
receptors (Gibbs, Sombati et al. 2000; Skradski and White 2000), modifies effects at NMDA 
receptors without directly blocking them (McDonald and Rogawski 2006), blocks voltage-
dependent Na+ and L-type voltage-gated Ca++ channels, and inhibits carbonic anhydrase, and 
enhances K+ conductance (McDonald and Rogawski 2006).  The drug’s effects on 
AMPA/kainate receptors are most potent and selective for those containing the GluK1 
(previously known as GluR5) and GluK2 (previously GluR6) subunits (Gryder and Rogawski 
2003; Kaminski, Banerjee et al. 2004). 
1.4.  Clinical Data  
Topiramate is approved by the FDA to: 1) treat seizure disorder, 2) prevent migraine, and 3) 
promote weight loss (in combination with phentermine).  It is associated with mild-to-moderate 
adverse effects and is best tolerated when initiated at a low dosage that is gradually increased 
over a period of weeks. 


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Two randomized controlled trials of topiramate 300 mg/day, including a single-center study 
(Johnson, Ait-Daoud et al. 2003) and a multicenter study in subjects with AD (Johnson, 
Rosenthal et al. 2007), showed it to have a medium-sized effect in reducing HD. In the first 
study (Johnson, Ait-Daoud et al. 2003), 150 subjects received an escalating dosage of 
topiramate (beginning with 25 mg/day) or matching placebo for 12 weeks.  The medication was 
well tolerated and topiramate-treated subjects reduced the percentage of HD days significantly 
more than those receiving placebo, with the groups beginning to separate significantly after the 
first month of treatment.  In the 14-week, double-blind, placebo-controlled, multicenter trial of 
371 subjects (Johnson, Rosenthal et al. 2007), topiramate was also significantly more 
efficacious than placebo at reducing the percentage of HDDs.  Miranda et al. (Miranda Jr, 
MacKillop et al. 2008) randomly assigned 61 non-treatment seeking heavy drinkers to receive 
topiramate 200 mg/day, topiramate 300 mg/day, or placebo.  The medication was titrated to the 
target dosage over a 32-day period and maintained there for one week.  During the titration 
period, the frequency of HD was significantly lower in both topiramate groups than with placebo.   
In a 12-week, open-label trial (Rubio, Ponce et al. 2004), topiramate (up to 400 mg/day) was 
well tolerated and associated with reduced drinking and craving by week 2 and decreased 
carbohydrate-deficient transferrin (CDT) levels beginning at week 6.  In a second open-label 
study (Paparrigopoulos, Tzavellas et al. 2011), subjects completing inpatient alcohol 
detoxification were assigned to receive either topiramate (up to 75 mg per day) plus 
psychotherapy (n = 30) or psychotherapy alone (n = 60).  During a 4-month follow-up period, 
significantly fewer (66.7%) of the topiramate-treated subjects than the psychotherapy-only 
subjects (85.5%) relapsed, with topiramate subjects’ median time to relapse being 10 weeks 
compared with four weeks for those in the psychotherapy-only group, a significant difference.  A 
placebo-controlled study failed to show a significant advantage for topiramate in reducing 
drinking (Likhitsathian, Uttawichai et al. 2013).  However, in that study, only 53% of the 
topiramate group and 47% of the placebo group completed treatment and adherence to the 
prescribed regimen was not evaluated, both of which seriously limit the interpretation of the 
results. 
Our recently published placebo-controlled trial of topiramate 200 mg/day in heavy drinkers 
(Kranzler, Covault et al. 2014) showed a robust treatment effect. We randomly assigned 138 
heavy drinkers (62.3% male, 92% with DSM-IV AD) to receive 12 weeks of treatment with 
topiramate 200 mg/day (n=67, 48.6%) or matching placebo (n=71, 51.4%), with medical 
management (MM, see section 6.7.2, below).  The only demographic or clinical variable on 
which the groups differed was age: placebo subjects were ~3.5 yr older than topiramate 
subjects.  Using the Timeline Follow-back Method (TLFB; see section 6.10, below) to measure 
drinking during the 90-day pre-treatment period, both groups drank heavily (men: > 5 drinks; 
women: > 4 drinks) on ~5 days/week and had 1 abstinent day/ week.  Fifty-six topiramate 
subjects (83.6%) and 61 placebo subjects (85.9%) completed the 12-week treatment period 
(p=0.70). There was a main effect of medication group (p<0.001) and an interaction with 
treatment week (p<0.0001).  Topiramate subjects had fewer heavy drinking days (HDDs) and 
decreased the number of HDDs/week more rapidly than placebo subjects.  During week 12, the 
odds that the placebo group would have at least one HDD was 5.32 (95%CI=1.68-7.30) times 
that of the topiramate group (p<0.001).  There was twice the number of treatment responders 
(i.e., those with no HDDs during the last four weeks of treatment) in the topiramate group (n=24, 
35.8%) as in the placebo group (n=12, 16.9%) with (OR=2.75, 95%CI=1.24-6.10).  There was a 
main effect of medication group (p=0.032) and an interaction with treatment week (p=0.013).  
Topiramate subjects had more abstinent days and increased the number of abstinent 
days/week more rapidly than the placebo group. During week 12, the odds of an abstinent day 
in the topiramate group was 2.57 (95%CI=1.13-5.84) times that of the placebo group.  


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1.5  Dosage Rationale and Risk/Benefits 
Dosage Rationale 
The dosage used in the only large prior study of topiramate was 300 mg/day, which resulted in a 
differential dropout between active and placebo treatments (Johnson, Rosenthal et al. 2007). 
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 (Johnson, Ait-Daoud et al. 2003; Johnson, Rosenthal et al. 2007; Miranda, MacKillop et 
al. 2008). Further, our previous study of 138 heavy drinkers who sought to reduce their drinking 
received a 12-week treatment with topiramate 200 mg/day (N=67) 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 (Kranzler, Covault et al. 2014). As 
recommended in the package insert, we will reduce the dosage of topiramate by one-half (i.e., a 
maximum of 100 mg/day) for anyone with a creatinine clearance <70 mL/min/1.73 m2.   
 
Potential Risks 
Topiramate is not reinforcing and is therefore not a drug of abuse. There are few serious 
adverse effects associated with topiramate treatment and none were seen in our recently 
completed study of topiramate.  The most common adverse effects of topiramate compared to 
placebo are numbness and tingling (49% vs. 6%).  The other most common side effects 
(experienced by 10-31% of subjects) 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 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 subjects) 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 subjects).  
Some individuals have had suicidal thoughts or actions (experienced by about 1% of subjects).  
Although these adverse effects have not been reported in alcohol-dependent subjects, study 
participants will be informed that, should they feel a change in their mood, feel depressed, or 
feel they may harm themselves, they should contact the study doctor.  
An adverse effect of topiramate, which is less common but potentially serious is renal calculi 
(experienced by about 2% of subjects).  Drinking an adequate volume of fluids is recommended 
while taking topiramate, and may reduce the risk of renal calculi.  Subjects will be counseled to 
drink water frequently throughout the day. 
Severe metabolic acidosis (increased bicarbonate levels) is associated with topiramate 
treatment in 3-7% of individuals taking the medication.  We will repeat bicarbonate levels at the 
visit six of the study to identify anyone with severe acidosis.  Further, individuals taking carbonic 
anhydrase inhibitors will be excluded from this study, due to the added risk of metabolic 
acidosis.  Treatment with topiramate may cause oligohidrosis (decreased sweating), which has 
primarily been reported in children.   
Acute secondary glaucoma has been described in some people taking topiramate, usually 
occurring at the beginning of treatment (less than 1%).  Individuals with a history of narrow 
angle glaucoma will be excluded from this study.  Subjects will be informed that should they 
have sudden, significant worsening of vision, blurred vision, or eye pain to contact the study 
doctor immediately. This adverse event is very rare.  Overdoses of topiramate have been 
associated with convulsions, drowsiness, speech disturbance, blurred vision, diplopia (double 


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vision), impaired mental activity, abnormal coordination, stupor, hypotension, abdominal pain, 
agitation, dizziness and depression. Deaths have been reported in overdoses.  
Rare and isolated cases of liver failure/hepatitis and blistering skin rashes (bullous skin 
eruptions) have been reported with topiramate (less than 1% for both).   Careful instructions on 
the use of topiramate and dispensing of limited quantities of the medication will serve to reduce 
the risk of accidental overdose.  Careful screening using module 2 of the MINI International 
Neuropsychiatric Interview 6.0 (MINI) will exclude individuals with significant suicidal risk and 
ongoing monitoring throughout the study will serve to reduce the risk of intentional overdose or 
other suicidal behavior. Suicidal risks will be assessed using the MINI Suicidality section (B) at 
each study visit, and if rated equal to or greater than 9 (i.e., clinically significant suicidal 
ideation), the physician will be consulted to decide the appropriate clinical management. 
It is possible that some hormonal contraceptives (birth control pills, hormonal implants or 
hormonal injections) may be made less effective by topiramate.  If appropriate, the study doctor 
will discuss alternatives or additional non-hormonal methods of birth control to be used during 
participation in the study.  Women of childbearing potential who are using hormonal 
contraceptives will be instructed to inform the study nurse about any changes in menstrual 
bleeding patterns. Further, at the time of randomization, for women using hormonal 
contraceptives, the study physician will discuss with the participant non-hormonal methods of 
birth control to be used during her participation in the study. 
Topiramate is labeled by the Food and Drug Administration as a category D medication. This 
means that there are data in humans from investigational or marketing experience showing that 
topiramate can cause harm to the fetus, but potential benefits may warrant the use of the 
medication in pregnant women despite risk to the potential risks. Data from pregnancy registries 
show that infants exposed to topiramate in utero have an increased risk for cleft lip and or cleft 
palate (oral clefts). Pregnancy testing of women of childbearing potential prior to study 
randomization (Screening and Informed Consent visit) and at visits 1 (week 1), 5 (week 5), 7 
(week 8), and 9 (week 11) will minimize the risk of fetal exposure to study medication.    
Topiramate does not produce clinically significant additive CNS depressant effects in 
combination with ethanol.  In placebo-controlled clinical trials of topiramate treatment of AD, 
individuals who consume alcohol have not reported ill effects of the combination.  This was the 
case in the recently completed study of topiramate in heavy drinkers, who were drinking from 
the outset of the study.  The medication was well tolerated in that study and there was no 
evidence of differential attrition in the topiramate group. 
 
Potential Benefits   
Benefits to subjects include careful evaluation of their medical and psychiatric status and 
alcohol use and potential reduction in or discontinuation of their alcohol consumption, which 
may improve their health and wellbeing. 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.  In addition, clinicians and scientists may better understand 
the effects of topiramate treatment of AUD.  An improved understanding of the genetic and 
other moderators of response to these medications will enhance their clinical utility and the 
process of medications development for alcohol treatment. 
 
Risk/Benefit Ratio 
Although treatment with topiramate presents some risks, it has been shown to be safe when 
administered for the 12 weeks of treatment to reduce heavy drinking for which it will be used in 
this study.  Problems with tolerability that have been observed in some studies have been 


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transient or have resolved upon discontinuation of the medication.  The potential risks of these 
treatments are minor compared to the risk incurred by individuals who continue to drink heavily.  
The risk/benefit ratio thus appears favorable to the proposed treatment. 
2 Study Objectives 
2.1. Primary Objective:  To examine the moderating effect of rs2832407 in GRIK1 on the 
efficacy of topiramate 200 mg/day in reducing the frequency of heavy drinking in the last six 
weeks of the treatment trial.  We expect that subjects treated with topiramate will report 
significantly fewer heavy drinking days (HDDs) than those receiving placebo.  
Our primary hypothesis is that the effect will be significantly larger in rs2832407 C-allele 
homozygotes than in A-allele carriers.  We will also examine the SNP’s moderating effects on 
the efficacy of topiramate in improving other self-reported drinking measures (e.g., abstinent 
days), adverse consequences of drinking (e.g., the Short Index of Problems score: SIP; see 
section 6.8.3 below), and biological measures of heavy drinking (e.g., %dCDT, an improved 
assay for carbohydrate deficient transferrin). Finally, we will conduct 3- and 6-month post-
treatment assessments on the hypothesis that rs2832407 C-allele homozygotes will show 
greater reduction in primary and secondary outcomes after the medication is discontinued. 
The primary outcome for the study is the frequency of heavy drinking (defined as 4 or more 
drinks in a day for women and five or more drinks in a day for men). 
Secondary outcomes include the number of abstinent days, absence of any heavy drinking 
days during the last month of treatment, mean daily alcohol consumption, drinks/drinking day, 
%dCDT and gamma glutamyl transpeptidase (GGTP) levels, and severity of alcohol-related 
problems (i.e., SIP score), using models similar to those described below for the primary 
outcome. 
  
2.2. Secondary Objective: To examine daily processes, including expectancies regarding 
the positive effects of drinking and confidence in resisting heavy drinking and their interaction 
with genotype and medication group to predict the intensity of nighttime drinking.  We expect 
that evening reports of a high level of positive expectations regarding alcohol’s effects and a low 
level of confidence in resisting heavy drinking will be associated with heavier drinking later that 
night. 
Our secondary hypotheses are that topiramate treatment will significantly reduce both positive 
alcohol-outcome expectancies and confidence in resisting heavy drinking across the weeks of 
the study and nighttime drinking measured daily in rs2832407 C-allele homozygotes, but not A-
allele carriers. 
 
2.3 Optional MRI Sub-Study Objective: Conduct an optional sub-study to examine the 
effects of topiramate on resting baseline (RB) cerebral blood flow and alcohol cue reactivity 
using functional magnetic resonance imaging (fMRI). The goals, rationale, background and 
study methods for this objective are described in Appendix I: “Brain Mechanisms of 
Topiramate’s Effects on Heavy Drinking.”  
3 Study Design 
3.1 General Design 
This is a 12-week, prospective, randomized clinical trial of the moderating effect of rs2832407 
on the efficacy of topiramate in reducing HD in 200 individuals of European descent with DSM-5 


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AUD.  We will stratify the randomization on genotype and oversample rs2832407*C 
homozygotes, the most topiramate-responsive genotype, to ensure comparable numbers of 
subjects in the four medication x genotype groups.  We will compare the efficacy of topiramate 
to placebo in reducing the frequency of HDDs in subjects with AUD using a two-arm, parallel-
groups design.  Subjects will either have a goal to reduce their drinking to safe levels or to stop 
drinking entirely.  We will use daily data collection to examine changes in relevant process 
variables and their interaction with genotype and medication group as predictors of HD. This 
study will be registered on clinicaltrials.gov. 
At each visit, all subjects will receive MM (Pettinati, Weiss et al. 2004) (see section 6.7.2), which 
was developed for the COMBINE Trial and which we modified to be relevant for both reducing 
heavy drinking and promoting abstinence.  Random assignment to treatment group and double-
blind conditions will be maintained throughout the study.  Raters will be trained in the reliable 
use of all assessments.  We will use serum GGTP and percent disialotransferrin (%dCDT), an 
improved assay for carbohydrate deficient transferrin (Helander, Wielders et al. 2010), to 
validate subject reports.  Following a one-week pre-treatment assessment period, subjects will 
receive 12 weeks of treatment.  There will be a 6-day taper period, during which subjects will 
reduce their dosage of topiramate gradually and then discontinue it completely.  Daily reports 
during the treatment period will be obtained using interactive voice response (IVR) to identify 
subjective correlates of medication effects and to monitor medication use.  Following the 12-
week treatment period, subjects will be asked to return to the clinic for 3-month and 6-month 
post-treatment follow-up visits to evaluate the durability of treatment effects.   
Two hundred men and women of European descent will be recruited using referrals from 
treatment programs throughout Philadelphia; IRB-approved advertisements on mass transit, on 
local radio and television stations and in newspapers, social media, and broadcast email 
messages at institutions (e.g., the University of Pennsylvania Health System) that offer such a 
service and by posting/distributing recruitment materials in community and college settings.  To 
ensure adequate representation of Hispanics of European descent, we will conduct outreach via 
English-language advertisements in Spanish-language media in the greater Philadelphia area.  
Respondents will initially be evaluated by telephone prior to an in-person visit to the Treatment 
Research Center of the University of Pennsylvania Perelman School of Medicine.   
 
Up to 100 men and women veterans of European descent will be recruited from the 
CMCVAMC. Recruitment at the CMCVAMC site will be focused on patients identified in primary 
care settings. The Behavioral Health Laboratory (BHL) conducts clinical assessments on all 
patients referred from primary care.  At the completion of the clinical assessment, all patients 
potentially eligible to participate in this research, which has been approved by the CMCVAMC 
IRB and the Mental Illness Research, Education and Clinical Center (MIRECC), will be informed 
of the project and asked if they may be contacted by appropriate study personnel to discuss the 
study in accordance with that protocol’s procedures. Additionally, the study will seek referrals 
from the Mental Health Clinic (MHC) and Addictions Recovery Unit (ARU) within the 
CMCVAMC.  An investigator and study staff will meet with the staff of the BHL, the MHC and 
ARU to explain the goals of the research study and ask for assistance with patient referrals.  
The PI and study staff will have ongoing in-service meetings with the providers to facilitate 
engagement in the recruitment process.  Recruitment flyers and informational brochures will be 
available for potential participants in the Primary Care Clinic, MHC, and ARU.  
At both the UPenn and CMCVAMC sites, we will stratify subjects based on their genotype to 
ensure comparable numbers of individuals who are rs2832407 C-allele homozygotes and A-
allele carriers in each of the treatment groups.  We will also stratify by site and block randomize 
subjects to balance the groups on treatment goal (i.e., reduced drinking or abstinence).  


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3.2 Primary Study Endpoints 
3.2.1 To examine the moderating effects of the GRIK1 SNP rs2832407 on the response to 
topiramate:  The primary outcome measure will be the frequency of HDDs (>5 standard drinks 
in a day for men and >4 in a day for women).  We chose this outcome because it is a sensitive, 
clinically relevant measure in alcohol treatment trials (Falk, Wang et al. 2010).  Subjects will be 
followed irrespective of whether they continue to receive treatment, so that the analysis of all 
outcomes will be based on all of the data available for all randomized subjects.  Drinking data 
for this aim will come from the TLFB (see section 6.10 below).    
 
3.2.2 To examine the relations among daily process measures, medication use, and 
drinking level:  We will use multilevel models to evaluate the associations of alcohol 
expectancies and self-efficacy (confidence in resisting drinking and heavy drinking) with daily 
drinking and how these associations vary as a function of medication group and rs2832407 
genotype.  Similar to Kranzler, Armeli et al. (2013), we will focus on predicting nighttime drinking 
(i.e., drinks consumed after the early evening report), but here we will use alcohol-related 
expectancies reported during the early evening in the daily survey.  Nighttime drinking levels will 
be determined by subtracting the number of drinks consumed during the current day from the 
total number of drinks consumed for that day (reported the following day). 
3.3  Secondary Study Endpoints 
Secondary endpoints include: the number of abstinent days, absence of any heavy drinking 
days [the FDA-recommended outcome measure (Anton, Litten et al. 2012)], mean daily alcohol 
consumption, drinks/drinking day, %dCDT and GGTP levels, and severity of alcohol-related 
problems (i.e., SIP score), using models similar to those described below for the primary 
outcome.  All outcomes (primary and secondary) will also be evaluated at 3- and 6-month post-
treatment assessments.  
3.4  Primary Safety Endpoints 
Subjects will be monitored carefully for adverse events including the development of renal 
calculi or metabolic acidosis. At each study visit, participants will provide subjective reports of 
side effects using the adverse events checklist developed from prior studies of topiramate for 
alcohol treatment.  Using data from that periodic inquiry, we will compare the medication groups 
on the overall frequency of adverse events during treatment, the frequency of severe adverse 
events during treatment, and the frequency of adverse events during treatment that are rated 
moderate or severe. 
4 Subject Selection and Withdrawal 
4.1  Inclusion Criteria 
1) Determined to be physically healthy, based on medical history and physical examination 
and approval of the study physician 
2) Age 18 to 70 years, inclusive  
3) Self-identified European ancestry  
4) Meets DSM-5 criteria for AUD 
5) Average weekly ethanol consumption of >24 standard drinks for men and >18 standard 
drinks for women, with a weekly average of > 2 HDDs during the month before screening  
6) Stated goal to reduce drinking to safe levels or to stop drinking 
7) Able to read English at an 8th grade or higher level and no gross cognitive impairment  


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8) Willingness to nominate an individual who will know the subject’s whereabouts to 
facilitate follow up during the study 
9) Women of child-bearing potential (i.e., who have not had a hysterectomy, bilateral 
oophorectomy, tubal ligation or is less than two years postmenopausal): must be non-
lactating and practicing a reliable method of birth control, and have a negative urine 
pregnancy test prior to the initiation of treatment.  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. 
10) Willingness to provide signed, informed consent and commit to completing the 
procedures in the study 
 
4.1.1. Inclusion of Women, Children and Minorities 
1) Based on prior treatment studies for AUD, we estimate that approximately 32% of 
participants in this study will be women.  This approximates the proportion of the 
population with AUD that is female, so no specific outreach will be required to ensure 
adequate representation of women in the study sample.   
2) Children between the ages of 18 and 20 will be included in the study.  Because we will 
be recruiting on college campuses in Philadelphia, we anticipate that up to 10% of the 
sample will be in that age range.  We will limit children to those who are at least 18 years 
of age because data are insufficient to support the use of topiramate to reduce heavy 
drinking in younger children. 
3) The primary hypothesis to be tested in this study is genetic moderation of the response 
to topiramate by the single nucleotide polymorphism rs2832407.  Preliminary results in a 
sample of 8,051 individuals that were recruited to participate in genetic studies of alcohol 
and drug dependence showed that the prevalence of the rs2832407 C allele was 65.1% 
in European Americans, with 43.1% of individuals being C-allele homozygotes. In 
contrast, among African Americans, the C allele was the minor allele, with a frequency of 
17.9% and a C-allele homozygote frequency of 3.5%.  Based on the low prevalence of 
the CC genotype (which is hypothesized to moderate the beneficial effects of 
topiramate), it is not feasible to recruit an adequate number of African American subjects 
to test the hypothesis in that population.  Thus, for scientific reasons, this study will enroll 
only subjects who self-identify as being of European ancestry.  Of this number, about 
15% of the subjects will be Hispanic.  To ensure adequate representation of Hispanic 
subjects (~15% of the total), we will conduct outreach via English advertisements in 
Spanish-language newspapers, radio, and television in the greater Philadelphia area.    
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, including direct bilirubin 
elevations of >110% or a transaminase elevation >300% of normal  
2) A history of nephrolithiasis  
3) A history of glaucoma 
4) Current treatment with carbonic anhydrase inhibitors, due to the added risk of metabolic 
acidosis. 


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5) Current, serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe or 
psychotic major depression, panic disorder, borderline or antisocial personality disorder, 
organic mood or mental disorders, eating disorder, or imminent suicide or violence risk)  
6) Current DSM-IV diagnosis of dependence on a drug other than alcohol or nicotine  
7) A history of hypersensitivity to topiramate 
8) Current regular treatment with a psychotropic medication (e.g., benzodiazepines, 
antidepressants), which affect neurotransmitter systems, or a medication to treat alcohol 
dependence 
9) Currently taking any tricyclic antidepressant (e.g., Adapin (doxepin), Anafranil 
(clomipramine), Elavil (amitryptyline), Pamelor (nortryptyline), Tofranil (imipramine), 
Sinequan (doxepin) 
10) Urine drug screen positive for recent use of opioids, cocaine, or amphetamines (may be 
repeated once and if the result is negative on repeat it is not exclusionary) 
11) Because co-administration of topiramate with dolutegravir reduced plasma 
concentrations of the antiretroviral through induction of CYP3A, the use of dolutegravir is 
exclusionary. 
12) Judged by the principal investigator or his designee to be an unsuitable candidate for 
receipt of an investigational drug 
4.3  Subject Recruitment and Screening 
Subjects at the UPenn site will be recruited using the following methods: referrals from 
treatment programs throughout Philadelphia; advertisements on mass transit, on local radio 
stations and in newspapers; social media; and broadcast email messages at institutions 
(including the University of Pennsylvania Health System, Craigslist, community agencies, local 
college campuses) that offer such a service; and by posting/distributing recruitment materials in 
community settings with public posting areas or other means of providing community access to 
materials (such as hospitals, town halls, public libraries, YMCAs, health fairs).  We will obtain 
permission at selected locations before distributing or posting the approved recruitment 
materials (ensuring compliance with other institutions’ guidelines, including seeking IRB 
approval as needed to conduct recruitment activities). We will use the Penn Data Store to 
obtain patient demographics, medical diagnosis codes related to AUD, individual names and 
addresses, and provider names. We will request permission of providers to contact the 
individuals with an IRB-approved letter and recruitment materials (i.e., the study brochure, 
outreach letter). We will also use Research Match (Vanderbilt University), iConnect (UPenn) 
and the Treatment Research Center (UPenn) website for Internet recruitment. 
To ensure adequate representation of Hispanics (~15% of the total), we will conduct outreach 
via English-language advertisements in Latino newspapers, radio, and television in the greater 
Philadelphia area. We will also invite individuals with Spanish surnames identified through the 
University of Pennsylvania Health System electronic medical record that appear to qualify for 
study participation to contact our screening line.  The study sample will include children (i.e., 
individuals who are 18-20 years old). 
We will request a partial waiver of consent and HIPAA Authorization from the IRB to allow for 
preliminary phone screening for calls initiated by potential subjects.  Individuals deemed eligible 
for in-person screening will sign a HIPAA Authorization and study consent form at their first 
visit. During the in-person screening visit (once telephone screening shows preliminary 
eligibility), each subject will receive an explanation of the study protocol and 2), its risks, 
potential benefits, and alternative treatments by a study staff member.  Following resolution of 
any questions, individuals 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 


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given to each subject.  Based on our experience with this method of recruitment, we anticipate 
that about 30% of subjects eligible and willing to participate will be female.  Because of the 
genetic moderator analysis, in which European Americans (EAs) have a higher prevalence of 
the C allele of rs2832407 than other population groups in the Philadelphia area (e.g., African 
Americans), we will limit study participation to self-identified EAs.  Because we will be enrolling 
individuals as young as 18 years old, and recruiting on college campuses where there are 
substantial rates of heavy drinking, children will be included in the study sample. 
 
Subject recruitment at the CMCVAMC site will be focused on patients identified in the primary 
care settings. The BHL conducts clinical assessments on all patients referred from primary care.  
At the completion of the clinical assessment, all patients potentially eligible for this IRB- 
approved and MIRECC-approved project will be informed of the project and asked if they may 
be contacted by appropriate study personnel to discuss the study in accordance with the 
protocol. Additionally, the study will seek referrals from the Mental Health Clinic (MHC) and 
Addictions Recovery Unit (ARU) at the CMCVAMC.  The PI and study staff will meet with the 
BHL, MHC, and ARU providers to explain the goals of the research study and ask for assistance 
with patient referrals. An investigator and study staff will have ongoing in-service meetings with 
the providers to facilitate engagement in the recruitment process.  Recruitment flyers and 
informational brochures will be available for potential participants in the Primary Care Clinic, 
MHC, and ARU  
 
Subjects who are referred or who express interest by responding to recruitment flyers will be 
contacted by phone to participate in a telephone screening interview. We will describe the 
nature of the study, including the number of visits, subject protections and confidentiality. If the 
caller is interested in participating, we will obtain verbal consent to perform a phone screening 
interview. As part of the verbal consent process, callers will be told that if they are ineligible to 
participate in the study, the only information collected during the interview that will be retained 
is their name, phone number, and the reason that they were deemed ineligible. They will not be 
told why they were excluded. Only individuals who give verbal consent will be asked to 
complete the phone screen interview.  If we determine the applicant to be eligible based on this 
screening, s/he will be asked whether s/he is interested in participating.  If the caller is still 
interested, s/he will be scheduled for an initial informed consent and screening visit. The 
information collected during the phone interview will be retained only if the subject is eligible to 
participate and signs a study ICF at the screening visit. The phone interview will be stored in 
the research record once the participant has signed the ICF. We will maintain a log of subjects 
contacted, which will include their name, phone number, date of call, study status, eligible or 
not eligible, and, for those excluded, the reason the participant was not eligible to ensure that 
we don’t call the same person multiple times.    
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 who withdraw consent will be withdrawn from the study and 
if applicable, referred for appropriate clinical care. Suicidal risks will be assessed using the MINI 
Suicidality section (B) at each study visit, and if rated equal to or greater than 9 (i.e., clinically 
significant suicidal ideation), the physician will be consulted to decide the appropriate clinical 
management. 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 


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sponsor 
discontinue all drinking. Any subject experiencing a serious adverse event felt to be related to 
study drug will be withdrawn from the study.  
4.4.2  Data Collection and Follow-up for Withdrawn Subjects 
For subjects that leave treatment prematurely, the study nurse or research coordinator will 
complete the Early Termination Form, indicating the subject’s level of functioning at termination.  
The form is used to identify the reasons for early termination (e.g., symptomatic failure, adverse 
effects) and other relevant circumstances. Additionally, 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.  We will invite subjects to return to the clinic for 
assessment at the time of their discontinuation from treatment and again at the scheduled end 
of treatment, as well as all post-treatment follow-up visits.  The following efforts will be made to 
contact subjects who discontinue treatment prior to the twelfth week: 2 telephone calls by the 
research coordinator or technician resulting in contact (either with the subject or by leaving a 
message on voicemail or a person answering the subject’s telephone, followed by 2 telephone 
calls by a study physician, followed by a letter.  Only if all of these efforts are unsuccessful in 
obtaining follow-up information (either during an in-person visit or a telephone interview), the 
subject will be considered to be lost to follow-up. 
5 Study Drug  
5.1  Description 
Topiramate is an anticonvulsant medication for oral administration approved in the United 
States for the treatment of seizures, the prevention of migraine headache, and for weight loss 
(in combination with phentermine). The molecular formula of this sulfate-substituted 
monosaccharide is C12H21NO8S and the molecular weight is 339.35. It is designated 
chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate. According to the FDA-
approved labeling, topiramate has been found to be safe at doses of 200 mg and 400 mg per 
day in adults.  For more detailed information, see section 1.2 (Investigational Agent). 
5.2  Treatment Regimen 
The maximal dosage of topiramate in this study will be 200 mg/day orally in two divided doses, 
based on prior evidence of the efficacy and greater tolerability of this dosage (Kranzler, Covault 
et al. 2014). Although a 300-mg dosage of topiramate has been used most commonly to treat 
AD, we will use a lower dosage to reduce adverse effects. We will use a six-week titration 
period (see Table 1 below), which we found in our completed topiramate study to be well 
tolerated. We will reduce the dosage of topiramate by one-half for anyone with a creatinine 
clearance <70 mL/min/1.73 m2.   
Table 1. Topiramate or Placebo Dose Titration/Taper Schedule 
 
Medication 
Dispensed 
Morning Dose 
Evening Dose 
Total Daily Dose 
Screening Visit  
Week 0 
No medication 
No medication 
0 mg 
Visit 1 Baseline 
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  
Weeks 6 and 7 
100 mg 
100 mg 
200 mg 
Visit 7 
Weeks 8 and 9 
100 mg 
100 mg 
200 mg 
Visit 8 
Weeks 10 and 11 
100 mg 
100 mg 
200 mg 


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Visit 9  
Week 12 and            
6- day Taper 
 
100 mg 
100 mg 
200 mg 
Reduce dose by 50 mg every 2 days over 6 days: 150 mg for 
2 days, 100 mg for 2 days, 50 mg for 2 days, then D/C 
Visit 10  
Week 14 
No medication 
No medication 
0 mg 
Visit 11 (3-Month 
Follow-up) 
Week 24 
No medication 
No medication 
0 mg 
Visit 12 (6-Month 
Follow-up) 
Week 36 
No medication 
No medication 
0 mg 
The dosage of medication will be increased only as tolerated and subjects experiencing 
intolerable adverse effects will have their dosage decreased gradually to the highest tolerated 
dosage, which will be determined by the study physician.  Upward titration following a dose 
reduction will be allowed at the discretion of the study physician during the trial. Dose titration 
will be carefully documented in the study chart along with the clinical rationale.  The study 
nurse, in consultation with the study physician, will provide guidance for subjects as they 
increase their medication dosage, per the titration schedule (Table 1 in section 5.2). At the end 
of the 12-week treatment period, subjects will be titrated off study medication over a period of 6 
days (i.e., 150 mg/day for 2 days, 100 mg/day for 2 days, and 50 mg/day for 2 days). The 
titration schedule for subjects on a reduced dosage (less than 200 mg/day of topiramate or 
placebo equivalent) will be determined by the study physician 
5.3  Method for Assigning Subjects to Treatment Groups 
Subjects will be randomly assigned to one of two treatment conditions using a block 
randomization scheme: topiramate 200 mg/day (n = 100) or placebo (n = 100).  A designated 
randomization staff member who is not otherwise involved in the conduct of the study will work 
with the Investigational Drug Service (IDS) staff to implement the randomization.  The process 
for randomization is: 1) a study coordinator will complete a “block randomization form,” which 
includes the variables to be entered into the block randomization program [i.e., sex, genotype 
(i.e., C-allele homozygote vs A-allele carrier), number of heavy drinking days in the past month 
(trichotomized)]; 2) the randomization staff member will enter the variables into the block 
randomization program; 3) the randomization staff member will fax the 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 the subject and complete and sign 
the IDS prescription form included in the starter kit; 5) the research coordinator will fax the 
completed form to IDS.  
 
Study drug for subsequent visits will be ordered by the research coordinator using the 
“Research Pharmacy Schedule” form (following the schedule in Table 1), a copy of which will be 
retained in the subject’s research file.  At each visit, the research nurse will dispense a supply of 
study medication. In the event that scheduled visits change or the subject’s dosage is adjusted 
by the study physician, medication will be mailed via a UPS or Fedex to the subject, to ensure 
that they have enough medication to get them to their next scheduled visit. The study physician 
will approve all medication mailed to subjects and the study nurse or physician will document 
the medication dispensed via mail and call to ensure and instruct the patient on how the 
medication should be taken and to document all AEs. Study staff will also document whether the 
mailed medication was received by the subject.  
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.   


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5.4  Preparation and Administration of Study Drug 
Topiramate will be purchased commercially and formulated by the IDS in opaque capsules.  
Placebo capsules will be formulated to match the active medication, so that inspection of the 
capsules cannot allow them to be differentiated. The IDS will be responsible for blinding study 
medication according to the protocol outlined by the study statistician. The UPenn IDS will 
supply medication to both the UPenn and CMCVAMC study sites.   
5.5  Subject Compliance Monitoring and Enhancement 
We will use three methods to monitor medication adherence:  
1) IVR technology. At home, subjects will use IVR daily to report their medication use. 
2) Pill counts. We will ask subjects to return any unused medication at each visit, conduct pill 
counts and record medication taken. 
3) Medical Management. Subjects in both medication groups will receive Medical Management 
(MM; section 6.8.2 below). MM supports the subject’s efforts to reduce his/her drinking and 
improve medication adherence, with the study nurse making direct recommendations for 
positive behavior changes. 
 
5.6  Prior and Concomitant Therapy 
Individuals who have completed prior alcohol treatment studies and meet study criteria will 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 a treatment program for alcohol use disorders may not participate. Self-help group 
participation will not be disqualifying and attendance will be monitored to provide a measure of 
participation.  Concomitant treatment with a psychotropic medication or a medication to treat AD 
is not permitted during the 12-week course of the study. See exclusion criteria, section 4.2. 
5.7  Packaging 
The UPenn Investigational Drug Service (IDS) will package bulk drug on-site.  The child-safe 
prescription bottles will contain 8 days of medication. Subjects will be provided with an extra day 
of medication to ensure that they 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 decision to break the study blind is determined at the end of the study 
(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. 
5.9  Receiving, Storage, Dispensing and Return 
5.9.1    Receipt of Drug Supplies 
There is no industry sponsor for this study. The UPenn IDS will compound the study medication 
using commercially available product. IDS will periodically dispense coded, blinded study drug 
kits to the research coordinator for both the UPenn and CMCVAMC sites. IDS will supply the 
study drug kits coded in such a way that the UPenn site study medication can be easily 


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distinguished from the CMCVAMC site study medication. The study medication will be stored at 
the TRC medication storage room, which is temperature controlled and monitored daily for 
temperature excursions. The room is locked and the medication will be stored in a locked file 
cabinet that only study staff will have access to.  The research coordinator will maintain 100% 
drug accountability at the clinic for the duration of the study. The research coordinator will 
document all medication using a drug accountability log to track the study medication from time 
it leaves IDS to the time it is returned to IDS for reconciliation and disposal. For the CMCVAMC 
site, the UPenn IDS will send a monthly report to the VA investigational pharmacy with a list of 
all subjects randomized to study medication. 
5.9.2   Storage 
Study drug will be stored at the IDS at controlled room temperature (59-86 degrees F). Study 
drug kits dispensed from the pharmacy to the clinic will be stored in a locked cabinet under 
control room temperature until dispensed. Any returned study medication will also be kept under 
locked condition until returned to the pharmacy for disposal. 
5.9.3   Dispensing of Study Drug 
The study nurse and study coordinator will maintain a dispensing record, documenting the 
amount of medication dispensed to the subject, the amount returned, and the amount taken. 
The dispensing record will also document the amount of study drug returned to the pharmacy 
and the date returned.  
5.9.4  Return or Destruction of Study Drug 
A final reconciliation of all remaining study medication will be made at the end of the study. All 
unused kits and medications dispensed and later returned by the subjects will be returned to the 
IDS. The IDS will be responsible for the disposal/destruction of all unused study medication. 
The study coordinator will return each subject’s unused study medication and empty medication 
bottles to IDS for reconciliation as each subject completes the treatment phase of the study. All 
attempts will be made to collect the study medication and bottles from subjects at the end of the 
study and during follow-up sessions as needed. 
6.1  Initial Telephone Screen (approximately 20 minutes)  
Subjects will be recruited through local advertisements. Subjects who express interest by 
responding to advertising will be contacted by phone to participate in a telephone screening 
interview. We will describe the nature of the study, including the number of visits to the center, 
subject protections and confidentiality. If the caller is still interested, we will obtain verbal 
consent for the phone screening. Screening questions cover general health, psychiatric history 
and alcohol consumption. If we determine the applicant eligible based on this screening, s/he 
will be asked whether they accept or decline to participate.  If the caller is still interested, s/he 
will be scheduled for an initial consenting appointment.  
 
6.2  Informed Consent and Screening Visit (Week 0) 
Upon arriving to the Informed Consent and Screening Visit, which will be conducted at the 
Treatment Research Center at 3535 Market Street, Philadelphia, PA, subjects will be asked to 
show legal photo identification and undergo a breathalyzer test to ensure a breath alcohol 
concentration (BrAC) of 0.00% to ensure that the subject is able to provide informed consent. 
Reading ability will be evaluated (Slosson Oral Reading Test-Revised (SORT-R; Shaw, 1998) to 
verify reading ability at an eighth grade level and the capacity to understand the informed 
consent form.  Subjects will then be given the informed consent form to read, which a study staff 


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member will review with the subject, providing an explanation of the study protocol, its risks, 
potential benefits, and alternative treatments. Following resolution of any questions, subjects will 
be asked to sign the study informed consent form.  An entire copy of the informed consent form 
will be given to the subject, who will be reminded that the consent addresses his or her 
willingness to participate but that the subsequent screening process will determine his or her 
eligibility to do so. Further, the subject will be reminded that participation is voluntary, and at any 
time, he or she may withdraw from the study.  
The subject will then meet with the study nurse who will obtain a medical history, conduct a 
physical examination, and obtain weight and vital signs (blood pressure and heart rate). 
Baseline laboratory measures will include:  
 
CBC 
 
Blood chemistries (i.e., standard blood work and lipids) 
 
Serum bicarbonate (which can be reduced by topiramate) 
 
GGTP (to assess the validity of self-reported drinking) 
 
%dCDT (to assess the validity of self-reported drinking) 
   DNA extraction (followed by immediate genotyping) 
 
Urinalysis  
 
Urine toxicology (presence of psychoactive drugs) 
 
Urine pregnancy test for women of childbearing potential 
 
Oral HIV test (only if agreeable and otherwise eligible to participate in the MRI sub-
study) 
 
A total of approximately 3 tablespoons of blood will be drawn by study staff trained in 
phlebotomy.  A portion (approximately 1.75 tablespoons) of this blood sample will be used to 
extract DNA for genotyping.  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


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6  Study Procedures 
Table 2. Schedule of Study Assessments and Procedures 
Assessment or Procedure 
Visit 0 
Screen 
Wk 0 
 
Visit 1 
Baseline 
Wk 1 
Visits 
2-5     
Wks 2-5 
Visit 6 
Wk 6 
 
Visits 7 & 8 
Wks 8 & 10 
 
Visit 9  
(Wk 12) & 
Taper 
Visit 10 
Endpoint
Wk 13  
Visits 11&12 
Follow-up 
Wks 24 & 36 
ALL VISITS 
 
Breathalyzer, weight & vitals 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
SCREENING 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
Med Hx & Physical Exam  
X 
 
 
 
 
 
 
 
 
 
 
LABORATORY TESTS 
 
Chemistry Panel, CBC, DNA 
X 
 
 
 
 
 
 
 
 
 
GGTP, %dCDT 
X 
 
 
 
X 
 
 
 
X 
X 
Bicarbonate 
X 
 
 
 
X 
 
 
 
 
 
Urinalysis & urine toxicology 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for 
women of childbearing 
potential 
X 
 
X 
X (Visit 5 
only) 
 
 
X (Visit 7 
only) 
X 
 
 
ASSESSMENTS 
 
SORT 
X 
 
 
 
 
 
 
 
 
 
Demographic Interview 
X 
 
 
 
 
 
 
 
 
 
Locator information                  
X 
 
 
 
 
 
 
 
 
 
SCID (with DSM-5 AUD) 
X 
 
 
 
 
 
 
 
 
 
SCID (only DSM-5 AUD) 
 
 
 
 
 
 
 
 
X 
X 
FHAM 
X 
 
 
 
 
 
 
 
 
 
TLFB 
X 
 
X 
X  
X  
 
X  
X 
X 
X 
SIP  
 
 
X 
 
 
 
 
 
X 
X 
PHQ-9 
 
 
X 
X 
X 
 
X 
X 
X 
X 
Digit Span 
X 
 
 
 
 
 
 
 
X 
X 
FTND 
X 
 
 
 
 
 
 
 
X 
X 
COWA 
X 
 
 
 
 
 
 
 
X 
X 
SF-12 
 
 
X 
 
 
 
 
 
X 
X 
MINI 6.0 (Section B only)  
X 
 
X 
X 
X 
 
X 
X 
X 
X 
CIWA-AR 
X 
 
X 
X 
X 
 
X 
X 
X 
 
AUQ 
 
 
X 
 
 
 
 
 
X 
X 
CSM 
 
 
X 
 
 
 
 
 
 
 
ISI 
 
 
X 
X 
X 
 
X 
X 
X 
X 
GGTP=gamma-glutamyltranspeptidase, %dCDT=% disialotransferrin, SORT= Slosson Oral Reading Test, SCID=Structured Clinical Interview for DSM-IV, AUD=Alcohol Use Disorder, 
FHAM=Family History Assessment Module, TLFB=Timeline Follow-back Interview, SIP=Short Index of Problems, PHQ-9=Patient’s Health Questionnaire, FTND=Fagerstrom Test for Nicotine 
Dependence, COWA= Controlled Oral Word Association Test, SF-12=Short Form Health Survey, MINI=Mini International Neuropsychiatric Interview, CIWA-Ar=Clinical Institute Withdrawal 
Assessment for Alcohol-revised, AUQ=Alcohol Urge Questionnaire, CSM= Composite Scale of Morningness, ISI=Insomnia Severity Index, **Performed only if sub-study visit is not done on 
same day as main study visit, when these assessments are routinely done. 


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Assessment or Procedure 
Visit 0 
Screen 
Wk 0 
 
Visit 1 
Baseline 
Wk 1 
Visits 2-5  
Wks 2 
through 5  
Visit 6  
 Wk 6 
 
Visits 7 & 8 
Wks 8 & 10 
 
Visit 9 
(Wk 12) & 
taper  
Visit 10 
Endpoint 
Wk 13  
Visits 11&12 
Follow-up 
Wks 24 & 36 
CLINICAL TREATMENT 
Dispense Study Medication 
 
 
X 
X 
X 
 
X 
X 
 
 
Return Study Medication 
 
 
 
X 
X 
 
X 
X 
X 
 
Adverse Events Checklist 
 
 
X 
X 
X 
 
X 
X 
X 
X 
Measures of Treatment 
Received 
 
 
X 
X 
X 
 
X 
X 
X 
X 
Medical Management 
 
 
X 
X 
X 
 
X 
X 
X 
 
IVR Reports/Daily Diary 
 
 
X 
X 
X 
 
X 
X 
 
 
Medication Questionnaire  
 
 
 
 
 
 
 
 
X 
 
Early Termination Form*** 
 
 
 
 
 
 
 
 
 
 
 
MRI SUB-STUDY ONLY  
(Visits or tests will only be completed only for subjects enrolled in the sub-study.) 
 
Sub-study 
Screening 
Visit 
Scan 1 
 
 
 
Scan 2 
 
 
 
 
Breathalyzer 
X** 
X** 
 
 
 
X** 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Urine toxicology 
X** 
X 
 
 
 
X 
 
 
 
 
Urine pregnancy 
X** 
X** 
 
 
 
X 
 
 
 
 
Rapid HIV test (Oral) 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
Blood sample (Hormone 
concentrations; women only) 
 
X 
 
 
 
X 
 
 
 
 
CIWA 
 
X** 
 
 
 
X** 
 
 
 
 
AUQ 
 
X 
 
 
 
X 
 
 
 
 
WASI 
X 
 
 
 
 
 
 
 
 
 
MCQ 
X 
 
 
 
 
 
 
 
 
 
MRI Scan 
 
X 
 
 
 
X 
 
 
 
 
MRI video 
X 
 
 
 
 
 
 
 
 
 
MRI Safety Sheet (Metal) 
X 
X 
 
 
 
X 
 
 
 
 
Within-session rating scale 
 
X 
 
 
 
X 
 
 
 
 
CogBias Tasks 
 
X 
 
 
 
X 
 
 
 
 
CogState Battery 
X 
X 
 
 
 
X 
 
 
 
 
IVR=interactive Voice Response, HIV=human immunodeficiency virus, WASI= Wechsler Abbreviated Scale of Intelligence; MCQ=Menstrual Cycle Questionnarie; 
MRI=magnetic resonance imaging  ***Performed only if subject discontinues treatment prematurely 
 


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repeat the test(s).  For subjects who are otherwise eligible and interested in participating in 
the MRI sub-study, an oral HIV test will be administered.  If the oral HIV test is positive, the 
nurse will inform the subject of the results, counsel the subject regarding the need to confirm 
the finding with a blood test and to avoid potential exposure of others to HIV, and draw an 
additional tablespoon (i.e., a total of 4 tablespoons) of blood to conduct a confirmatory HIV 
blood test. If the blood test is positive for HIV, the subject will be referred for medical care 
and given a copy of the test to provide to the doctor for the follow-up visit. 
Study staff with complete the following assessments with subjects: 
 
Sociodemographic/general subject information: An assessment of medical history, 
personal and family history of alcoholism, marital status, educational and occupational 
information and substance abuse treatment history will be obtained, along with the 
individual’s self-identified ancestry.  
 
Slosson Oral Reading Test: A standardized assessment used to determine reading 
level.  
 
Locator information:  The research coordinator will select subject locators on the basis of 
relationship to the subject, duration and current status of relationship, frequency of 
contact with the subject, and willingness to participate. Locators are contacted when 
efforts to reach a subject are unsuccessful, which enhances retention of subjects in 
treatment and data collection. 
 
The Structured Clinical Interview for DSM-4 (SCID) will be used to classify subjects 
according to the presence or absence of standard psychiatric disorders according to 
DSM-criteria. The alcohol use disorder criteria will be modified to permit a DSM-5 
diagnosis as well. 
 
The International Neuropsychiatric Interview 6.0 (Mini 6): Suicidal risk will be assessed 
using the MINI Suicidality section (B) at each study visit and, if rated greater or equal to 
9 (i.e., clinically significant suicidal ideation), the physician will be consulted to decide on 
the appropriate clinical management. 
 
The Family History Assessment Module (Rice, Reich et al. 1995) systematically queries 
the subject about the presence of an alcohol use disorder (AUD) in relatives.  The 
subject will provide information concerning parents’ and siblings’ history of alcohol use 
without their being identified.   
 
The Timeline Follow-back (TLFB) (Sobell and Sobell 1992) will be used to estimate past 
90-day drinking at intake and at every treatment visit going back in time from the last 
assessment.  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.  However, it is less useful than 
daily measures for detecting patterns of alcohol consumption that vary on a day-to-day 
basis (Carney, Tennen et al. 1998; Searles, Helzer et al. 2000).   
 
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 (Ruff, Light et al. 1996). This measure will be used to 
examine the effects of topiramate on verbal fluency. 
 
Wechsler Adult Intelligence Scale-Third Edition Digit Span subtest (Wechsler 1997) will 
be used to assess verbal working memory and explore the potential effects of topiramate 
on verbal working memory. 


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 
Fagerstrom Test for Nicotine Dependence (FTND) (Fagerstrom and Schneider 1989) is 
a 6-item, self-report measure of nicotine dependence derived from the Fagerstrom 
Tolerance Questionnaire.   
 
The Clinical Institute Withdrawal Assessment for Alcohol Scale–revised (CIWA-Ar) 
(Sullivan, Sykora et al. 1989) is a  10-item scale for clinical quantification of the severity 
of alcohol withdrawal. 
6.3  Visit 1 (Week 1; Baseline and First Treatment Visits) 
Subjects will be informed of their eligibility status within 5 days and scheduled for a baseline 
assessment within 30 days of the screening visit. All subjects not eligible for the study will be 
referred to the appropriate treatment center or other research study. Eligible subjects will 
undergo a baseline research evaluation (lasting up to 2 hours) within 30 days of completing the 
screening visit. 
Subjects will be asked to complete a breathalyzer test.  If a subject’s breath alcohol 
concentration is > 0.02%, an investigator will evaluate whether the subject is too impaired to 
complete the study assessments. The study visit may be completed at the discretion of the 
investigator.  If the subject is deemed to be unable to complete assessments, the investigator 
may ask the subject to wait until his or her blood alcohol level decreases or if that is not feasible 
to return the next day after having consumed no alcohol.  Prior to discharge from the TRC, a 
clinician will assess the subject to ensure that it is safe for the subject to leave. Study staff will 
complete the following assessments with all subjects (the exception being that only for women 
of childbearing potential, will study staff obtain a urine sample for a pregnancy test).  
 
The Patient Health Questionnaire (PHQ-9), a validated 9-item self-report measure of 
depressive symptoms that yields a total score of 0-27 (Kroenke, Spitzer et al. 2001), will be 
administered at each visit. 
 
The International Neuropsychiatric Interview 6.0 (Mini 6): Suicidal risk will be assessed 
using the MINI Suicidality section (B) at each study visit and, if rated greater or equal to 9 
(i.e., clinically significant suicidal ideation), the physician will be consulted to decide on the 
appropriate clinical management. 
 
Daily Interactive Voice Response (IVR) Telephone Call (daily for 12 weeks, beginning 
with the initiation of treatment) 
a. Drinking diary:  Every evening, as part of the daily IVR diary report, subjects will 
record their alcohol consumption by reporting the number of standard drinks of 
beer, wine, liquor and "other" category.  The daily assessment will also include 
the number of cigarettes smoked that day.  To capture all drinking during the 
preceding 24-hour period, subjects are asked to report separately drinking from 
yesterday (in total), and any drinking during the current day, up until the time of 
the IVR report.  This will allow us to examine lagged associations (Kranzler, 
Armeli et al. 2013)  The time of the calls (5-8 PM) was chosen to minimize the 
potential for subjects to have begun drinking heavily prior to making the calls.  
Subjects are taught to complete the telephone interview, which requires less than 
5 minutes/day.  Daily measures of alcohol consumption obtained via IVR will 
enable us to examine co-variation of alcohol-related subjective reports and 
drinking behavior to test for moderator effects. 
b. Daily medication usage: Subjects will use Interactive Voice Response (IVR) daily 
to report whether they took their medication as prescribed.  We previously found 
that subjects used the IVR system to report their use of medication that day, 


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which correlates highly (r=0.91) with electronic monitoring (i.e., MEMS cap) 
(Feinn, Tennen et al. 2003). 
c. Subjective Reports 
i. Daily mood:  Patients will be asked to rate their overall mood daily during 
the 12 weeks of active treatment using an adjective checklist.  The 
checklist consists of 4 mood adjectives, each of which will be rated on a 
5-point scale (0 = "not at all" to 4 = "extremely").  The items will measure 
unpleasant (sad, angry, nervous) and pleasant (happy) mood.   
ii. Expectancies of the effects of alcohol: These will include 4 items 
assessing anticipated positive (n=3) and negative (n=1) outcomes for 
drinking later that day. The positive expectancy items, adapted from 
existing expectancy scales (Rohsenow 1983; Fromme, Stroot et al. 1993; 
Leigh and Stacy 1993), correspond to the commonly identified 
expectancy domains of general pleasure, tension reduction, and social 
expressiveness. Specifically, subjects will be asked “If you were to drink 
tonight how likely is it that you” (a) “would have a good time?”, (b) “would 
feel less tense/more relaxed?”, and (c) would be more outgoing/friendly? 
The negative expectancy item will be “would you get sick or have a 
hangover later?”  Responses will be made on a 5-point.   
iii. Thoughts about drinking: Based on anecdotal reports by subjects that 
topiramate substantially reduced the extent to which they thought about 
drinking (which they differentiated from desire to drink), they will be asked 
to rate this measure daily on a 5-point scale.   
iv. Self-efficacy:  We will measure both confidence to avoid drinking and 
confidence to resist heavy drinking on a 5-point scale. 
v. Desire to drink:  We will measure desire to drink using three items from 
the Alcohol Urge Questionnaire (Bohn, Krahn et al. 1995), which will be 
rated on a 5-point scale 
vi. Experience of an alcohol-induced blackout:  We will ascertain whether the 
subject experienced an alcohol-induced blackout using the following 
yes/no questions: (a) “Since your last call, after or while you were drinking 
alcohol, did you experience a period of time that you could not remember 
things you said or did? (b) (Follow-up question if the person responds 
yes): “When you experienced difficulty remembering something you said 
or did while drinking, did you later remember when given cues or 
reminders about it?” 
 
Medication Adverse Effects Checklist:  Subjects will be interviewed by the study nurse 
and asked to report adverse effects at each study visit using a checklist of adverse 
medication effects derived from completed studies of topiramate for alcohol treatment. This 
method worked well in our completed trial using the 200-mg/day dosage (Kranzler, Covault 
et al. 2014). 
 
Measures of treatment received:  Records of medication taken will be kept and subjects 
will be asked to return the unused portion of study medication at each visit.  The nurse will 
also record the number of contact hours subjects have been exposed to any alcohol 
treatment outside of the study. 
 
The Short Index of Problems (SIP). The SIP, a 15-item instrument subset of the 50-item 
DrInC (Miller, 1995), measures alcohol dependence symptoms and medical, psychological, 


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social, occupational, and legal problems.  This shorter questionnaire reduces respondent 
burden (Feinn, Tennen et al., 2003b). 
 
The RAND 12-Item Health Survey (SF-12) (Ware Jr, Kosinski et al. 1996), a self-report 
measure of life functioning in various domains, will be completed at study baseline and 
endpoint. We will focus on the mental health component of the SF-12. 
 
Alcohol Urge Questionnaire (AUQ) (Bohn, Krahn et al. 1995) 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 to 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. 
 
The Clinical Institute Withdrawal Assessment for Alcohol Scale–revised (CIWA-Ar) 
(Sullivan, Sykora et al. 1989) is a  10-item scale for clinical quantification of the severity of 
alcohol withdrawal. 
 
Composite Scale of Morningness (CSM) is a 13-item survey that assesses whether the 
participant is most alert in the morning or later in the day, e.g. an “owl” or a “lark.” (Smith, 
Reilly  et al. 1989)  
 
Insomnia Severity Index (ISI) is a five-item questionnaire that assesses the quality of 
sleep and its effect on activities of daily living. (Bastien, Vallieres et al. 2001) 
Study staff will train subjects to use the IVR phone system. Subjects will be instructed on when 
to call in each day and how to use the phone system to complete the daily assessment. They 
will receive a written copy of the directions with all of the questions and responses. Study staff 
will program subjects’ study identification number into the IVR phone system after they have 
been randomized to study medication.  
Subjects will receive the first counseling session and study medication (topiramate or placebo) 
during the first treatment session scheduled on the same day as the baseline assessment 
(after all assessments have been completed). At this visit, the subject will also meet with the 
physician. At this (and every) visit, the study nurse experienced in the use of Medical 
Management in alcohol pharmacotherapy trials will use the method to counsel the subject.  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 stop or reduce their drinking, 
with the study nurse making direct recommendations for reducing drinking to sensible levels.   
The first counseling session (which will last approximately 30 minutes) will consist of a review of 
the results of the initial evaluation, identifying any concerns the subject may have.  The subject 
is then provided with a rationale and information about pharmacotherapy and the importance of 
adherence.  Subsequent treatment sessions (approximately 20 minutes) will be conducted at 
each treatment visit.  During these sessions, the study nurse will obtain the subjects’ vital signs 
and weight, ask about medication side effects and concurrent medications, perform a brief 
assessment of the subjects’ drinking and medication adherence, and in some cases, make 
recommendations on strategies for the subject to follow until the next visit.  Men will be advised 
to consume no more than 3 standard drinks per day and 12 standard drinks per week and 
women will be advised to consume no more than 2 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. 


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The physician will meet with the subject at the beginning of treatment and discuss clinical 
management with the study staff weekly.  The physician will evaluate the subject for any severe 
or persistent adverse effects. 
6.4  Visits 2-8 (Weeks 2-11; Treatment Visits) 
At each visit, the study nurse will dispense study medications as shown in Table 1. In the event 
that scheduled visits change or the subject’s dosage is adjusted by the study physician, 
medication will be mailed via a UPS or Fedex to the subject, to ensure that they have enough 
medication to get them to their next scheduled visit. The study physician will approve all 
medication mailed to subjects and the study nurse or physician will document the medication 
dispensed via mail and call to instruct the subject on how the medication should be taken and to 
document all AEs. Study staff will also document whether the mailed medication was received 
by the subject.  
The dosage of medication will be increased only as tolerated and subjects experiencing 
intolerable adverse effects will have their dosage decreased gradually to the highest tolerated 
dosage, which will be determined by the study physician.  Upward titration following a dose 
reduction will be allowed during the trial to minimize adverse effects while maximizing potential 
efficacy. Dose titration will be carefully documented in the study chart along with the clinical 
rationale.  The study nurse, in consultation with the study physician, will provide guidance for 
subjects as they increase their medication dosage, per the titration schedule. Subjects will be 
given study medication consisting of topiramate or matching placebo and titrated up to a 
maximum of 200 mg/day of topiramate or the placebo equivalent (see Table 1).       
During the 12-week treatment period, subjects will return to the clinic weekly (+/- 4 days) for the 
first 6 weeks and every other week (+/- 4 days) for weeks 7-12.  At each visit, the subject's 
BrAC, weight, and vital signs will be measured. Subjects will be asked not to drink before 
coming to the scheduled visits. Subjects will be asked to complete a breathalyzer test.  If a 
subject’s breath alcohol concentration is > 0.02%, an investigator will evaluate whether the 
subject is too impaired to complete the study assessments. The study visit may be completed at 
the discretion of the investigator.  If the subject is deemed to be unable to complete 
assessments, the investigator may ask the subject to wait until his or her blood alcohol level 
decreases or if that is not feasible to return the next day after having consumed no alcohol.  
Prior to discharge from the TRC, a clinician will assess the subject to ensure that it is safe for 
the subject to leave. Study staff will complete the following assessments with all subjects (the 
exception being that only for women of childbearing potential, will study staff obtain a urine 
sample for a pregnancy test).   
Subjects who are deemed suitable for assessment will complete questionnaires and be 
interviewed by the study nurse about their concomitant medications, adverse events, and 
protocol compliance.  At every treatment visit (i.e., for a total of 10 sessions), the study nurse 
will deliver the MM intervention.  Study staff will also administer the following assessments, as 
described above: 
 
The Timeline Follow-back (TLFB): To collect data on daily drinking, cigarette use, and 
medication taken.   
 
The Patient Health Questionnaire (PHQ-9): To measure depressive symptoms. 
 
The International Neuropsychiatric Interview 6.0 (Mini 6): Suicidal risk will be assessed 
using the MINI Suicidality section (B) at each study visit and, if rated greater or equal to 9 
(i.e., clinically significant suicidal ideation), the physician will be consulted to decide on the 
appropriate clinical management.   


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 
The Clinical Institute Withdrawal Assessment for Alcohol Scale–revised (CIWA-Ar) 
(Sullivan, Sykora et al. 1989) is a  10-item scale for clinical quantification of the severity 
of alcohol withdrawal. 
 
Medication Adverse Effects Checklist 
 
Measures of treatment received 
 
Daily Interactive Voice Response Telephone Call (daily for 12 weeks, beginning with the 
initiation of treatment) 
 
ISI 
Also, at the week six visit, the study staff will obtain a blood sample to measure bicarbonate 
levels, as topiramate can cause metabolic acidosis, and GGTP and %dCDT concentrations to 
corroborate self-reported alcohol consumption. At visits 5 (week 5) and 7 (week 8), study staff 
will obtain a urine sample for a pregnancy test for subjects who are women of childbearing 
potential. If a subject reports being pregnant or tests positive, she will immediately be withdrawn 
from treatment with study medication, referred for obstetric evaluation, and advised to 
discontinue all drinking. 
6.4.1 Visit 9 (Week 12 and taper) 
The study nurse will dispense study medications as shown in Table 1. At this visit (+/- 4 days), 
the subject will receive 1 more week of 100 mg BID (enough study medication to complete a 
total of 84 days on study medication) and the 6-day study medication taper (to reduce the dose 
by 50 mg every 2 days over 6 days: 150 mg for 2 days, 100 mg for 2 days, 50 mg for 2 days, 
then discontinue it). In the event that scheduled visits change or the subject’s dosage is 
adjusted by the study physician, medication will be mailed via a UPS or Fedex to the subject, to 
ensure that they have enough medication to get them to their next scheduled visit. The study 
physician will approve all medication mailed to subjects and the study nurse or physician will 
document the medication dispensed via mail and call to instruct the subject on how the 
medication should be taken and to document all AEs. Study staff will also document whether 
mailed medication was received by the subject. 
 
At this visit, the subject's BrAC, weight, and vital signs will be measured. Subjects will be asked 
not to drink before coming to the scheduled visits. Subjects will be asked to complete a 
breathalyzer test.  If a subject’s breath alcohol concentration is > 0.02%, an investigator will 
evaluate whether the subject is too impaired to complete the study assessments. The study visit 
may be completed at the discretion of the investigator.  If the subject is deemed to be unable to 
complete assessments, the investigator may ask the subject to wait until his or her blood alcohol 
level decreases or if that is not feasible to return the next day after having consumed no alcohol.  
Prior to discharge from the TRC, a clinician will assess the subject to ensure that it is safe for 
the subject to leave. Study staff will complete the following assessments with all subjects (the 
exception being that only for women of childbearing potential, will study staff obtain a urine 
sample for a pregnancy test).  Subjects who are deemed suitable for assessment will then 
complete questionnaires and be interviewed by the study nurse about their concomitant 
medications, adverse events, protocol compliance, and MM intervention. For women of 
childbearing potential, study staff will obtain a urine sample for a pregnancy test.  
 
Study staff will also administer the following assessments, as described above: 
 
The Timeline Follow-back (TLFB): To collect data on daily drinking, cigarette use, and 
medication taken.   


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 
The Patient Health Questionnaire (PHQ-9): To measure depressive symptoms. 
 
The International Neuropsychiatric Interview 6.0 (Mini 6): Suicidal risk will be assessed 
using the MINI Suicidality section (B) and, if rated greater or equal to 9 (i.e., clinically 
significant suicidal ideation), the physician will be consulted to decide on the appropriate 
clinical management.   
 
The Clinical Institute Withdrawal Assessment for Alcohol Scale–revised (CIWA-Ar) 
(Sullivan, Sykora et al. 1989) is a  10-item scale for clinical quantification of the severity 
of alcohol withdrawal. 
 
Medication Adverse Effects Checklist 
 
Measures of treatment received 
 
Daily Interactive Voice Response Telephone Call (daily for 12 weeks, beginning with the 
initiation of treatment) 
 
ISI 
 
6.5  Visit 10 (Week 13; Endpoint Visit) 
At the end of treatment, week 13 (+/- 4 days) we will repeat the research assessments and will 
query the subject as to his or her belief regarding their treatment condition using the Medication 
Questionnaire (MED-Q).  Blood samples for measurement of serum GGTP and %dCDT will be 
obtained to assess the validity of self-reported drinking. Subjects will be asked not to drink 
before coming to the scheduled visits. Subjects will be asked to complete a breathalyzer test.  If 
a subject’s breath alcohol concentration is > 0.02%, an investigator will evaluate whether the 
subject is too impaired to complete the study assessments. The study visit may be completed at 
the discretion of the investigator.  If the subject is deemed to be unable to complete 
assessments, the investigator may ask the subject to wait until his or her blood alcohol level 
decreases or if that is not feasible to return the next day after having consumed no alcohol.  
Prior to discharge from the TRC, a clinician will assess the subject to ensure that it is safe for 
the subject to leave. Study staff will complete the following assessments with all subjects (the 
exception being that only for women of childbearing potential, will study staff obtain a urine 
sample for a pregnancy test).  Subjects who are suitable for assessment will then complete 
questionnaires and be interviewed by the study nurse.  
All subjects will be asked to complete an end-of-treatment evaluation and to complete all 
scheduled assessments to facilitate intent-to-treat (ITT) analyses. All subjects will be informed 
of these procedures prior to study enrollment. Subjects will be compensated $50 for completing 
the end-of-treatment visit. Subjects who decide to terminate the study prior to visit 10 will also 
receive payment upon completion of the end-of-treatment procedures and 3- & 6-month follow-
up visits. For subjects 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.   
These subjects will also be asked to undergo in-person or telephone follow-up at the end-of-
treatment for collection of the remaining treatment-phase Timeline Follow-back data.  
If the subject cannot be reached by phone after three attempts, a final outreach letter will be 
mailed.  The study nurse and physician will follow continuing adverse events to their conclusion, 
as feasible.  Subjects requesting (or clearly needing) additional treatment for alcohol problems 
will be referred to local treatment centers.  
 


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 
Breathalyzer, weight, and vital signs 
 
Timeline Follow-back (TLFB) interview 
 
The International Neuropsychiatric Interview 6.0 (Mini 6): Suicidal risk will be assessed 
using the MINI Suicidality section (B) at each study visit and, if rated greater or equal to 9 
(i.e., clinically significant suicidal ideation), the physician will be consulted to decide on the 
appropriate clinical management. 
 
The Clinical Institute Withdrawal Assessment for Alcohol Scale–revised (CIWA-Ar)  
 
The Patient Health Questionnaire (PHQ-9) 
 
Word Association Test (COWA)  
 
Wechsler Adult Intelligence Scale-Third Edition Digit Span subtest  
 
Alcohol Urge Questionnaire (AUQ)  
 
Fagerstrom Test for Nicotine Dependence (FTND)  
 
Medical Management 
 
Medication Adverse Effects Checklist 
 
Measures of Treatment Received 
 
Medication Questionnaire (MED-Q)  
 
Short Index of Problems (SIP) 
 
RAND 12-Item Health Survey (SF-12) 
 
DSM-5 AUD Diagnosis (using the SCID for DSM-IV adapted for this purpose) 
 
Early Termination Form (for early withdrawal from the study) indicates the subject’s level 
of functioning at termination, and will be completed by the study staff or study nurse for 
any subjects that leave treatment prematurely.  The form is used to identify the reasons 
for early termination (e.g., symptomatic failure, adverse effects) and other relevant 
circumstances.   
 
ISI 
     6.6 Missed Visit 
Subjects will receive study medication from the study nurse or physician at each study visit. 
During the first 6 weeks they will receive 8 days of study medication, which is enough 
medication to get them to their next scheduled study visit, plus 1 extra day. Once the subject 
reaches the 200 mg daily dose, they will receive 16 days of study medication, which is enough 
to get them to their next scheduled study visit plus 2 extra days. The study coordinator will work 
with the study nurse to ensure that the treatment phase of the study is not extended beyond 12 
weeks. At visit 9, the study nurse will dispense the exact amount of study medication required 
for the subject to complete 84 days of study medication before starting the taper. These 
procedures will ensure that no subject is on study medication for more than 84 days before 
tapering off the study medication.  
If a subject anticipates missing a study visit (e.g., due to a vacation), the study nurse will provide 
the subject with enough study medication to ensure that the maintenance of the daily dosage of 
study medication until the next scheduled visit. In the event that study medication is not ready to 
be dispensed at the time of the study visit (e.g., nurse and/or physician determine at the time of 


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the study visit that the subject requires a reduced dosage), study staff will mail the study 
medication to the subject via UPS or Fedex, to ensure that they have enough medication to get 
them to their next scheduled visit. The study physician will approve all medication mailed to 
subjects and the study nurse or physician will document the medication dispensed via mail. The 
study nurse will call the subject to document that all mailed study medication was received by 
subjects, to provide instructions on how to take the study medication as per the dosing 
schedule, and to collect information on any AEs. Subjects will be instructed to call the Treatment 
Research Center (TRC) at any time to discuss problems or concerns they may have while 
participating in the study.  They will be provided phone numbers to contact the study staff during 
office hours and a pager number for off-hours contact. Subjects will be asked to come in for 
their next study visit as soon as possible.  
If a subject anticipates missing a study visit (e.g., due to vacation), the study staff and study 
nurse will attempt to schedule a day and time to conduct the study visit over the phone for 
safety monitoring and data collection purposes. Self-report assessments, completed by subjects 
at study visits, will be administered by study staff over the phone. Breathalyzer, weight, and vital 
signs will not be obtained for phone visits. Subjects will be compensated for completing phone 
visits at their next study visit.  If a subject is traveling out of the range of telephone access (e.g., 
internationally), he or she will be provided with paper copies of the daily IVR diary report to 
complete each evening instead of calling in to the system. The subject will be compensated for 
completing the IVR report on paper at their next study visit.  
If a subject calls to cancel a scheduled study visit due to an unforeseen event, the study visit will 
be rescheduled for as soon thereafter as possible. Study staff will mail study medication to the 
subject via UPS or Fedex, under the supervision of a study nurse to avoid having the subject 
run out of study medication. Subjects will be given only enough study medication to ensure that 
they maintain their daily dosage of study medication until their next scheduled visit. The 
physician or nurse will instruct the subject by phone regarding how to take the study medication 
per the dosing schedule and will 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 discuss any 
problems or concerns they may have while taking the study medication. Study staff will also 
document whether the mailed medication was received by the subject. Study staff will make 
efforts to reschedule missed study visits as soon as possible. The study physician will approve 
all medication mailed to subjects and determine how many additional weeks of study medication 
a subject will be allowed to receive without attending a study visit.  
 
6.8  Visits 11 and 12 (Weeks 24 and 36; Post-treatment Follow-up Visits) 
 
At the 3-month and 6-month follow-up visits, we will repeat the research assessment, 
focusing principally on alcohol consumption and alcohol-related problems over the 
preceding 12 weeks (or for individuals for whom data are missing, we will attempt to 
have them reconstruct their drinking history since the last assessment was completed).  
We will also obtain a blood sample for measurement of serum GGTP and %dCDT to 
assess the validity of self-reported drinking. 
 
Subjects will be asked not to drink before coming to the scheduled visits. Subjects will be 
asked to complete a breathalyzer test.  If a subject’s breath alcohol concentration is > 
0.02%, an investigator will evaluate whether the subject is too impaired to complete the 
study assessments. The study visit may be completed at the discretion of the 
investigator.  If the subject is deemed to be unable to complete assessments, the 
investigator may ask the subject to wait until his or her blood alcohol level decreases or 
if that is not feasible to return the next day after having consumed no alcohol.  Prior to 


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discharge from the TRC, a clinician will assess the subject to ensure that it is safe for the 
subject to leave. 
 
After the six-month follow-up visit, subjects who wish to learn whether they received 
treatment with topiramate or placebo will receive a “de-briefing letter” from IDS. Subjects 
will have the option to receive the “de-briefing letter” at the screening visit by initialing 
yes on the ICF. Study staff will provide IDS with an envelope that has the patient’s 
address along with the “de-briefing letter,” which notes the patient’s name and ID 
number. The pharmacy technician will complete the letter indicating the medication 
assignment, and mail it to the subject. Study staff (physicians, nurses, and coordinators) 
will remain blinded to study medication assignment.  
 
Breathalyzer, weight and vital signs 
 
Medication Adverse Effects Checklist (Follow-up with any unresolved AEs) 
 
Timeline Follow Back (TLFB) 
 
The International Neuropsychiatric Interview 6.0 (Mini 6): Suicidal risk will be assessed 
using the MINI Suicidality section (B) at each study visit and, if rated greater or equal to 9 
(i.e., clinically significant suicidal ideation), the physician will be consulted to decide on the 
appropriate clinical management. 
 
Word Association Test (COWA)  
 
Wechsler Adult Intelligence Scale-Third Edition Digit Span subtest  
 
Alcohol Urge Questionnaire (AUQ) Fagerstrom Test for Nicotine Dependence (FTND)  
 
SCID module for the AUD diagnosis (adapted from DSM-IV to yield a DSM-5 AUD 
Diagnosis)  
 
Short Index of Problems (SIP) 
 
The Patient Health Questionnaire (PHQ-9)  
 
RAND 12-Item Health Survey (SF-12) 
 
Measure of treatment received 
 
ISI 
6.9  Description of Study Treatments 
6.9.1  Pharmacotherapy:  
The maximal dosage of topiramate to be used in the present study is 200 mg/day in two divided 
doses.  We will use a six-week titration period, which was well tolerated in our completed 
topiramate study.  The dosage of medication (active or placebo) will be increased only as 
tolerated and subjects experiencing intolerable adverse effects will have their dosage decreased 
gradually to the highest tolerated dosage, which will be determined by the study physician. The 
study nurse, in consultation with the study physician, will provide guidance for subjects as they 
increase their medication dosage, per the titration schedule. 


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6.9.2  Medical Management Counseling:   
At each treatment visit, all subjects will receive medical management (MM), a standard, widely 
used, medically oriented intervention that supports the use of pharmacotherapy and enhances 
medication adherence in the treatment of AUD (Pettinati, Weiss et al. 2004).  Clinicians with 
minimal specialty training but who are knowledgeable about AUD can deliver this brief and 
effective intervention, which has been widely used.  In MM, the clinician highlights the 
individual’s AUD symptoms and need for treatment.  The subject is advised to reduce or stop 
drinking, is educated about AUD, is provided a rationale to take medication for its treatment, and 
is instructed on the importance of daily medication adherence.  The clinician and subject jointly 
develop an individualized medication adherence plan and the subject is given information on the 
medications.  MM enhances adherence and provides treatment that is feasible in most medical 
settings, but unlikely to obscure a medication effect on drinking outcomes. 
Subjects will receive MM at each of the treatment visits.  The first MM session will last 30 
minutes and subsequent sessions 20 minutes.  During all sessions, the study nurse will check 
the subject’s vital signs and weight, adverse effects, medication adherence, and concurrent 
medications; and make recommendations for the subject to follow until the next visit.  Individuals 
with severe psychological symptoms (e.g., suicidal thoughts) will be withdrawn from treatment 
and referred for appropriate clinical care. Suicidal risks will be assessed using the MINI 
Suicidality section (B) at each study visit, and if rated equal to or greater than 9 (i.e., clinically 
significant suicidal ideation), the physician will be consulted to decide the appropriate clinical 
management.   
 
Ensuring Adherence to MM Content and Procedures: Gail Kaempf, MSN, CRNP, nurse 
practitioner, has more than 10 years of experience with MM (Pettinati, Weiss et al. 2004), 
including in the completed topiramate trial (Kranzler, Covault et al. 2014). She will train the other 
nurses in its administration, which will entail a review of the protocol and MM manual, role-play, 
practice of initial and follow-up sessions, and review of taped practice sessions until adequate 
performance is achieved.  To assure the quality and uniformity of all sessions, audiotapes (with 
the consent of the participant) will be used to monitor the MM sessions for this study. The 
audiotapes will be reviewed by a trained clinician not involved in the counseling process. S/he 
will listen to 10% of recorded visits and will evaluate adherence to MM principles, record the 
total time in the treatment session, assess the therapeutic relationship, review the achievement 
of reduced drinking goals and clinical improvement during treatment, and provide individual 
feedback.  One session from each subject will be reviewed with equal frequency for each of the 
nine different MM sessions.  Weekly protocol adherence meetings will be held with the study 
nurses to assure protocol adherence.  Audiotapes will be destroyed after review. 
6.10  Description of Laboratory/Medical Assessments: 
These assessments serve to:  1) screen subjects for medical exclusion criteria, 2) assess 
potential adverse effects of topiramate, and 3) corroborate self-reported drinking.  Prior to 
entrance into the study, each subject will receive a physical exam, urinalysis and urine 
toxicology, CBC, a chemistry panel [which includes electrolytes, liver enzymes (ASAT, ALAT, 
GGTP), bilirubin, uric acid, BUN, and creatinine], %dCDT, and pregnancy testing for women of 
childbearing potential.  Bicarbonate levels will be repeated at the week six visit because 
topiramate can cause metabolic acidosis. Pregnancy testing for women of childbearing potential 
will also be repeated at visits 1 (week 1), 5 (week 5), 7 (week 8), and 9 (week 11).  If a subject 
reports being pregnant or tests positive, she will immediately be excluded or withdrawn from 
treatment with medication, referred for obstetric evaluation, and advised to discontinue all 
drinking.  At the week six visit and endpoint, GGTP and %dCDT will be repeated to corroborate 
self-reported alcohol consumption. %dCDT will be measured in the laboratory of Dr. Raymond 


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Anton, using the HPLC reference assay method, recommended for the measurement of 
%dCDT, the new standard analyte for measurement of CDT.  This method corrects for total 
transferrin concentration and increases the utility of CDT to evaluate heavy drinking in women 
(Helander, Wielders et al. 2010).  
6.11  Study Timeline: 
Table 3: Timeline of Performance Goals 
Activity 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Staff training & study preparation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoint assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data entry & cleaning  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Report writing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 Statistical Plan 
7.1  Sample Size Determination 
Power for the analysis for Specific Aim 1, as described below, will be determined by the 
patterns of outcomes in the final six weeks, so power estimates are based on weeks 7 through 
12 as a 6-week trial, with adjustments for loss to attrition between baseline and week 6.  Based 
on our prior study (Kranzler, Covault et al. 2014), we anticipate that, through the first six weeks, 
94% of subjects (i.e., n=47 per group) will provide data, despite up to 10% discontinuing 
medication.  We anticipate an additional 6% loss due to dropout from research during the final 
six weeks, also with 10% discontinuing treatment.  In these power estimates, we use a square 
root transform to approximate the Poisson distributions by Normal distributions, on which we 
base our estimates using the methods of Hedeker et al. (1995) and Stroup (1999).  Our primary 
comparison is the interaction effect of GRIK1 with TOP.  In our previous study, for the square 
root Poisson scale, we observed a standardized effect (Cohen 1988) of d=0.27 for TOP relative 
to PLA in the AA/AC group and a standardized effect of d=0.93 for TOP relative to PLA in the 
CC group. We have a single primary hypothesis, so we consider power for a two-sided test at 
=0.05, with a total of 4 x 47=188 subjects, with 6% research loss to attrition across six weeks. 
Finally, we assume a within-subject correlation of 0.35 for the repeated measures. With these 
assumptions, we have 81% power for the effects observed in our prior study. For Specific Aim 
2, we used simulation studies (Kreft and De Leeuw 1998) to evaluate the adequacy of our 
sample size in relation to moderation by the CC genotype of TOP’s effects on the contingent 
relation between early evening outcome expectancies and nighttime drinking (Kranzler, Armeli, 
et al. 2013).  These show that designs having at least 30 level-2 units with 30 observations each 
(i.e., 900 total person days) will provide power of 80% to detect small effect sizes.  Assuming a 
rate of missing data of about 20% (Kranzler, Armeli, et al. 2013), we will have approximately 
15,000 person days for the comparison of TOP and PLA, which will provide high power to detect 
a small effect.  
7.2  Statistical Methods 
To examine the moderating effects of the GRIK1 SNP rs2832407 on the response to TOP  
(Specific Aim 1.) 


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The four medication (Topiramate/Placebo) by GRIK1 genotype (CC vs. AA/AC) groups will be 
compared on the weekly number of heavy drinking days using mixed effects models for count 
responses (83, 84), fitted using PROC GLIMMIX in SAS and the HGLM module of the HLM7 
program.  Estimates of effects over the final six weeks from the models, with associated 
standard errors and confidence intervals, will be used to test the primary hypothesis, i.e., 
medication group by genotype contrasts within the final six weeks will directly address the 
significance and pattern of differences in distributions of HDDs among the four medication by 
genotype groups.   
The fixed effects for the primary models will include binary factors for intervention group 
(Topiramate/ Placebo) and GRIK1 genotype (CC or AA/AC), and their interaction, with 
covariates for linear and quadratic time trends and further terms for group by time, genotype by 
time, etc., as appropriate for model fit.  The random effects will include a random intercept and, 
if necessary, residual autocorrelations, random slopes, or other specifications will be used 
(Molenberghs, Verbeke et al. 2005, McCulloch, Searle et al. 2008).  Although the primary 
contrasts will concentrate on the final six weeks, these models utilize all available data from all 
subjects, so the analyses follow the intent-to-treat principle.  If the polynomial time trends 
described above do not capture the range of individual trajectories observed in the trial, then 
more flexible non-linear time trends can also be fitted.  Additional covariates can also be 
included in the models, allowing for sensitivity analyses for effects of covariate imbalances, and 
to examine moderation effects (see below) and group by goal of treatment (reduced drinking or 
abstinence) interactions.  For example, we will also include the proportion of European ancestry 
as a covariate, to adjust for admixture.  Here, AIMs genotype data will be used to calculate 
ancestry proportions using a principal components method implemented in EIGENSTRAT 
(Price, Patterson et al. 2006) or PLINK (Purcell, Neale et al. 2007), and the proportion will be 
included in the model as a covariate.  The models can also be extended to allow for zero 
inflation, where weekly patterns of abstinence may yield more zero counts of heavy drinking 
days than can be accommodated by a Poisson model.   
To examine the relations among daily process measures of expectancies, medication 
use, and drinking level (Specific Aim 2.) 
Multilevel models similar to those described above will be used to evaluate the associations 
between alcohol expectancies and daily drinking and how these associations vary as a function 
of medication group and rs2832407 genotype.  Similar to Kranzler et al. (2013), we will focus on 
predicting nighttime drinking (i.e., drinks consumed after the early evening report), but here we 
will use alcohol-related expectancies reported during the early evening in the daily survey.  
Nighttime drinking levels will be determined by subtracting the number of drinks consumed 
during the current day from the total number of drinks consumed for that day (reported the 
following day).  We will follow the general analysis scheme used by Kranzler, Armeli et al 
(2013), but will use mixed effects/multilevel models, rather than generalized estimating 
equations (GEE) models (Walls, Jung et al. 2006,Schafer 2006).  We will examine the number 
of drinks consumed (using a Poisson model).  We will use the HGLM module of the HLM7 
program, as it is more flexible for some of our models than PROC GLIMMIX in SAS.  Analysis 
will focus on the last six weeks of treatment, consistent with the analyses of the primary 
outcome in Specific Aim 1.   
 
Predictors in these models will include 6 day-of-the-week contrasts in the level-1 model 
(i.e., including responses that change over days within person), to control for day of the week 
trending in the outcomes [e.g., greater propensity to drink on weekends (Armeli, Carney et al. 
2000, Armeli, Tennen et al. 2000)], along with linear and quadratic study time contrasts and 
daytime drinking.  The day-level predictor of interest (i.e., expectation of positive effects of 
drinking) will also be included in the level-1 portion of the model.  The outcome expectancy 


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predictor will be person-mean centered (91).  The level-2 portion of the model (i.e., measures 
that do not change over days) will include treatment group, binary factors for rs2832407 
genotype (i.e., CC vs. A-carrier) and associated interaction terms.  This analysis will test the 
hypothesis that TOP will significantly reduce positive alcohol expectancies relative to PLA, but 
only in C-allele homozygotes, similar to the analysis of the primary outcome in Specific Aim 1. 
7.3  Subject Population for Analysis 
The study will be conducted using a modified intent-to-treat approach in which all randomized 
subjects who have received at least one dose of study medication and provided at least 10 days 
of data on drinking after initiating treatment will be used in the efficacy analyses.  All randomized 
subjects who received at least one dose of study medication will comprise the safety population. 
 
7.4  Genetic Analyses 
Genotyping will be performed by Dr. Richard Crist in the Department of Psychiatry at the 
University of Pennsylvania Perelman School of Medicine.  Whole blood will be coded and 
shipped to Dr. Crist’s lab.  Samples will be hand-delivered or transported via courier without 
identifiers, following University of Pennsylvania shipping procedures. Staff will send the blood 
sample after collection at screening visits. Staff will keep a log of all samples sent to Dr. Crist’s 
lab, maintaining tracking logs of all samples sent verified with results received within 5 days to 
determine inclusion criteria.  DNA will be purified from whole blood standard methods.  TaqMan 
allelic discrimination assays will be used to genotype rs2832407 using kits provided by Applied 
Biosystems Inc.  Genotyping will be performed using the 5’-nuclease TaqMan closed-tube 
fluorescence method and an ABI Sequence Detector System for post-PCR plate reads. Dr. 
Crist’s lab will send genotype information to study staff designated as the randomization staff 
member who is not otherwise involved in the conduct of the study.  That individual will maintain 
a log of all subjects’ genotype results and inform study staff if the subject is eligible for 
randomization to study medication due to genotype, keeping the study staff member blinded to 
the subject’s genotype.   
 
If necessary to ensure the timeliness of the genotyping, we will send a blood sample to the 
University of Pennsylvania’s Molecular Profiling Facility as an alternative to Dr. Crist’s 
laboratory.  Under those circumstances, procedures similar to those described above will be 
used to ensure privacy and maintenance of the blind. 
8 Safety and Adverse Events 
8.1  Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc.) 
 Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 
caused by the procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
Adverse Event 


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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 other serious outcomes noted above.  For example, drug overdose or abuse, 
a seizure that did not result in in-patient 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 study treatment follow-up.  
For this study, the study treatment follow-up is defined as 30 days following the last 
administration of study treatment.  
 
Pre-existing Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 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 should 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 study sponsor of any death or 


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adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should 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.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
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, study staff 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. 
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. 


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8.3  Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, 
formats and requirements of the various entities to which they are responsible, but at a 
minimum those events that must be reported are those that are: 
 related to study participation, 
 unexpected, and  
 serious or involve risks to subjects or others  
(see definitions, section 8.1).   
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes: 
 
Study identifier 
 
Study center 
 
Subject number 
 
A description of the event 
 
Date of onset
 
Current status 
 
Whether study treatment was 
discontinued 
 
The reason the event is classified as 
serious 
 
Investigator assessment of the 
association between the event and 
study treatment 
8.3.1 Data and Safety Monitoring Plan (DSMP) 
The DSMP is intended to ensure the safety of research participants and the integrity of the 
study data.  Dr. Henry Kranzler, M.D., the principal investigator of this study, or one of the 
other study physicians, will be charged with determining the severity rating of all adverse 
events. The study staff (P.I., co-investigators, clinical research coordinator) is responsible for 
collecting and recording all clinical data.  As these results are collected, all toxicities and 
adverse events will be identified, graded for severity and assigned causality, reported to the 
required entities, and compiled for periodic review.  After assigning causality, the P.I. will 
decide the course of action for the study participant. The P.I. will evaluate every adverse event 
and determine whether it affects the risk/benefit ratio of the study and whether modifications to 
the protocol or informed consent form are required.  The principal investigator (and, in his 
absence, physician co-investigators) will differentiate serious from non-serious adverse 
events.  Serious adverse events will be reported to the Penn IRB and the NIAAA project 
officer within 48 hours and an annual report summarizing all adverse events will be prepared 
and reported to the UPenn IRB, CMCVAMC IRB, and NIAAA.  The following information will 
be considered in the periodic safety report to the Data and Safety Monitoring Board (DSMB), 
which will be empanelled prior to initiation of the trial:  
• 
Summary of adverse events. 
• 
Dropout rates and reasons for the dropouts. 
• 
Number of patients who have completed the study. 
• 
Any other relevant information 
The DSMB, a full description of which is provided below, will follow guidelines established for 
monitoring clinical trials in the Center for Studies of Addiction.  It should be noted that, at no 
time will a DSMB member participate in the review of a study in which he or she is a co-
investigator or otherwise actively involved. 
Any patients thought to be at risk from drinking or psychiatric or medical disorders during 
treatment will be referred to appropriate clinical services. Given the anticipated moderate 
effect sizes, we will not conduct interim analyses, nor have we elaborated stopping rules for 


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the study in relation to efficacy.  An adequate evaluation of efficacy will require a sample size 
larger than what will be available before the study is completed as designed.  However, if it 
has been determined, for any reason, that the study should be suspended, we will discontinue 
enrollment of new patients, while continuing the treatment and monitoring of patients already 
enrolled in the study, unless to do so would create a risk that is not justified by any potential 
benefit to patients. 
Women of Reproductive Age: As noted above, precautions for pregnant or reproductive age 
women are in accordance with NIAAA requirements and this will be monitored as part of the 
DSMP. Women who are pregnant, nursing or of reproductive age and not using effective 
methods of birth control will be excluded from the study.  The study inclusion and exclusion 
criteria, in total and as specified in the protocol, will be the basis for determining study 
eligibility.   As mentioned above, it is possible that some hormonal contraceptives (e.g., birth 
control pills, hormonal implants or hormonal injections) may be made less effective by 
topiramate.  If appropriate, the study doctor will discuss with patients alternatives or additional 
non-hormonal methods of birth control to be used during participation in the study. 
Data and Record Safety/Confidentiality: 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. All electronic data 
and files (e.g., database, spreadsheet, etc.) containing identifiable patient information shall be 
password protected. Any computer hosting such files shall have a BIOS password to prevent 
access by unauthorized users. If patient 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. Blood will not be used for the purpose of establishing cell lines. 
Any hard copy records associated with the study will be kept in locked offices at the clinical 
site.  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 Treatment Research Center, 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.  
Data used for safety monitoring will include serious adverse events, dropout rates and 
reasons for dropout, enrollment numbers, patient interviews, medication compliance, review of 
symptoms or performance status, review of clinical/diagnostic test results, review of physical 
examination, review of vital signs, review of evaluation performed, protocol deviations, and 
blinded data. If it has been determined, for any reason, that there will be a suspension of this 
study, the PI will suspend enrollment of new patients but continue intervention/monitoring of 
previously enrolled patients if it is in the best interest of those patients. We have determined 
that this study involves more than minimal risk to patients, but that potential benefits outweigh 
potential risks of treatment.  


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Blood will be collected for DNA analysis. The information derived from analysis of the patients’ 
DNA will not be provided to the patient, since at the present time the existing preliminary 
genetic data to predict the response to topiramate treatment do not provide a basis for genetic 
counseling.  Should that situation change over the course of the treatment trial, procedures 
will be developed in conjunction with the Penn IRB to provide patients 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 patient’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 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. 
8.3.2 University of Pennsylvania School of Medicine, Center for Studies of 
Addiction, Data and Safety Monitoring Board  
Introduction:  The Center for the Studies of Addiction, here after referred to as the Center, has 
identified the need to assist investigators with meeting their ethical responsibility for ongoing 
study monitoring of treatment outcomes and safety monitoring.  Furthermore, NIH Guidelines 
(1998) specify that all clinical trials should have a system in place for appropriate oversight 
and monitoring to ensure the safety of participants and the validity of the data. In order to help 
meet these needs the Center is establishing a committee called a Data and Safety Monitoring 
Board (DSMB). 
Purpose: The purpose of the DSMB is to assure that the safety of study subjects is protected 
while the scientific goals of the ongoing studies are being met. Specifically, the DSMB is 
charged with monitoring the safety of participants and the quality of the data, as well as the 
appropriate termination of studies either when significant benefits or risks have been 
uncovered or when it appears that a clinical trial cannot be concluded successfully. 
Objectives:  
A.  To determine which studies conducted at the Center require a Data and Safety Monitoring 
Board. 
B.  To review initial protocols for studies to ensure the following (see Appendix 1): 
• Each protocol captures the information necessary to evaluate the safety and efficacy 
of the study when it is ongoing and completed and to provide recommendations that 
may improve the protocol.  
• Each protocol includes a detailed Data Safety and Monitoring Plan (DSMP).  This 
plan, in turn, also references this DSMB plan as well as specifying modifications to the 
Board plan that are necessary.  The DSMP should also include stopping rules that 
specify the outcome differences detected between groups during an interim analysis 
that can stop a clinical trial.  In general, stopping rules will reflect one of the following 
conditions: 
1. There is clear evidence of harm or harmful side-effects of the treatment; 2. 
There is no likelihood of demonstrating treatment benefit; or 3. There is overwhelming 
evidence of the benefit of the treatment. 
C.  To monitor ongoing protocols to evaluate the following (see Appendix 2):  
• The safety of the subjects as pre-specified in the DSMP of each protocol and 
independently the DSMB will make recommendations to researchers to continue, to 


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amend, or to terminate a clinical trial based on the interim analysis of the safety data 
(e.g., terminate a clinical trial because of high incidence of an SAE).  
• The efficacy of the treatments being tested as pre-specified in the interim monitoring 
plan of each protocol and independently make recommendations to researchers to 
continue, to amend or to terminate a clinical trial based on the interim analysis for 
efficacy (e.g., terminate a clinical trial because the analyses indicate the study is 
having a negative effect, the intervention is not adequately implemented or there is no 
evidence of a treatment effect after the prescribed level of power is reached).  
• The presence of early unanticipated therapeutic results, side effects or adverse 
consequences for each protocol, and independently make recommendations to 
continue, to amend or to terminate a clinical trial based on the interim analysis for 
efficacy (e.g., terminate a clinical trial because it would be unethical to continue the 
non-treatment compared to the treatment-as-usual arm).  
• The performance of each trial (e.g., protocol violations, improper entry criteria, slow 
accrual rate, low participation rate, failure of randomization, inadequate treatment 
adherence, inadequate follow-up rate, severely compromised validity), and to 
independently make recommendations for improvement or termination if the trial would 
be unable to prove anything meaningful, regardless of modifications. 
8.3.3. Studies Requiring a DSMP and DSMB 
All clinical trials involving human subjects require study-specific IRB approval and a detailed 
DSMP, and will be reviewed by the Center’s DSMB. The DSMB will make a determination 
regarding studies that require ongoing DSMB review.  The National Institutes of Health policy 
on data and safety monitoring will serve as a guide to the DSMB in making decisions 
regarding trials that require DSMB oversight and monitoring.  As such, all phase III clinical 
trials are required to have data safety and monitoring in the form of a DSMB.  Phase I or II 
trials will be required to have DSMB oversight for the following reasons: if the investigator is 
the investigational new drug (IND) holder, if the study has multiple clinical sites, is blinded, or 
employs a particularly high-risk intervention or vulnerable population.  Additionally, a DSMB 
may be indicated when there are special concerns regarding subject safety, a study 
investigator is inexperienced or where study integrity could be enhanced by the independence 
of the DSMB. The DSMB’s role is oversight above and beyond that of the Institutional Review 
Board.  The intent of the board is not to place an onerous burden on investigators.  If a trial 
has the oversight of an external DSMB there does not need to be duplication of effort. 
8.3.4. Scope of Data Monitoring 
The precise nature of the data to be monitored and the analyses used per protocol will be 
determined by the DSMB. The primary source of the data will be the Case Report Form 
developed for each protocol. The study investigators, as requested by the DSMB, will provide 
additional detailed information regarding serious adverse events.  
A.  Study Admission Data:  The DSMB will assess the sites’ performance with respect to 
subject recruitment. Monitoring of admission data will include the number of subjects calling 
for treatment for substance use/abuse problems, number of subjects scheduled for an intake 
appointment, number of subjects who attended an intake appointment, and number of 
subjects admitted to the study. The DSMB may request a report of the reason why subjects 
were disqualified from participating in the study.  For subjects admitted to the study, the 


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DSMB will review eligibility criteria for admitted subjects, any protocol violations, and the 
demographic distribution of the subjects (by group if required) (see Appendix 2).  
B.  Protocol Compliance:  The DSMB will monitor the data per protocol to assess compliance 
with the protocol including adherence to protocol participation rules for safety or administrative 
adherence. Examples of participation rules might include, for example, stopping participation 
or withholding treatment for elevations of liver function tests, severe neuropsychiatric 
disturbances or changes in vital signs. The DSMB will also monitor the quality and 
completeness of the data being collected. For data collected at specified times the Board 
should monitor the frequency of missing or erroneous data, and presence and frequency of 
outliers.  
C.  Safety Data:  Monitoring of safety data will include per protocol a review of Adverse Events 
(AE’s) and Serious Adverse Events (SAE’s), and data commonly accepted to reflect 
differences in safety between treatment groups such as clinical laboratory data, treatment 
retention, and reason for drop out. Safety information for all studies will be reported to the 
Board in a blinded manner. The Board may determine if a review of unblinded data is 
indicated. Unblinded information will only be discussed during closed meeting sessions. 
Furthermore, the Board may request formal statistical analyses of the safety data.  
For non-serious AE’s, data may be summarized by treatment groups, with data on individual 
subjects available for DSMB review as needed and if the study blind is not compromised. For 
SAE’s, data will include all of the adverse event data that meet the FDA definition of serious 
adverse events. In the assessment of SAE’s, the DSMB will review each individual case 
including treatment group assignment.  
After each meeting of the DSMB, the executive secretary will forward a summary report of all 
serious and unexpected adverse experiences to each investigator per protocol. The report will 
document that a review of data and outcomes took place on the date of the meeting. It will 
summarize the Board's review of cumulative serious and unexpected adverse events reported 
without specific disclosure by treatment arm. Furthermore, the report will inform investigators 
of the Board's recommendations with respect to progress or need for modification of the 
protocol. The principal investigator is required to transmit the report to the local IRBs.  
The DSMB will follow up on the outcome of AE’s and SAE’s, and that all appropriate AE’s 
and/or SAE’s are reported to the UPenn IRB, CMCVAMC IRB, FDA, NIH or other pertinent 
regulatory agency.  
D.  Efficacy Data:  Efficacy data determined by the protocol are based on the primary and 
secondary outcome variables detailed in the DSMP for each component which will be required 
to have been reviewed and accepted by the DSMB.  The data may be presented for all 
treatment groups combined or by treatment groups. Data by treatment groups can be 
presented to the DSMB blinded and then the DSMB may request to unblind the data. In the 
event that a safety concern arises that requires an interim analysis of efficacy data, an 
analysis may be made on a for-cause basis. Any for-cause interim analysis requested by the 
DSMB should specify in advance the efficacy outcome of interest, the number of comparisons 
to be made for purposes of the analysis, the statistical method to be employed in the analysis, 
the significance required to reach a decision, and the new p value necessary to reject the null 
hypothesis should the study run to completion (such that the probability of a Type 1 error is 
maintained at <0.05 for all primary analyses that would be conducted).  


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For studies that are conducted in a blinded manner, the presentation of data relating 
specifically to outcome measures should be presented to the DSMB in the manner and timing 
described in the DSMP for that study. Additionally, the Board will determine whether interim 
analyses of efficacy data are required. Studies that include interim analysis of efficacy data 
should provide the proposed number of interim analyses to be made, the specific comparisons 
to be made at each such analysis, the stopping rules on the basis of efficacy findings, 
including both standards for the determination of 'overwhelming efficacy' and an 'inevitable 
failed trial', and the methods of statistical correction to be used to control the final overall Type 
1 error. When defining this interim review in the protocol, consideration should be given to 
whether the data can be prepared for the DSMB review in a sufficiently timely manner so that 
any resulting decision can in fact impact on the study if the study is largely completed before 
the conclusions are made, the interim review may be unnecessary.  
E.  Establishing a DSMB 
• Board membership:  The DSMB will consist of at least four members.  Three members will 
constitute a quorum. The Center’s Executive Committee will approve the composition of the 
DSMB, and appoint the members. The term of membership for the DSMB will be for three 
years. 
• The DSMB members will include James McKay, Ph.D. (Chair), Kyle Kampman, M.D., 
Daniel Weintraub, M.D., Deborah Dunbar, MSN, CRNP, ANP-BC, David Metzger, 
Ph.D., Reagan Wetherill, Ph.D., Cynthia Clark, Ph.D., CRNP, Kevin Lynch, Ph.D. 
(biostatistician) and Richard Feinn, Ph.D. (alternate biostatistician). 
• Because board members should be free of financial interest that could be 
substantially affected by the outcome of the trial, conflict of interest disclosure 
documentation is necessary to avoid real or apparent conflict of interest of the DSMB 
members. Individuals invited to serve on the DSMB should disclose in writing to the 
sponsor any potential conflicts of interest, actual or implied by appearance. Should an 
unanticipated situation arise that the Board member feels represents a conflict of 
interest, the Board member should recuse themselves from deliberations.  At the start 
of each new member's term, the individual will sign a confidentiality statement 
promising not to disclose any proprietary and nonproprietary data. Furthermore, no 
disclosure should be made of the deliberations of the Board.  
• The DSMB may identify the need for inclusion of scientists or non-scientists that may 
provide unique insights to a particular study or aspect of a study.  These individuals 
could be a clinical pharmacologist, a medical ethicist or an individual that could bring 
the perspectives of the population under study.  Whenever a project is reviewed that 
directly involves one of the board members, alternate members will be chosen to 
review the study or studies in question.  At no time will a board member be involved in 
the review of his or her own study. 
F.  Board meeting schedule:  The DSMB meetings will be held annually.  The Board has the 
option of expedited meetings to review unexpected SAEs or other urgent issues that may 
arise during the course of the trials. Unscheduled meetings may be recommended and 
initiated by the Chair of the DSMB or the sponsor (or the principal investigator) of the study. 
The data and any other relevant materials to be reviewed by the DSMB will be made available 
to the Board members at least two weeks before the meeting.  Investigators will be informed 
that their protocol is scheduled for on-going review by the DSMB at least two months before 


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the meeting. Should an investigator wish to have a non-emergent item placed on the agenda 
of an upcoming DSMB meeting, the investigator should place their request in writing to the 
Chair of the DSMB.  The investigator will be notified of the outcome regarding their request at 
least two weeks before the scheduled meeting. 
G.  Conduct of the Meetings:  The DSMB meetings will be divided into three sessions: open, 
closed and executive. The Principal Investigator and other study staff per protocol will attend 
the open session and will present relevant information to the Board about general aspects of 
the trial. The open session may focus on the background of the study, the protocol, status of 
the study, problems with accrual and follow-up, baseline demographic data, compliance 
issues, frequency of adverse events, documentation of endpoints, data quality issues, flow of 
forms, data based protocol modification issues, and any other issue regarding the studies 
under review that can be discussed without reference to interim comparative results.  
Following the open session, a closed session will be held. During the closed session, the 
DSMB chair or representative will conduct the review of all issues and put each issue to a 
vote.  A quorum for the DSMB is (4) voting members. This session will be attended by the 
DSMB members, the DSMB executive secretary, and if necessary the principal investigator. 
During the closed session, the discussions will focus on the treatment safety, efficacy data, 
whether the primary study question has been answered, the interim results by treatment arm 
(usually masked), determining when study data may be released and reviewing requests for 
access to the results of the interim analysis, and updating the Board on actions taken related 
to their actions and recommendations of the previous meeting.  
Following the closed session, an executive meeting may be held. The executive meeting is 
restricted to DSMB members (voting and non-voting members). During these sessions, the 
Board may discuss any unmasked analysis of a blind clinical trial and any sensitive issues 
surrounding the clinical trials under review.  
H.  Report Format:  Reports to the DSMB may include reports from the Data Management 
Center that reflects the status of the study, progress or findings to date, and any relevant 
issues.  Additionally, data are presented that describe the administrative status of the study 
including recruitment.  Reports should also provide a safety assessment and may include 
copies of monitoring reports.  Recommendations related to clinical trials will be made in writing 
by the Board's Chairperson to the principal investigator of the trial. Normally, results of the 
interim analysis will not be disseminated. Only under certain conditions should the results be 
released. The Board should make the final decision related to the release of this information.  
The Board Chairperson will prepare the draft report of the meeting, with the assistance of the 
Executive Secretary. The Executive Secretary will be responsible for the preparation of meeting 
minutes for inclusion in the DSMB report. The report will outline and summarize all discussions 
during the open and closed sessions of the meeting. Recommendations and action items will be 
clearly marked within the body of the report. If the DSMB decides to conduct an executive 
session, a statement will be included in the Minutes of the Meeting stating an executive session 
was conducted, but should not disclose the contents of the discussions. Minutes for the 
executive session will be recorded separately and not distributed beyond the DSMB members. 
The draft report will be reviewed and edited by all Board members prior to issuance of the final 
report. The Principal Investigators will ensure that their reports are sent to the UPenn IRB, 
CMCVAMC IRB, NIH or others, as indicated. 
8.3.1  Investigator reporting: Notifying the Penn IRB 


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This section describes the requirements for safety reporting by investigators who are Penn 
faculty, affiliated with a Penn research site, or otherwise responsible for safety reporting to the 
Penn IRB. The University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those 
events related to study participation that are unforeseen and indicate that participants or others 
are at increased risk of harm.  The Penn IRB will not acknowledge safety reports or bulk 
adverse event submissions that do not meet the criteria outlined below.  The Penn IRB requires 
researchers to submit reports of the following problems within 10 working days from the time the 
investigator becomes aware of the event: 
 Any adverse event (regardless of whether the event is serious or non-serious, on-site or 
off-site) that occurs any time during or after the research study, which in the opinion of 
the principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved informed consent 
document and other relevant sources of information, such as product labeling and 
package inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in 
the opinion of the principal investigator or sponsor, the event was more likely than not to 
be caused by the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
Penn IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including 
Reportable Adverse Events” or as a written report of the event (including a description of the 
event with information regarding its fulfillment of the above criteria, follow-up/resolution and 
need for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 
 
Reporting Deaths:  more rapid reporting requirements 
Deaths that occur during the course of a research study and that are:  
 
Unexpected; AND  
 
Related to the research study; AND  
 
When other participants are believed to be at an increased risk of harm 
 
Must be reported to the IRB within 3 days from the time the investigator becomes aware of the 
death.  
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
 Any adverse event that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to assure 
protection of human subjects. 


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 Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more 
frequent than initially expected. 
– A paper is published from another study that shows that an arm of your research 
study is of no therapeutic value. 
 Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol. 
 Breach of confidentiality 
 Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant. 
 Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain 
on the study. 
 Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
 Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants 
at increased risk, or affects the rights or welfare of subjects. 
8.3.2   Sponsor reporting: Notifying the FDA 
 
N.B. This protocol is being submitted to the FDA as suggested by the agency to determine 
whether an IND is required.  The following information will only be relevant if an IND is required. 
 
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  
These written notifications of adverse events are referred to as IND safety reports. The following 
describes the safety reporting requirements by timeline for reporting and associated type of 
event: 
 
 Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening, and  
 
 Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to 
fit the criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
Any finding from tests in laboratory animals that:  


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– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current event in light of the 
previous reports. 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A or in a narrative format. If supplied as in 
a narrative format, the minimum information to be supplied is noted above at the beginning of 
section 8.3. The contact information for submitting IND safety reports is noted below: 
Ayanna Augustus, PhD, RAC 
Sr. Regulatory Health Project Manager  
FDA/CDER/OND/ODEII/DAAAP  
301-796-3980  
8.4  Unblinding Procedures 
In the event that subjects are prematurely discontinued from participation in treatment, 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 
requesting that the study blind be broken for a subject, and Dr. Kranzler or another study 
physician is not reachable via pager, the pharmacist will act according to his/her best judgment 
in deciding whether 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.  Dr. Kranzler 
should be notified of the need to unblind the subject as soon as is feasible by the individual 
making that decision. 
8.5  Medical Monitoring 
The Principal Investigator will oversee the safety of the study.  This safety monitoring will 
include careful assessment and appropriate reporting of adverse events as noted above, and 
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. 
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 


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authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should 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. 
Separate Certificates of Confidentiality from the National Institute on Alcohol Abuse and 
Alcoholism (NIAAA) will be obtained for both the main study and the sub-study described in this 
protocol. As per the NIAAA’s website: Certificates of Confidentiality are issued by NIH Institutes 
pursuant to Section 301 (d) of the Public Health Service U.S.C. Section 241 (d) to afford special 
privacy protection to subjects enrolled in biomedical, behavioral, clinical, or other research 
within NIH mission areas. A Certificate helps the researcher avoid compelled 'involuntary 
disclosure' (e.g., subpoenas) of identifying information about a research subject. It does not 
prevent voluntary disclosures such as disclosure to protect the subject or others from serious 
harm, as in cases of child abuse. Also, a researcher may not rely on a Certificate to withhold 
data if the subject consents to the disclosure. When a researcher obtains a Certificate of 
Confidentiality, the subjects must be told about the protections afforded by the Certificate, and 
any exceptions to that protection. This information is usually included in an 'informed consent'. 
All subjects will be informed about the protections afforded by the Certificate in the Informed 
Consent Form for both the main and sub-study using the language inserted below: 
“To further help us protect your privacy, we have obtained a Certificate of Confidentiality from 
the United States Department of Health and Human Services (DHHS).  
With this Certificate, we cannot be forced (for example by court order or subpoena) to disclose 
information that may identify you in any federal, state, local, civil, criminal, legislative, 
administrative, or other proceedings. The researchers will use the Certificate to resist any 
demands for information that would identify you, except to prevent serious harm to you or 
others, and as explained below.  
You should understand that a Certificate of Confidentiality does not prevent you, or a member of 
your family, from voluntarily releasing information about yourself, or your involvement in this 
study.  
If an insurer or employer learns about your participation, and obtains your consent to receive 
research information, then we may not use the Certificate of Confidentiality to withhold this 
information. This means that you and your family must also actively protect your own privacy.  
You should understand that we will in all cases, take the necessary action, including reporting to 
authorities, to prevent serious harm to yourself, children, or others (for example, in the case of 
child abuse or neglect).” 
This language is located in the section of both of the Informed Consent Forms titled “Who can 
see or use my information?  How will my personal information be protected?” 
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 


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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 TRC, 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 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.  
Data used to process subject payments with the Greenphire Clincard program are entered 
electronically using secure web-based interfaces. Greenphire Clincard is HIPAA compliant. 
Please see document titled, “ClinCard Data Security and Privacy Statement,” located in the 
appendix. The Greenphire system requires that we complete a W9 for each subject, entering 
the subject’s name, address and social security number.  
9.2  Source Documents 
Source data include all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  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, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, 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 pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
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.  DO NOT ERASE OR WHITE OUT ERRORS.  For 


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clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
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 TRC 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.  
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).  


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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 TRC provides comprehensive data collection training for all research technicians (RTs).  
RTs receive training on how to proceed with problematic subjects. 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: 
· 
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. 
 


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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. 
Monitoring activities include: 
 Oversight of Investigator conduct, including supervision of study site staff and data 
reporting 
 Review of the  study site’s processes and procedures (e.g., process for investigational 
product administration) 
 Review of site records for completeness and accuracy  
 Ongoing evaluation of safety data and the emerging benefit-risk profile of an 
investigational product 
 Review of recruitment rates  
 Review of protocol deviations and non-compliance 
 Review of subjects who dropped out 
 Review of the timeliness of data collection and submissions  
 Verification  that informed consent was obtained appropriately 
 Verification of adherence to the protocol, including  eligibility criteria, study test and 
procedures, investigational product accountability 
 Verification of the disposition of the investigational product 
 Review of evaluation, assessment, documentation and reporting of Adverse Events 
 100% source data verification will be performed for all subjects. 
 100% review of all off-site tracking logs and the source documents that confirm the data 
and samples transferred were received.  
 
Enrollment will take place at the Treatment Resarch Center.  For all subjects consented, the 
Monitor will:  
 Review the informed consent form (ICF) and informed consent process  
 Verify eligibility (i.e., review of inclusion/exclusion criteria)  
 Assess treatment compliance  
 Review subject evaluations, testing and follow-up per the protocol  
 Assess and follow-up safety issues  
 Review and compare source documents and CRFs for completion and accuracy  
 Review investigational agent accountability and adherence to product labels  


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 Review any regulatory documents for amendments/modifications/updates 
 
Timing and Frequency of Monitoring Visits: 
 
Monitoring visits will be done twice each year that the study is active. 
o The first monitoring visit will be held no later than four weeks (and no earlier than 
two weeks) after the baseline visit of the first subject in any new site added.  
Subsequent monitoring visits will take place twice each year. 
o A study closeout visit at each active site will be conducted no later than 1 month 
after the final subject has completed the study at that site. 
 Review of the Informed Consent Form  
 Review the ICFs to verify that consent was obtained in accordance with regulations and 
guidelines. 
 Regulatory Document Review  
 The site regulatory documents will be maintained in the site regulatory binder. The 
regulatory binder will be reviewed by the Monitor at each monitoring visit. The Monitor 
will review the binder to ensure its completeness and that study documents are filed 
appropriately in a timely manner. 
 Adverse Event (AE) and Serious Adverse Event (SAE) Reporting  
AEs: The Monitor will confirm during review of the collected data and source 
data/documentation that SAEs, AEs, and protocol deviations have been reported as required by 
the IRB, FDA, and otr regulatory agencies.   
 
 
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 Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
government regulatory bodies, and University compliance and quality assurance groups of all 
study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, 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. 


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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. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the sponsor. 
 
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.  The Subject Informed 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 consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent.  
12 Study Finances 
12.1  Funding Source 
This study is financed through a grant from the US National Institute on Alcohol Abuse and 
Alcoholism of the National Institutes of Health. 
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 that has been reviewed and approved by the study sponsor prior to 
participation in this study.  All University of Pennsylvania investigators will follow the University 
conflict of interest policy. 
12.3  Subject Stipends or Payments 
Subjects will receive $1.00 for each phone call they make or $10 for each week they complete 
all 7 phone calls (up to $120 for all calls across the 12-week monitoring period). They will 
receive $3 for returning medication bottles at each study visit, $4 to cover the cost of mass 
transit for roundtrip travel, $25 for completing the week visit 6 and $50 for completing the 
endpoint visit. They will receive $50 for each of the two follow-up visits. The total amount that 
subjects can receive for full participation in the research study is $374. Subjects will be paid at 
the visits shown in Table 3 based on their daily phone calls, medication bottles returned, and 
assessment visits completed. Payments will be made at each study visit for which a payment is 
due, as shown in Table 3. Payments will be made with a GreenPhire ClinCard. Clincards are 
reloadable prepaid cards that may be used for in-store purchases (by selecting either the 
“credit” or “debit” option), online purchases, at an ATM to get cash, or for cash advances at a 
bank. 
 
 


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Table 3. Schedule for Study Payments 
 
Visit  
Returned 
Medication 
Bottle 
Travel Cost 
Completed 
Visit 
Daily Phone call:  
$1/day or $10 for  
all 7 days/week  
Maximum 
Payment 
Screening Visit -0 
N/A 
$4 
$0 
N/A 
$4 
Visit 1 Baseline 
N/A 
$4 
$0 
N/A 
$4 
Visit 2 
$3 
$4 
$0 
0 
$7 
Visit 3 
$3 
$4 
$0 
0 
$7 
Visit 4 
$3 
$4 
$0 
0 
$7 
Visit 5 
$3 
$4 
$0 
0 
$7 
Visit 6  
$3 
$4 
$25 
$50 
$82 
Visit 7 
$3 
$4 
$0 
$20 (2 wks) 
$27 
Visit 8 
$3 
$4 
$0 
$20 (2 wks) 
$27 
Visit 9  
$3 
$4 
$0 
$20 (2 wks) 
$27 
Visit 10 Endpoint 
visit 
$3 
$4 
$50 
$10 
$67 
Visit 11 (3-Month) 
N/A 
$4 
$50 
N/A 
$54 
Visit 12 (6-Month) 
N/A 
$4 
$50 
N/A 
$54 
Totals 
$27 
$52 
$175 
$120 
$374 
 
Note:  Subjects will receive a portion of the payment based on completion of study visits, daily 
phone calls and returning both medication containers (i.e., $1.50 for returning only one of the 2 
bottles).  Payments will be deferred if they fail a Breathalyzer test.  Payments for phone calls 
made during the first five weeks will occur at Visit 6 and then as shown above. 
 
13 Appendix I:  (Sub-study) Brain Mechanisms of Topiramate’s 
Effects on Heavy Drinking 
13.1  Background 
Alcohol is the third leading risk factor for premature death and disability (Alcoholism 2013), as 
well as a leading cause of preventable cancers (Nelson, Jarman et al. 2013). Alcohol 
dependence affects 18-20 million Americans (i.e. 1 in 12), and alcohol problems cost our society 
nearly $225 billion annually (Alcoholism 2013). 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 (Harris, Kivlahan et al. 2010). Empirical evidence 
suggests that naltrexone reduces the reward properties of and cravings for alcohol (Sinclair 
2001) and acamprosate supports abstinence (Mason, Goodman et al. 2006); however, their 
effect sizes compared to placebo are small (Mark, Kranzler et al. 2003; Rosner, Hackl-
Herrwerth et al. 2010; Oliva, Maisel et al. 2011). 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 (Franck 
and Jayaram-Lindstrom 2013). There is limited evidence of the efficacy of disulfiram, and its 
potential for toxicity limits it use (2009). These concerns about safety and limited efficacy likely 
contribute to the fact that FDA-approved medications for AUD are not widely prescribed (Mark, 
Kranzler et al. 2003; Mark, Kranzler et al. 2003). Indeed, only 2.8% of patients treated in the 
Veterans Health Administration who were diagnosed with an AUD received pharmacotherapy 
(Oliva, Maisel et al. 2011). Given these issues and concerns, several medications, other than 


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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 (Hargreaves and McGregor 2007; Breslin, 
Johnson et al. 2010) and clinical studies (Johnson, Ait-Daoud et al. 2003; Rubio, Ponce et al. 
2004; Johnson, Rosenthal et al. 2007; Miranda, MacKillop et al. 2008) show that topiramate is 
effective in reducing heavy drinking. Specifically, topiramate reduced alcohol craving (Rubio, 
Ponce et al. 2004); had a moderate treatment effect in reducing heavy drinking in three 
published placebo-controlled trials (Johnson, Ait-Daoud et al. 2003; Johnson, Rosenthal et al. 
2007; Miranda, MacKillop et al. 2008), and appears to have a larger effect size than naltrexone 
(Baltieri, Daro et al. 2008; Florez, Saiz et al. 2011) and acamprosate (Kenna, Lomastro et al. 
2009). Kranzler, Covault et al. (2014 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 (Childress, Mozley et al. 1999; Grusser, Wrase et al. 2004; Hutchison, Rutter 
et al. 2004; Franklin, Wang et al. 2007; Langleben, Ruparel et al. 2008; Goldman, Szucs-Reed 
et al. 2013). 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 (Myrick, 
Anton et al. 2008), 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 (Johnson, Ait-Daoud et al. 2003; Johnson, Rosenthal et al. 2007; Miranda, MacKillop et al. 
2008) and self-reported craving (Rubio, Ponce et al. 2004), 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 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, 


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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) (Kranzler and Edenberg 2010). 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 (Kranzler, Gelernter et al. 
2009), 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 (Del Re, 
Gordon et al. 2013), 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 (Johnson, Ait-Daoud et al. 2003; Rubio, Ponce et al. 2004; Johnson, 
Rosenthal et al. 2007; Miranda, MacKillop et al. 2008), 2) appears to have a larger effect size 
than naltrexone (Baltieri, Daro et al. 2008; Florez, Saiz et al. 2011) and acamprosate (Kenna, 
Lomastro et al. 2009), and 3) has dual GABAA-mediated inhibitory impulses and AMPA and 
kainate antagonist effects (Johnson and Ait-Daoud 2010) 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.   
13.2  Risk/Benefits 
Potential Risks 
The potential risks of this study include the small risk incurred by venipuncture 
Potential Benefits 
Subjects will 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.  
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.  
14 Sub-Study Objectives 
Objective 1:  Demonstrate neuromodulatory effects of a GABA/glutamate modulator, 
topiramate, on RB and alcohol cue reactivity 


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     Hypothesis 1: 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 2: Examine the mechanism underlying topiramate’s ability to blunt alcohol cue 
reactivity and reduce heavy drinking days 
     Hypothesis 2: 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. 
15 Sub-Study Design 
15.1  General Design 
 
Phase II Study - This is a phase 2 research study aimed at identifying the brain and 
behavioral mechanisms underlying the GABA/glutamate modulator, topiramate. 
 
Design – One hundred heavy drinkers who meet DSM-5 criteria for AUD and express 
an interest in reducing or stopping drinking will be recruited from the main study, 
screened, consented, and if eligible, receive 2 MRI scans. Scan 1 will occur before 
Topiramate or placebo is administered in the main study. Scan 2 will occur after subjects 
have received at least six weeks of medication in the main study (i.e., 6-8 weeks from 
the first dose of study medication). We will use perfusion and blood oxygen-level 
dependent (BOLD) fMRI during resting state and alcohol cue exposure to acquire brain 
and behavioral responses when the brain is “at rest” and during exposure 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.  
15.2  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. 
15.3  Secondary Study Endpoints 
The effects of rs2832407 on topiramate’s neural mechanisms 
16 Sub-Study Subject Selection and Withdrawal 
16.1  Inclusion Criteria 
1) 
Subjects have consented to main study protocol and are eligible to randomize to 
study medication 


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2) 
Age 18 to 60 years, Inclusive  
3) 
Provide voluntary informed consent 
4) 
Intelligence quotient of ≥ 80, as estimated by the 2-subtest score of the Wechsler 
Abbreviated Scale of Intelligence (WASI) (Wechsler 1999) 
5)        Agree to complete the first MRI visit before being randomized to study medication 
in the main study and agree to complete the second MRI after taking 6 weeks of 
study medication and before 8 weeks on study medication. 
 
16.2  Exclusion Criteria 
1) 
History of head trauma or injury causing loss of consciousness, lasting more than  
five (5) minutes or associated with skull fracture or intracranial bleeding or  
abnormal MRI 
 
2)   
History of seizures 
3) 
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 
4) 
Claustrophobia or other medical condition preventing subject from lying in the 
MRI for approximately one (1) hour 
5)  
Vision problems that cannot be corrected with glasses  
6)  
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] 
7) 
Individuals suffering from or with a history of stroke and/or stroke related 
spasticity 
8) 
Individuals who are HIV positive, as the human immunodeficiency virus affects 
neurocognitive function, even in otherwise asymptomatic individuals (Woods et 
al. 2009), which can confound the results of fMRI testing. 
9) 
Individuals who have taken topiramate for alcohol use disorder and report no 
treatment response 
10) 
Urine drug screen positive for recent use of opioids, cocaine, or amphetamines. 
11) 
Positive urine pregnancy test for females.  
16.3  Subject Recruitment and Screening 
Subjects will be recruited from among those who have completed the main study phone screen 
and are deemed eligible for a screening visit for the main study. Subjects will first be given 
information about this optional study over the phone when the study staff schedules the subject 
for the main study Informed Consent and Screening visit. If the subjects are interested, they will 
be provided with an overview of the study and asked a few more questions related to the Sub-
study, to assess eligibility. All potential subjects will be informed that participation in the optional 
sub-study will in no way affect their opportunity to participate in the main study. Additionally, 
they will be informed that they must be eligible for randomization into the main study to 
participate in this sub-study. If the individual satisfies preliminary criteria and shows continued 
interest in participating in the optional sub-study, he or she can choose either to schedule their 
screening visit for the sub-study on the same day as the screening visit for the main study or to 
schedule the visits separately. In all cases, the subject will be consented to the main study and 
complete all procedures for the main study screening visit and be deemed eligible, before being 
consented to the sub-study and completing the sub-study screening visit.  
At the sub-study screening visit, subjects who otherwise meet inclusion/exclusion criteria for the 
MRI sub-study and express an interest in participating in the sub-study will undergo oral HIV 


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testing, as HIV seropositivity is an exclusion criterion for the sub-study.  If the oral HIV test is 
positive, the nurse will inform the subject of the results, counsel the subject regarding the need 
to confirm the finding with a blood test and to avoid potential exposure of others to HIV, and 
draw 1 tablespoon of blood to conduct a confirmatory HIV blood test. If the blood test is positive 
for HIV, the subject will be referred for medical care and given a copy of the test results to 
provide to the doctor of his or her choice for the follow-up visit. 
 
If the individual satisfies study inclusion/exclusion criteria and shows continued interest in 
participating in the sub-study, an appointment will be made for the Laboratory/MRI Scanning 
Session 1. This visit can be scheduled in conjunction with the subjects’ main study baseline visit 
or separately depending on the subject’s availability and MRI scan times.  This will help to 
ensure that the subject completes the screening visit and the MRI visit prior to beginning the 
study medication (i.e. before or at the baseline visit). The initial screening process will be 
described and the individual will also be informed that s/he must be available for at least one 
more scan visit to be scheduled after the completion of 6 weeks of study medication (to achieve 
a maximal dosage of topiramate 200 mg/day or placebo equivalent).  The second scan will be 
scheduled before the 8-week treatment visit (i.e., 6-8 weeks from the first dose of the study 
medication). 
16.4  Early Withdrawal of Subjects 
16.4.1  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. Suicidal risks will be assessed using the MINI 
Suicidality section (B) at each of the Main study visits, and if rated equal to or greater than 9 
(i.e., clinically significant suicidal ideation), the physician will be consulted to decide the 
appropriate clinical management. 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. Subjects that withdraw from the Main study will be withdrawn 
from this sub-study. 
The PI, Dr. Wetherill, will determine whether a subject who experiences a serious adverse event 
judged to be related to the study drug will be withdrawn from the sub-study. 
16.4.2  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. 
 
Study Procedures 
There are 3 main parts to this study. Depending on the subject’s availability, the parts may be 
combined with visits for the Main Study. Thus, it is possible that one, two or all three of the MRI 
study visits (i.e., screening and the two MRI scan visits) will be combined with regular study 
visits.  
16.5  Screening and Informed Consent (approximately1.5 hours) 
Upon arriving to the Informed Consent and Screening Visit, subjects will be asked to complete a 
breathalyzer test to ensure a breath alcohol concentration (BrAC) of 0.00 g%. Subjects will then 
undergo the informed consent process. 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 


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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 and meet with study staff to complete study assessments.  They will also be 
asked to complete an MRI safety sheet.  Baseline laboratory measures include: 1) urine drug 
screen (to determine the presence of psychoactive drugs); 2) electrocardiogram; 3) oral swab 
rapid HIV test (If the test is positive, study staff will draw a tablespoon of blood to conduct a 
confirmatory HIV blood test); and 4) for all females: a urine pregnancy test.  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).  
Measures obtained (in addition to those obtained routinely for the Main Study): 
 
a. 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 (Epperson, O'Malley et al. 2005), and these changes influence CBF (Krejza, 
Rudzinski et al. 2013) and behavior (Silveri, Sneider et al. 2013). Thus, this questionnaire (and 
progesterone/estrogen levels) will help us determine if females are pre-, peri- or post-
menopausal. 
 
b. Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler 1999) 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 (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. 
All screening assessments will be performed to determine subject eligibility, and the results will 
be documented. The PI or study physician will confirm and sign off on the inclusion and 
exclusion criteria on a case report form prior to the subject being formally included in the study. 
Subjects will be called within 5 days of the screening visit to be informed of their eligibility for the 
sub-study. Eligible subjects will be booked for the Laboratory/MRI Scanning visit either before or 
on the day of the Main Study baseline visit based on their and the MRI scanner’s availability. 
Subjects must complete MRI Scanning Visit 1 before starting to take the study medication.     
c. CogState computerized battery is a 20-minute assessment of the cognitive effects 
of changes in drinking behavior and of topiramate treatment.  A practice session of the 
CogState will be administered at the Screening and Informed Consent visit. Subsequent 
sessions of the CogState will be administered at the Laboratory/MRI session 1 and 2 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. 


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 
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. 
 
16.6 Laboratory/MRI Scanning Visit 1 (approximately 3 hours) 
Upon arriving to the Laboratory/MRI Scanning visit, subjects will be asked to complete a 
breathalyzer test to ensure a breath alcohol concentration (BrAC) of 0.00 g%. 
 
Baseline laboratory measures include:  
o 1) urine drug screen (to determine the presence of psychoactive drugs);  
o 2) in all females: a urine pregnancy test and an additional blood sample for 
biochemical measurement of progesterone and estradiol levels to determine their 
menstrual cycle phase. A total of approximately 1 tablespoon of blood will be 
taken.  
 


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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).  
Measures obtained (in addition to those obtained routinely for the Main Study): 
a. CogState Computerized Battery: Described above. 
b. Cognitive Bias Computer Tasks: 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 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.  
 
c. Within Session Rating Scale (WSRS): This scale is used to assess a person’s 
desire to consume alcohol and their thoughts about the audio/visual images viewed during the 
scanning session.  
 
Prior to the scan session, subjects will complete the CIWA-Ar and the AUQ to assess 
withdrawal symptoms and alcohol craving. Study staff will walk or take a taxi with the subject to 
the 3.0 Tesla scanner to complete the MRI scan. Prior to entering the scanner, subjects will be 
asked to drink to satiety 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.  
 
MRI scanning will be conducted on a Siemens 3.0 Tesla 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 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.   


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16.7  Laboratory/MRI Scanning Visit 2 (approximately 3 hours) 
After the subject has completed 6 weeks of medication in the main study, they will complete the 
second scanning session. Upon arriving at the TRC, subjects will be asked to complete a 
breathalyzer test to ensure a breath alcohol concentration (BrAC) of 0.00 g%.  Procedures for 
the Laboratory/MRI Session 2 visit are identical to those for the first Laboratory/MRI Session.  
 
17  Sub-Study Statistical Plan 
17.1  Sample Size Determination 
The current sample size is based on our previous research examining drug cue reactivity using 
audio-visual videos both on- and off-magnet through computerized tasks and during fMRI 
scanning.  
17.2  Statistical Methods 
17.2.1  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. 
17.2.2  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 GRIK1 on topiramate effects using 
the same simple regression analyses described above.  We will limit this analysis to European 


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Americans, as that is the population in which the preliminary findings were obtained and allele 
frequencies differ significantly by population. 
17.2.3  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. 
17.3  Subject Stipends or Payments 
Subjects will be paid $50 to complete the Screening and Informed Consent visit. They will also 
be paid $150 to complete the initial MRI session visit, and $200 to complete the second MRI 
visit. The total amount that subjects can receive for full participation in the sub-study is $400. 
Payments will be made with a GreenPhire ClinCard. Clincards are reloadable prepaid cards that 
may be used for in-store purchases (by selecting either the “credit” or “debit” option), online 
purchases, at an ATM to get cash, or for cash advances at a bank. 
 
Schedule for Sub-Study Payments 
Visit  
Payment 
 
Total  
Screening and Informed Consent 
$50 
 
$50 
MRI Scanning Visit 1 
$150 
 
$150 
MRI Scanning Visit 2 
$200 
 
$200 
Totals 
Up to $400 
 
$400 
*Subjects will receive a pro-rated portion of the payment based on the extent to which they 
complete the study visit.   
 
*ALL REMAINING ASPECTS OF THE SUB-STUDY ARE DESCRIBED ABOVE IN SECTIONS 8-12. 
 
18  Confidentiality 
 
A Certificate of Confidentiality from the National Institute on Alcohol Abuse and Alcoholism 
(NIAAA) that is separate from the one for the main study will be obtained for the sub-study 
described in this protocol. As per the NIAAA’s website: Confidentiality Certificates are issued by 
NIH Institutes pursuant to Section 301 (d) of the Public Health Service U.S.C. Section 241 (d) to 
afford special privacy protection to subjects enrolled in biomedical, behavioral, clinical, or other 
research within NIH mission areas. A Certificate helps the researcher avoid compelled 
'involuntary disclosure' (e.g., subpoenas) of identifying information about a research subject. It 
does not prevent voluntary disclosures such as disclosure to protect the subject or others from 
serious harm, as in cases of child abuse. Also, a researcher may not rely on a Certificate to 
withhold data if the subject consents to the disclosure. When a researcher obtains a Certificate 
of Confidentiality, the subjects must be told about the protections afforded by the Certificate, 
and any exceptions to that protection. This information is usually included in an 'informed 
consent'. 


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All subjects will be informed about the protections afforded by the Certificate in the Informed 
Consent Form for both the main and sub-study using the language inserted below: 
“To further help us protect your privacy, we have obtained a Certificate of Confidentiality from 
the United States Department of Health and Human Services (DHHS).  
With this Certificate, we cannot be forced (for example by court order or subpoena) to disclose 
information that may identify you in any federal, state, local, civil, criminal, legislative, 
administrative, or other proceedings. The researchers will use the Certificate to resist any 
demands for information that would identify you, except to prevent serious harm to you or 
others, and as explained below.  
You should understand that a Certificate of Confidentiality does not prevent you, or a member of 
your family, from voluntarily releasing information about yourself, or your involvement in this 
study.  
If an insurer or employer learns about your participation, and obtains your consent to receive 
research information, then we may not use the Certificate of Confidentiality to withhold this 
information. This means that you and your family must also actively protect your own privacy.  
You should understand that we will in all cases, take the necessary action, including reporting to 
authorities, to prevent serious harm to yourself, children, or others (for example, in the case of 
child abuse or neglect).” 
This language is located in the section of both of the Informed Consent Forms titled “Who can 
see or use my information?  How will my personal information be protected?” 
 
19    APPENDIX II: CLINCARD PROGRAM: DATA SECURITY & 
PRIVACY STATEMENT 
 
ClinCard Program: Data Security & Privacy Statement 
Updated 14 January 2016 
 
Confidentiality of Protected Health Information (PHI) 
All clinical trial participant information is stored securely. Greenphire does not sell, use or distribute 
clinical trial participant information for any purpose other than those needed to execute, service and 
maintain the ClinCard program (including ClinCard Direct Deposit and Travel Reimbursement methods).  
Greenphire protects the privacy of Electronic Protected Health Information (“EPHI”), disclosed or provided 
to us in compliance with the Security Standards for the Protection of Electronic Protected Health 
Information at 45 CFR Sections 160 and 164 (the “Security Rules”). Towards that end, Greenphire has 
implemented administrative, physical, and technical safeguards (detailed below) that reasonably and 
appropriately protect the confidentiality, integrity, and availability of EPHI; ensures that any agent or 
subcontractor to whom we provide EPHI agrees to implement reasonable and appropriate safeguards to 
protect it; and will report any Security Incident involving EPHI of which it becomes aware within five (5) 
days of learning of the Security Incident.  
 
Data Information Security  
As a matter of policy and commitment to clients and clinical trial participants, Greenphire takes great 
strides to protect all information relating to cardholders. Greenphire has deliberately designed its 
payments and communication platform including all of Greenphire’s externally facing web toolsto actively 
protect all data transfers and data stored with Greenphire’s infrastructure:  
 
Database and Encryption– All passwords within our database are protected using the one-way 
SHA1 algorithm to encrypt passwords, which are then encrypted by the one-way MD5 algorithm. Where 


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necessary, Greenphire’s platform makes use of encryption using the 256 bit Advanced Encryption 
Standard (AES or otherwise known as Rijndael), which is one of the most popular algorithms used in 
symmetric key cryptography. AES is approved by the US National Intelligence Agency (NSA) for top 
secret information.  
 
Web Tools – All of Greenphire’s web tools that are involved in transferring data between an end-
user's web browser and Greenphire’s platform (and vice versa) are secured by 256 bit Secured Socket 
Layer (SSL) with TLS 1.2 encryption. Greenphire is able to track the activities performed on accounts by 
site administrators through a system of unique logins which allow users access to the clincard.com web 
tool. In addition, all user activities in the Greenphire Platform are auditable.  
 
Financial Data Transfer - Communications between the Greenphire platform and financial 
networks are executed via Web Service (API) or sFTP transport. 
 
Physical Protection – Greenphire houses its internal database on servers that are located in a 
highly secure, off-site facility. Access to the physical servers at the facility is limited to Network Operations 
Center (NOC) Engineers and Technicians. The facility is secured with a bio-metric security system that 
can track access to the facility and is monitored by digital security video surveillance, includes multiple 
suppliers for network connectivity and redundant power supplies including on-site power generation in the 
event of emergency.  
 
Authorized Access – Greenphire restricts access to sensitive data to only a limited number of 
essential internal personnel. Authorized individuals are only permitted to access data if it is required to 
service our client, their authorized users or the clinical trial participant. The number of authorized 
individuals remains limited to protect against internal threats to the security of sensitive data. 
  
Proactive Design - Greenphire’s internal technology platform has been intentionally designed to 
exclude the requirement of certain sensitive information that other similar companies require to be stored 
in their systems, such as PIN numbers. If new types of sensitive data must be introduced and stored, per 
the design of a specific protocol, Greenphire will protect the data using the encryption methods described 
previously.  
 
Customer Service - Greenphire provides all of its cardholders with 24/7/365 customer service. 
Customer service is handled by both an automated IVR system and a call center where live customer 
service representatives may provide financial assistance to cardholders. Customer service functionality is 
intentionally kept separate from implementation and client support and, consequently, no information is 
shared with customer service representatives related to the protocol, sponsor, structure of the trial, 
medical indication or other potentially sensitive information.  
 
Quality Control Process - Greenphire’s Quality Control (QC) Department performs system 
testing in an isolated environment to test and ensure that the software is functioning properly. Each new 
piece of functionality is thoroughly tested individually. In addition, QC conducts integration and regression 
testing before new code is approved for movement into production. When a change to the system 
necessitates a change to the database, the required changes and process to make the changes are 
documented and tested prior to being performed on production. No code is pushed to production until it 
has passed QC testing. Data used in QC is test data and does not include data that is, or ever was, 
production data.  
 
Safe Harbor 
Greenphire has voluntarily obligated itself to the jurisdiction of the U.S. Department of Commerce by 
selfcertifying to the Safe Harbor framework necessary to receive personal data from companies doing 
business in the European Union and Switzerland. Further information regarding the U.S. – EU and U.S. - 
Swiss Safe Harbor Frameworks is available at export.gov/safeharbor/index.asp 


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20  References 
 
(2009). VA/DOD Clinical Practice Guidelines for Management of Substance Use Disorder (SUD): 
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Agrawal, A., A. C. Heath, et al. (2011). "DSM‐IV to DSM‐5: the impact of proposed revisions on diagnosis 
of alcohol use disorders." Addiction 106(11): 1935-1943. 
 
 
Alcoholism, N. I. o. A. A. a. (2013). "NIAAA recognizes alcohol awareness month." Retrieved April 29, 
2013, April 1, 2013, from http://www.niaaa.nih.gov/news-events/alcohol-awareness-month-2013. 
 
 
Baltieri, D. A., F. R. Daro, et al. (2008). "Comparing topiramate with naltrexone in the treatment of alcohol 
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Bohn, M. J., D. D. Krahn, et al. (1995). "Development and initial validation of a measure of drinking urges 
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Breslin, F. J., B. A. Johnson, et al. (2010). "Effect of topiramate treatment on ethanol consumption in 
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Carney, M. A., H. Tennen, et al. (1998). "Levels and Patterns of Alcohol Consumption Using Timeline 
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Childress, A. R., P. D. Mozley, et al. (1999). "Limbic activation during cue-induced cocaine craving." The 
American journal of psychiatry 156(1): 11-18. 
 
 
Del Re, A. C., A. J. Gordon, et al. (2013). "Prescription of topiramate to treat alcohol use disorders in the 
Veterans Health Administration." Addiction science & clinical practice 8(1): 12. 
 
 
Epperson, C. N., S. O'Malley, et al. (2005). "Sex, GABA, and nicotine: the impact of smoking on cortical 
GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy." 
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Fagerstrom, K. O. and N. G. Schneider (1989). "Measuring nicotine dependence: a review of the 
Fagerstrom Tolerance Questionnaire." Journal of behavioral medicine 12(2): 159-182. 
 
 
Feinn, R., H. Tennen, et al. (2003). "Measurement and prediction of medication compliance in problem 
drinkers." Alcoholism: Clinical and Experimental Research 27(8): 1286-1292. 
 
 
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Franklin, T. R., Z. Wang, et al. (2007). "Limbic activation to cigarette smoking cues independent of 
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Gibbs, J. W., S. Sombati, et al. (2000). "Cellular Actions of Topiramate: Blockade of Kainate‐Evoked 
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Goldman, M., R. P. Szucs-Reed, et al. (2013). "Reward-related brain response and craving correlates of 
marijuana cue exposure: a preliminary study in treatment-seeking marijuana-dependent subjects." 
Journal of addiction medicine 7(1): 8-16. 
 
 
Grant, B. F., D. A. Dawson, et al. (2004). "The 12-month prevalence and trends in DSM-IV alcohol abuse 
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234. 
 
 
Grusser, S. M., J. Wrase, et al. (2004). "Cue-induced activation of the striatum and medial prefrontal 
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Gryder, D. S. and M. A. Rogawski (2003). "Selective antagonism of GluR5 kainate-receptor-mediated 
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Hamburg, M. A. and F. S. Collins (2010). "The path to personalized medicine." New England journal of 
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Hargreaves, G. A. and I. S. McGregor (2007). "Topiramate moderately reduces the motivation to 
consume alcohol and has a marked antidepressant effect in rats." Alcoholism, clinical and experimental 
research 31(11): 1900-1907. 
 
 
Harris, A. H., D. R. Kivlahan, et al. (2010). "Pharmacotherapy of alcohol use disorders in the Veterans 
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Helander, A., J. P. Wielders, et al. (2010). "Toward standardization of carbohydrate-deficient transferrin 
(CDT) measurements: II. Performance of a laboratory network running the HPLC candidate reference 
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Laboratory Medicine 48(11): 1585-1592. 
 
 
Hutchison, K. E., M. C. Rutter, et al. (2004). "Olanzapine attenuates cue-elicited craving for tobacco." 
Psychopharmacology 175(4): 407-413. 
 
 
Johnson, B. A. and N. Ait-Daoud (2010). "Topiramate in the new generation of drugs: efficacy in the 
treatment of alcoholic patients." Current pharmaceutical design 16(19): 2103-2112. 
 
 
Johnson, B. A., N. Ait-Daoud, et al. (2003). "Oral topiramate for treatment of alcohol dependence: a 
randomised controlled trial." The Lancet 361(9370): 1677-1685. 
 
 
Johnson, B. A., N. Ait-Daoud, et al. (2003). "Oral topiramate for treatment of alcohol dependence: a 
randomised controlled trial." Lancet 361(9370): 1677-1685. 
 
 
Johnson, B. A., N. Rosenthal, et al. (2007). "Topiramate for treating alcohol dependence: a randomized 
controlled trial." Jama 298(14): 1641-1651. 
 
 
Johnson, B. A., N. Rosenthal, et al. (2007). "Topiramate for treating alcohol dependence: a randomized 
controlled trial." JAMA : the journal of the American Medical Association 298(14): 1641-1651. 
 
 
Kaminski, R. M., M. Banerjee, et al. (2004). "Topiramate selectively protects against seizures induced by 
ATPA, a GluR5 kainate receptor agonist." Neuropharmacology 46(8): 1097-1104. 
 
 
Karhuvaara, S., K. Simojoki, et al. (2007). "Targeted Nalmefene With Simple Medical Management in the 
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Kenna, G. A., T. L. Lomastro, et al. (2009). "Review of topiramate: an antiepileptic for the treatment of 
alcohol dependence." Current drug abuse reviews 2(2): 135-142. 
 
 
Kranzler, H. R., S. Armeli, et al. (2013). "Variation in OPRM1 moderates the effect of desire to drink on 
subsequent drinking and its attenuation by naltrexone treatment." Addiction biology 18(1): 193-201. 
 
 
Kranzler, H. R., S. Armeli, et al. (2003). "Targeted naltrexone for early problem drinkers." Journal of 
clinical psychopharmacology 23(3): 294-304. 
 
 
Kranzler, H. R., J. Covault, et al. (2014). "Topiramate treatment for heavy drinkers: moderation by a 
GRIK1 polymorphism." American Journal of Psychiatry 171(4): 445-452. 
 
 
Kranzler, H. R. and H. J. Edenberg (2010). "Pharmacogenetics of alcohol and alcohol dependence 
treatment." Current pharmaceutical design 16(19): 2141-2148. 
 
 
Kranzler, H. R., J. Gelernter, et al. (2009). "Association of markers in the 3' region of the GluR5 kainate 
receptor subunit gene to alcohol dependence." Alcoholism, clinical and experimental research 33(5): 925-
930. 
 
 
Kranzler, H. R., J. Gelernter, et al. (2009). "Association of markers in the 3′ region of the GluR5 kainate 
receptor subunit gene to alcohol dependence." Alcoholism: Clinical and Experimental Research 33(5): 
925-930. 
 
 
Kranzler, H. R., H. Tennen, et al. (2009). "Targeted naltrexone for problem drinkers." Journal of clinical 
psychopharmacology 29(4): 350. 
 
 
Krejza, J., W. Rudzinski, et al. (2013). "Cerebrovascular reactivity across the menstrual cycle in young 
healthy women." Neuroradiol J 26(4): 413-419. 
 
 
Kroenke, K., R. L. Spitzer, et al. (2001). "The Phq‐9." Journal of general internal medicine 16(9): 606-613. 
 
 
Langleben, D. D., K. Ruparel, et al. (2008). "Acute effect of methadone maintenance dose on brain FMRI 
response to heroin-related cues." The American journal of psychiatry 165(3): 390-394. 
 
 
Leigh, B. C. and A. W. Stacy (1993). "Alcohol outcome expectancies: Scale construction and predictive 
utility in higher order confirmatory models." Psychological Assessment 5(2): 216. 
 
 
Lieberman, R., E. S. Levine, et al. (2012). "Pilot Study of iPS‐Derived Neural Cells to Examine Biologic 
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1678-1687. 
 
 
Mark, T. L., C. A. Kassed, et al. (2009). "Alcohol and opioid dependence medications: prescription trends, 
overall and by physician specialty." Drug and alcohol dependence 99(1): 345-349. 
 
 
Mark, T. L., H. R. Kranzler, et al. (2003). "Understanding US addiction physicians' low rate of naltrexone 
prescription." Drug and alcohol dependence 71(3): 219-228. 
 
 
Mark, T. L., H. R. Kranzler, et al. (2003). "Understanding US addiction physicians’ low rate of naltrexone 
prescription." Drug and alcohol dependence 71(3): 219-228. 
 
 
Mark, T. L., H. R. Kranzler, et al. (2003). "Physicians' opinions about medications to treat alcoholism." 
Addiction 98(5): 617-626. 
 
 
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Addiction 98(5): 617-626. 


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ICF_003.pdf: 
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NCT02371889   UNIQUE PROTOCOL ID: 821035   SECONDARY IDS: 821035, 
R01AA023192 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Title: A Randomized, Double-blind Placebo-Controlled Pharmacogenetic 
Study of Topiramate in European-American Heavy Drinkers (TOPG) Protocol with 
Statistical Analysis Plan 
Feburary 19, 2019 


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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT 
INFORMED CONSENT AND HIPAA AUTHORIZATION FORM 
 
Protocol Title: 
A Randomized, Double-blind Placebo-controlled 
Pharmacogenetic Study of Topiramate in 
European-American Heavy Drinkers 
Protocol Number: 
821035 
Principal Investigator 
 
Henry Kranzler, M.D. 
Professor of Psychiatry 
Center for Studies of Addiction 
3535 Market St., Fifth Floor, Suite 500 Philadelphia. 
PA 19104 
(215) 746-1943 
Study Contact: 
Study Coordinator 
(215) 746-1902 or Press 0 for the Operator 
Emergency Contact: 
 
 
24 - Hour Emergency Pager #: 215-505-3799 
 
 
Why am I being asked to volunteer? 
 
You are being invited to participate in a research study because you are a regular drinker and 
expressed an interest in trying to reduce or stop your drinking. Your participation is voluntary, 
which means that you can choose whether you want to participate. If you choose not to be in the 
study, you will not lose any benefits to which you are otherwise entitled. Before you can make 
your decision, you will need to know what the study is about, the possible risks and benefits of 
being in this study, and what you will have to do as a participant in this study. We will give you 
this consent form to read and a copy to keep for future reference. You may also decide to discuss 
it with your family, friends, or family doctor. You may find some of the medical language difficult to 
understand. Please ask the study doctor and/or the research team about this form or about any 
other aspects of the study. If you decide to participate, you will be asked to sign this form. 
 
What is the purpose of this research study? 
This is a research study involving 12 weeks of study medication, topiramate or a placebo (a 
harmless, inactive substance) and brief counseling to reduce or stop drinking.  Topiramate is 
approved by the U.S. Food and Drug Administration to treat epilepsy, prevent migraine headaches 
and, combined with another medication (phentermine), for weight loss. Its use in the treatment of 
alcohol dependence is experimental. An earlier study by this research team showed that 
topiramate was more effective than placebo in people with a certain genotype (a person’s unique 
DNA makeup) than in other people. This genotype is more common in people of European descent 
than in other groups. The purpose of this study is to evaluate the safety and effectiveness of 


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topiramate compared to placebo in reducing the number of drinking days among European-
Americans who want to stop or reduce their drinking. 
We will draw a blood sample from you to extract your DNA to determine your genotype.  Because 
we will select people to participate based on their genotype, we may not be able to include you.  
Based on your genotype, we will evaluate you to determine whether you are otherwise eligible to 
participate in this study.  We will also use your genotype (DNA) to test it with your response to the 
study medication.  We will examine a number of genes thought to be involved in the effects of 
topiramate, including the one that we identified in our last study. Because the DNA analysis is a 
key part of the study, if you choose not to provide blood for a DNA sample, you will not be able to 
participate in the study.  
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by 
U.S. Law. This web site will not include information that can identify you. At most, the web site will 
include a summary of the results. You can search this web site at any time. 
 
MRI Sub-study: You may also have the opportunity to enroll in a separate sub-study that uses 
magnetic resonance imaging (MRI) to compare the effects of topiramate with placebo on your 
brain’s response to certain visual reminders of alcohol use. If you are eligible to enroll in the MRI 
sub-study, we will contact you to provide you with more detailed information about it. You will then 
be given a separate consent form to review and sign prior to participating in that study.  You are 
not required to participate in the MRI sub-study in order to participate in this research study. 
 
How long will I be in the study? How many other people will be in this 
study? 
The total duration of your involvement in this study is approximately 9 months. There is a 12-week 
period during which you will receive topiramate or placebo and brief counseling and a 6-day period 
at the end to taper and discontinue the study medication. There will also be 2 follow-up visits at 3 
and 6 months after completion of the study medication. The entire study will last for 5 years and 
will include up to 200 people, up to 100 of whom will be recruited from the Corporal Michael J. 
Crescenz Philadelphia VA Medical Center (CMCVAMC). 
 
What am I being asked to do? 
Before you enter the study, your eligibility to participate will be determined at a screening 
evaluation. You will be asked not to drink before this and all other visits. At all visits, the study 
nurse will check your breath alcohol level using a Breathalyzer. If your breath alcohol level is 
greater than 0.02%, you may not be able to complete the visit. 
1. Screening Visit: The screening visit will determine whether the study is a good fit for you. 
The entire visit should take about three hours. 
• 
First, we will ask you to show us a legal photo ID and then undergo a breathalyzer test to 
ensure that you are able to make a well-reasoned decision about whether or not to 
participate in the study. You must have a 0.00 breath alcohol level to complete this visit. 
Your reading ability will also be evaluated, so that we know that you can understand the 
consent form and study assessment questionnaires.   
• 
Once you have read this informed consent form and all of your questions have been 
answered, you will be asked to sign this form.  An entire copy of the informed consent form 
will be given to you. You will be reminded that your participation is voluntary, and at any 
time, you may withdraw from the study. Signing the consent form does not automatically 
enroll you in the study since the screening process might show the study is not a good 
match for you.  


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• 
The study staff will ask you to provide information on your medical history and family history 
of alcoholism. We will not ask you for your family members’ names or any other identifying 
information.    
• 
The study nurse will ask you questions about your medical history and perform a physical 
examination.  Study staff trained in drawing blood will draw a total of approximately 3 
tablespoons of blood for standard laboratory tests and to test your DNA. Your DNA will be 
studied to identify specific genetic markers that might influence risk of alcohol dependence 
(and related behaviors and disorders) and response to the study drug. It is possible that 
your bloodwork will need to be repeated due to unforeseen events (abnormal findings or 
potential lab errors).  Study staff will also ask you to provide a urine sample to conduct a 
urinalysis, drug screen, and for women of childbearing potential (i.e., who have not had a 
hysterectomy, bilateral removal of the ovaries, or a tubal ligation or is less than two years 
postmenopausal), a urine pregnancy test.  If you are pregnant, breast-feeding, or if you test 
positive for certain illegal drugs, you will not be eligible for the study. 
• 
If you are eligible and decide to participate in the study you will be required to provide the 
names and contact information of one or two people (trusted friends or family members) 
who may serve as additional contacts if we cannot locate you for safety or other study-
related reasons. We will only tell them that you are in a study and that you gave us their 
names to help us contact you, if we are unable to reach you during the study. 
• 
Study staff will then ask you to complete 6 assessments about your psychological health, 
alcohol and drug use history. You will also be asked to perform 2 tasks that will test your 
working memory. 
 
2. First Study Drug Visit (Week 1): We will contact you within 5 days after your screening 
visit to tell you whether you are eligible to participate in the study and to set up your next study 
visit. 
• 
This visit will take approximately one and one-half hours to complete and will occur no 
longer than 30 days after the screening visit.  
• 
You will be asked to complete a breathalyzer test and study staff will measure your weight 
and vital signs (blood pressure and heart rate). 
• 
If you are a woman of childbearing potential, study staff will obtain a urine sample from you 
for a pregnancy test.  
• 
You will be asked to complete 11 assessments about your psychological health and your 
alcohol and drug use history.  
• 
We will instruct you how to use the interactive voice response (IVR) system: Once you have 
started taking the study medication you will be asked to call a toll-free phone number each 
day, between 5:00 and 8:00 p.m. to connect you to an IVR system. The system uses your 
study ID and a password, which we will give you. You can access the system from a touch-
tone phone. The IVR system will prompt you to answer questions about your feelings, 
whether you used medication, and your use of alcohol each day and the preceding day.  
Once you become familiar with the system, the time required for completion of this interview 
is less than 5 minutes per day. If you do not call the IVR system by 8:15 p.m., you will 
receive a reminder call from the system at a phone number that you provide; the reminder 
prompt will not relay any details of the study or its purpose.  You will then have until 9:00 
p.m. to call the number for that day. 
• 
You will have your first brief counseling session, which will last about 30 minutes.  The 
study nurse will discuss with you your goal with respect to your drinking and encourage you 
to take your medication regularly.  The nurse will also encourage you to consider ways to 
reduce or stop your drinking, depending upon whether your goal is to drink less or become 
completely abstinent. 


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• 
With your permission, we will make an audiotape of this and all other counseling sessions 
that you receive during the study.  These tapes will be destroyed after they have been 
reviewed to ensure that the study nurse has followed correct counseling procedures.  
• 
You will be assigned to receive study medication, which will be either topiramate or placebo 
(a harmless, inactive substance) and will receive your first week’s supply of study 
medication. The decision on which medication you will receive is random, like a flip of a 
coin. The topiramate or placebo will look the same. Neither you nor any of the study 
personnel will know which medication you will receive. In an emergency, though, the 
pharmacist in charge of the study medication can be contacted. 
The study nurse will provide you with detailed dosing instructions and will adjust your study 
medication dose as necessary during the 12-week period.  Study medication will be 
provided in capsules and will be packaged in child-resistant bottles.  It is important that you 
follow your study nurse’s instructions on when and how to take the study medication.  At 
each visit, study staff will ask you about any side effects or other adverse events that you 
may have experienced. 
3.  Weekly Visits (Weeks 2-6): At each weekly visit:  
• 
Your breath alcohol concentration (Breathalyzer), weight, and vital signs will be checked 
and you will be asked about any side effects or other adverse events that you may have 
experienced. 
• 
The study staff will ask you to complete 6 assessments about your psychological health and 
your alcohol and drug use history. These should take about 20 minutes to answer. 
• 
You will receive brief counseling from the study nurse, which will last about 15 minutes. 
• 
The study nurse will collect your study medication bottles with any remaining capsules and 
dispense another week’s supply of study medication. In the event that study medication is 
not ready to be given to you at the time of the study visit (because for example, the nurse 
and/or physician determine at the time of the study visit that you require a reduced dosage), 
study staff will mail you the study medication via UPS or FedEx to prevent you running out 
of study medication. You will be asked to sign for the delivery and the study nurse will call 
you to ensure that you received the study medication, to provide you with instructions on 
how to take the study medication, and to ask you about any side effects you may have 
experienced.   
• 
You will continue to call the IVR toll-free number nightly. 
• 
At week 5, if you are a woman of childbearing potential, you will have another urine 
pregnancy test. If the test is positive, showing that you are pregnant, we will discontinue the 
medication and you will be referred to an obstetrician for care. 
• 
Every week, for the first 6 weeks, the dose of the medication will be gradually increased.  
4.  Week 6 Visit: At this visit:  
• 
Your breath alcohol concentration (Breathalyzer), weight, and vital signs will be checked 
and you will be asked about any side effects or other adverse events that you may have 
experienced. 
• 
The study staff will ask you to complete 6 assessments about your psychological health and 
your alcohol and drug use history. These should take about 20 minutes to answer. 
• 
Study staff will draw 1 tablespoonful of blood for lab tests.  
• 
If you are a woman of childbearing potential, you will have another urine pregnancy test. If 
the test is positive, you will be referred to an obstetrician and you will not be allowed to 
continue in the study. 
• 
You will receive brief counseling from the study nurse, which will last about 15 minutes. 
• 
The nurse will collect your study medication bottles with any remaining capsules and 
dispense another week’s supply of study medication 


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• 
In the event that study medication is not ready to be given to you at the time of the study 
visit (because for example, the nurse and/or physician determine at the time of the study 
visit that you require a reduced dosage), study staff will mail you the study medication via 
UPS or FedEx to prevent you running out of study medication. You will be asked to sign for 
the delivery and the study nurse will call you to ensure that you received the study 
medication, to provide you with instructions on how to take the study medication, and to ask 
you about any side effects that you may have experienced.   
• 
You will continue to call the IVR toll-free number nightly. 
5.  Biweekly Visits (Weeks 8 and 10): At each biweekly (every other week) visit: 
• 
Your breath alcohol concentration (Breathalyzer), weight, and vital signs will be checked 
and you will be asked about any side effects or other adverse events that you may have 
experienced. 
• 
The study staff will ask you to complete 6 assessments about your psychological health and 
your alcohol and drug use history. These should take about 20 minutes to answer. 
• 
You will receive brief counseling from the study nurse, which will last about 15 minutes. 
• 
The nurse will collect your study medication bottles with any remaining capsules and 
dispense another week’s supply of study medication.  
• 
In the event that study medication is not ready to be given to you at the time of the study 
visit (because for example, the nurse and/or physician determine at the time of the study 
visit that you require a reduced dosage), study staff will mail you the study medication via 
UPS or FedEx to prevent you running out of study medication. You will be asked to sign for 
the delivery and the study nurse will call you to ensure that you received the study 
medication, to provide you with instructions on how to take the study medication, and to ask 
you about any side effects that you may have experienced.   
• 
At week 8, if you are a woman of childbearing potential, you will have another urine 
pregnancy test. 
• 
You will continue to call the IVR toll-free number nightly. 
6.  Week 12 Visit and Taper: 
• 
Your breath alcohol concentration (Breathalyzer), weight, and vital signs will be checked 
and you will be asked about any side effects or other adverse events that you may have 
experienced. 
• 
The study staff will ask you to complete 6 assessments about your psychological health and 
your alcohol and drug use history. These should take about 20 minutes to complete.  
• 
You will receive brief counseling from the study nurse, which will last about 15 minutes. 
• 
If you are a woman of childbearing potential, you will have another urine pregnancy test. 
• 
The study nurse will collect your study medication bottles with any remaining capsules and 
dispense the final supply of medication.  
• 
In the event that study medication is not ready to be given to you at the time of the study 
visit (because for example, the nurse and/or physician determine at the time of the study 
visit that you require a reduced dosage), study staff will mail you the study medication via 
UPS or FedEx to prevent you running out of study medication. You will be asked to sign for 
the delivery and the study nurse will call you to ensure that you received the study 
medication, to provide you with instructions on how to take the study medication, and to ask 
you about any side effects that you may have experienced.   
• 
At this visit, you will be instructed on how to safely taper the medication dose over 6 days.  
• 
You will continue to call the IVR toll-free number nightly to complete 12 weeks of phone 
calls. 
7.  Endpoint Visit (Week 13): 


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• 
Your breath alcohol concentration (Breathalyzer), weight, and vital signs will be checked 
and you will be asked about any side effects or other adverse events that you may have 
experienced. 
• 
The study staff will ask you to complete 11 assessments about your psychological health 
and your alcohol and drug use history. These should take about 45 minutes to complete. 
You will also be asked to perform 2 tasks that will test your working memory. 
• 
Study staff will draw 1 tablespoonful of blood for lab tests. 
• 
You will receive brief counseling from the study nurse, which will last about 15 minutes. 
• 
The nurse will collect your study medication bottles with any remaining capsules. 
 
8.  Follow-up Visits (Months 3 and 6): At the two follow-up visits (one hour each): 
• 
The study staff will check your breath alcohol concentration (Breathalyzer), weight and vital 
signs.    
• 
Study staff will draw 1 tablespoonful of blood for lab tests.  
• 
Study staff will ask you to complete 9 assessments about your psychological health and 
your alcohol and drug use history.  You will also be asked to perform 2 tasks that will test 
your working memory. 
• 
Once you have completed this study visit you will have the option of receiving a letter from 
the UPenn Investigational Pharmacy to tell you whether you received topiramate or 
placebo.     
Early Termination Visit 
• 
If you choose to withdraw from the study early, we will ask you to return to the research 
center for a visit to allow these procedures to be done and the study nurse to instruct you 
on how to decrease and stop taking the study medication.   
 
What are the possible risks or discomforts?  
Risks and Side Effects Associated with Topiramate  
The most common adverse effect of topiramate compared to placebo is numbness and tingling 
(49%of patients).  The other most commonly reported side effects (experienced by 10-31% of 
patients) include: change in sense of taste, tiredness/sleepiness, fatigue, dizziness, loss of 
appetite, nausea, diarrhea, weight decrease, difficulty concentrating and difficulty with memory.    
Other side effects (experienced by 5-9% of participants) in some clinical trials include: 
nervousness, slow thinking, abnormal vision, confusion, decreased sensitivity, anxiety, abdominal 
pain, dry mouth, involuntary muscle contractions, and language problems.    
Depression and mood problems have also been reported (by 5-9% of participants). Some 
participants (about 1%) have had suicidal thoughts or actions. If you feel a change in your mood or 
if you feel depressed, or that you may harm yourself, please contact study staff, or if that is not 
possible, seek emergency care. 
Other side effects that are less likely to occur with topiramate treatment but that are potentially 
serious include kidney stones (experienced by about 1% of participants).  Drinking an adequate 
amount of fluids is recommended while taking topiramate. This may reduce the risk of kidney 
stones.  
Psychosis was reported in trials with seizure disorder patients (less than 1%) but was likely related 
to the underlying epilepsy, since it was not identified as being related to topiramate treatment in 
trials for other disorders (including trials of alcohol dependence and studies of topiramate for 
treatment of migraine headache). 


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Metabolic acidosis (a severe increase in the level of acidity in the blood) may be associated with 
topiramate treatment.  This effect was experienced by about 3 to 7% of participants in other studies 
of topiramate. Metabolic acidosis can cause symptoms such as tiredness and loss of appetite, or 
more serious conditions including irregular heartbeat (arrhythmia) or coma.  IF YOU EXPERIENCE 
ANY SIGNS OR SYMPTOMS LIKE THIS THAT CONCERN YOU, CALL A DOCTOR 
IMMEDIATELY. Long-term metabolic acidosis can result in thinning of the bones (osteoporosis) 
with an increased risk for fractures.  Metabolic acidosis may increase the risk for kidney stones.  
Participants on carbonic anhydrase inhibitor medications, commonly used to treat glaucoma, 
should not participate in this study, due to the increased chance of metabolic acidosis from 
combining these medications with topiramate. These medications include Diamox (acetazolamide), 
Neptazane (methazolamide), or Trusopt (dorzolamide). 
Treatment with topiramate may rarely (in less than 1% of cases) cause decreased sweating, which 
has primarily been reported in children treated with topiramate.  Activities such as exercise or 
exposure to warm temperatures while using topiramate may increase the risk of heat-related side 
effects, such as heat stroke.  We recommend that you drink plenty of fluids while participating in 
this study. 
Patients with a history of narrow angle glaucoma should not participate in this study.  A medical 
condition consisting of sudden worsening of vision and an elevation of fluid pressure in the eyes 
(acute secondary glaucoma) has been described in a few cases (less than 1%) of patients taking 
topiramate, usually occurring in the beginning of treatment.  If you have sudden, significant 
worsening of vision, blurred vision, or eye pain you should contact study staff immediately, or if that 
is not possible, you should seek emergency care. 
Rare and isolated cases of hepatitis/liver failure (experienced by less than 1% of patients) and 
blistering skin rashes (experienced by about 1% of patients) have been reported with topiramate.   
Signs and symptoms of hepatitis include: dark urine and pale or clay colored stools, loss of 
appetite, fatigue, stomach pain, general itching, yellowing of the skin or whites of the eyes, nausea 
and vomiting, fever, weight loss, and breast development in males.  If you experience any of these 
symptoms, you should contact study staff immediately, or if that is not possible, you should seek 
emergency care. 
Overdoses of topiramate have been associated with convulsions, drowsiness, speech disturbance, 
blurred vision, double vision, impaired mental activity, abnormal coordination, stupor, hypotension, 
abdominal pain, agitation, dizziness and depression.  Deaths have been reported in overdoses.  
Topiramate may cause a change (increase or decrease) in the effect of some other medications.  If 
you are taking other medications during your participation in this study, your doctor will explain 
whether topiramate may have an effect and if necessary, may adjust your study drug dose. 
There may be risks to topiramate that are not now known.  You will be notified of any new 
significant findings that might affect your willingness to continue in the study.   
Due to the possibility of dizziness or drowsiness, you must be cautious when operating a vehicle or 
heavy equipment while in this study, until you have experience using topiramate. 
 
What Safeguards Should I Take? 
You should drink a minimum of three, 8 oz. glasses of water daily. We will ask about any side 
effects or other adverse events that you may experience.  If you experience any side effects, 
please contact our study staff immediately. You can call our 24-hour pager at (215) 505-3799 
during non-office hours or Dr. Henry Kranzler at (215) 746-1943.   
Topiramate or placebo capsules will be given to you only during the study drug portion trial and not 
during the 3- and 6- month follow-up periods. 
 
What Other Types of Risk Are Involved If I Choose To Participate?  


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The study assessments will address potentially sensitive matters, including your drinking, drug use, 
psychiatric symptoms, and possible health, legal, family, and other problems.  The counseling you 
receive will not differ much from standard medical counseling for drinking problems, and should 
pose no particular risk to you.  However, it is possible that the counseling, even when 
accompanied by topiramate, may not adequately help you to reduce your drinking to non-
hazardous levels. 
 
There is a chance that people outside of the research team may learn of your study participation.  
If this happens, you may be unable to obtain health, disability or life insurance. This may also result 
in other types of financial or emotional problems.  For example, you might be refused employment 
or you might lose your current job.   
 
Risks Associated with Blood Draws   
There will most likely be some mild discomfort from the blood draw. Some people develop a bruise 
at the needle site; some people report dizziness after the blood is drawn; and, some people 
develop minor infections. Other risks of blood drawing include possibly fainting. 
Safeguards To Be Taken 
Only study staff trained to perform venipuncture will perform the blood draws. The area where the 
needle is to be inserted will be wiped with a disinfectant before the needle is inserted. Only sterile 
needles will be used. The puncture site will be covered with a bandage.  You will be seated at the 
time blood is drawn and will be permitted to lie down if you feel faint. 
 
Risks for Women of Childbearing Potential:   
Topiramate is labeled by the Food and Drug Administration as a category D medication. This 
means that there are data in humans from investigational or marketing experience showing that 
topiramate can cause harm to the fetus, but potential benefits may warrant the use of the 
medication in pregnant women despite risk to the potential risks. Data from pregnancy registries 
show that infants exposed to topiramate in utero have an increased risk for cleft lip and or cleft 
palate (oral clefts). Therefore, participation in this study could possibly have an adverse effect on a 
developing fetus. You must inform the study physician/study nurse if you are pregnant/possibly 
pregnant.  As part of the screening process and before you take the first dose of study drug, a 
urine pregnancy test will be done if you are able to become pregnant or are less than two years 
post-menopausal.  You will also have urine pregnancy tests at visits 1 (week 1), 5 (week 5), 7 
(week 8), and 9 (week 11).  If you have had a hysterectomy, then a pregnancy test will not be 
required. While you are participating in this study, you must continue to use an effective method of 
birth control.  
Acceptable methods of birth control 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.  
It is possible that some hormonal contraceptives (e.g., birth control pills, implants or injections) may 
be made less effective by topiramate.  If you are using a hormonal contraceptive, your study doctor 
will discuss with you non-hormonal methods of birth control to be used during your participation in 
the study. 
 
If you are using hormonal contraceptives, you should report to the study nurse any change in your 
bleeding patterns. 
If you become pregnant during this study, you must tell the investigator and consult an obstetrician 
or maternal-fetal specialist.  You will be discontinued from the study and the study medication will 
be stopped immediately.   


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Confidentiality 
Every attempt will be made by the investigators to maintain all information collected in this study strictly 
confidential. However, authorized representatives of the University of Pennsylvania will have access to 
and may copy, both your medical records and records from your participation in this study.  This access 
is necessary to insure the accuracy of the findings and your safety and welfare.  If any publication or 
presentations result from this research, you will not be identified by name. The data are kept in secure, 
locked areas and access to these areas is possible only through the investigator or research 
technician. 
If we learn that you or someone else is in serious danger of harm (such as in cases of child or elder 
abuse) we may make disclosures to protect you and/or the other persons.  
 
 
Risks related to Genetic (DNA) Testing:   
The principal risk of genetic testing is breach of confidentiality, with sensitive information 
concerning your genetic risk for disease becoming known.  Such information, if available to you, 
could cause distress and if available to health or life insurers could adversely affect your access to 
insurance or its benefits.   
Differences in some genes are known to be directly related to risk for certain illnesses, and other 
genes that we may study using your DNA may be shown at some point in the future to be related 
to illness. Certain genetic research may reveal that you are at risk for certain diseases or that you 
are a carrier of a genetic disorder.  This could mean that you or members of your extended family 
may have an increased likelihood of developing the disorder, or may be carriers.   
Some states have laws that help to protect against genetic discrimination. A recent federal law 
(Genetic Information Non-Discrimination Act, GINA) helps reduce the risk from health insurance or 
employment discrimination. The law does not include other types of misuse by life insurance or long 
term care insurance. If you want to learn more about the GINA Law, you can find information about 
it on the Internet or ask the study staff. Study staff will provide you with a GINA handout for your 
information. 
Variation in some genes is known to be directly related to risk for certain illnesses, and other genes 
we may study in your DNA may be shown at some point in the future to be related to illness. 
Certain genetic research may reveal that you are at risk for certain diseases or that you are a 
carrier of a genetic disorder.  This could mean that you or members of your extended family may 
have an increased likelihood of developing the disorder, or may be carriers.   
 
Risks associated with providing personal information 
You will have to take the time to come to the clinic for regular visits each week. Some of the 
questions about your personal and sexual habits, lifestyle, and drug and alcohol use may make 
you feel uncomfortable.  
 
Safety 
The study drug must be kept out of the reach of children. Please do not share your study drug with 
others as the study drug (or dose level) you are receiving in the research study may have 
unpredicted negative side effects in other individuals. You have been screened for safely taking the 
research study drug, but others have not undergone this screening. 
Who can I contact in case of an emergency? If at any time you have a question regarding 
your participation in this study, you may call Dr Kranzler at (215) 746-1943.  You may also call the 
24-hour research emergency line at HUP (215)-349-5412. If assistance is not available by either 
of these methods, you are instructed to go to the emergency room of the Hospital of the University 
of Pennsylvania. You will receive a copy of this consent form containing these instructions for 
managing any complications, which may occur after leaving the hospital. 


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What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to you.  This 
includes information that, once learned, might cause you to change your mind about being in the 
study.  We will notify you as soon as possible if such information becomes available. 
 
What are the possible benefits of the study?  
You are not expected to get any benefit from being in this research study.  You may benefit from 
the screenings and medical examinations and medical management counseling provided during 
the study.  You may have a good response to the study medication and successfully reduce 
drinking.  However, it is possible that you will receive no direct health benefit from being in this 
study. Other people who have alcohol problems may benefit from the information learned from the 
study in the future.  We might find a better way to treat them.  Societal benefits may include a 
better understanding within the medical community of how best to treat heavy drinking.  However, 
there is also the possibility that no benefit will come from this study.   
You will not directly benefit from the genetic testing. Potential societal benefits may include a 
greater understanding of the genetic basis of alcohol use disorders and related psychiatric 
conditions, and potentially an understanding of the genetic moderators of the response to 
treatment with topiramate. 
What other choices do I have if I do not participate?  
Your participation in this trial is entirely voluntary and you may choose not to participate.  If you 
choose not to participate in the study, alternative options are available to you .Topiramate (study 
medication) is being prescribed off-label to treat alcohol dependence in this study.  As an 
alternative to study participation, you may obtain treatment with other medications (including three 
that are approved for the treatment of alcohol dependence: acamprosate, disulfiram and 
naltrexone), and standard counseling, including individual and group therapy. You could also 
request that your medical provider prescribe topiramate “off-label” to treat your alcohol problem.   
 
Will I be paid for being in this study? 
You will be paid for completion of different parts of the study. Payments will be made to you with a 
GreenPhire ClinCard. A Greenphire ClinCard is a reloadable prepaid card that may be used for in-
store purchases (by selecting either the "credit" or “debit" option), online purchases, ATMs to get 
cash, and cash advances at a bank (though there are fees associated with ATM withdrawals or 
bank cash advances). The study doctor or other study staff member will tell you more about when 
you will get paid and provide you with an information sheet about how to use the Greenphire 
ClinCard. Funds added to the card should be available immediately, however in some cases it may 
take up to 1 business day. If you lose the card, please contact our study staff immediately. The 
study coordinator and cancel the original card and reissue a new card to you.  
The total amount will be between $4 and $374, depending on the parts of the study that you 
complete: 
• 
$1.00 for each IVR phone call OR a total of $10 for completing all 7 calls in each week for 
a maximum payment of $120 for all calls during the 12-week  study drug period 
• 
$3 for returning study medication bottles at each visit 
• 
$4 to cover the cost of mass transit for roundtrip travel to each visit 
• 
$25 for completing Visit 6 
• 
$50 for completing the Endpoint Visit 
• 
$50 for completing each of the two Follow-up Visits 
 
Study Payment Schedule 


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Visit  
Returned Medication 
Bottle 
Travel Cost Completed Visit 
Daily Phone call:  
$1/day or $10 for  
all 7 days/week  
Maximum Payment
Screening Visit -0 
N/A 
$4 
$0 
N/A 
$4 
Visit 1 Baseline 
N/A 
$4 
$0 
N/A 
$4 
Visit 2 
$3 
$4 
$0 
0 
$7 
Visit 3 
$3 
$4 
$0 
0 
$7 
Visit 4 
$3 
$4 
$0 
0 
$7 
Visit 5 
$3 
$4 
$0 
0 
$7 
Visit 6  
$3 
$4 
$25 
$50 
$82 
Visit 7 
$3 
$4 
$0 
$20 (2 wks) 
$27 
Visit 8 
$3 
$4 
$0 
$20 (2 wks) 
$27 
Visit 9  
$3 
$4 
$0 
$20 (2 wks) 
$27 
Visit 10 Endpoint visit $3 
$4 
$50 
$10 
$67 
Visit 11 (3-Month) 
N/A 
$4 
$50 
N/A 
$54 
Visit 12 (6-Month) 
N/A 
$4 
$50 
N/A 
$54 
Totals 
$27 
$52 
$175 
$120 
$374 
Payments will be deferred if you fail a breathalyzer test, so please avoid drinking before coming in 
for a visit.  Additionally, please note that the University of Pennsylvania is required to report to the 
IRS any cumulative payments for participation in research studies that exceed a total of $600 in a 
calendar year.  
 
What information about me may be collected, used, or shared with others?   
• 
Name 
• 
Address 
• 
Telephone number 
• 
Email address 
• 
Date of Birth 
• 
Social Security Number 
• 
You will be asked to show your driver’s license or another form of photo identification at the 
screening visit for study staff to confirm your identity. Study staff will not copy your 
identification or record any specific information from the license or other identification.  
• 
Allergies 
 
 
 
 
 
• 
Current and past medications or therapies 
• 
Medical Record Number 
• 
Full face photographic images and any comparable images 
• 
Audio-recordings, if you agree to have your counseling sessions taped.  These will be 
destroyed as soon as they are checked to ensure that the session is completed properly. 
• 
Information from a psychiatric examination, which includes a series of interviews and 
questionnaires that obtain information on your substance abuse, family/social, legal, and 
psychiatric histories 
• 
Information from a physical examination that includes routine labs (urine and blood work), 
blood pressure reading, heart rate, breathing rate and temperature, electrocardiogram 
 
Why is my information being used? 
• 
Your information will be used by the research team to contact you during the study. Your 
information and results of tests and procedures are used to: 
• 
do the research 


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• 
oversee the research 
• 
to see if the research was done right.   
 
Who may use and share information about me?   
• 
The following individuals may use or share your information for this research study: 
• 
The Principal Investigator and the Investigator’s study team (other University staff 
associated with the study) 
• 
The University of Pennsylvania Institutional Review Boards (the committees charged with 
overseeing research on human subjects) and University of Pennsylvania Office of 
Regulatory Affairs 
• 
The University of Pennsylvania Office of Human Research (the office which monitors 
research studies) 
• 
Authorized members of the University of Pennsylvania and the University of Pennsylvania 
Health System and School of Medicine workforce who may need to access your information 
in the performance of their duties (for example: to provide treatment, to ensure integrity of 
the research, accounting or billing matters, etc.).  
• 
The Principal Investigator and study team at the Corporal Michael J. Crescenz Philadelphia 
VA Medical Center (CMCVAMC) (the coded study data from both sites will be merged and 
a copy will be stored at the CMCVAMC). 
• 
The Corporal Michael J. Crescenz Philadelphia VA Medical Center Institutional Boards (the 
committees charged with overseeing research on human subjects there). 
• 
Greenphire ClinCard for processing study payments. 
 
Oversight organizations 
• 
The Food and Drug Administration 
• 
The Office of Human Research Protections 
• 
The study data and safety monitoring board 
 
Once your personal health information is disclosed to others outside the School of Medicine, it may 
no longer be covered by federal privacy protection regulations. In all disclosures outside of the 
University of Pennsylvania Health System and School of Medicine, you will not be identified by 
name, social security number, address, telephone number, or any other direct personal identifier.   
The Principal Investigator or study staff will inform you if there are any additions to the list above 
during your active participation in the trial. Any additions will be subject to University of 
Pennsylvania procedures developed to protect your privacy. 
 
How long may the School of Medicine use or disclose my personal health 
information?   
Your authorization for use of the information we collect about you for this specific study does not 
expire. Your information may be held in a research database.  However, the School of Medicine 
may not re-use or re-disclose information collected in this study for a purpose other than this study 
unless: 
• You have given written authorization  
• The University of Pennsylvania’s Institutional Review Board grants permission 
• As permitted by law  
 
Can I change my mind about giving permission for use of my information? 
You may withdraw or take away your permission to use and disclose your health information at any 
time.  You do this by sending written notice to the investigator for the study.  If you withdraw your 
permission, you will not be able to stay in this study. We will de-identify all of your study information 
and retain your information for study reporting purposes. 
 


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What if I decide not to give permission to use and give out my health information? 
You will not be able to be in this research study.  
 
Will I have to pay for anything? 
There is no charge for participating in this research study. You may have to take time away from 
work to come to the appointments.  You may be responsible for some of your travel expenses to 
attend study visits.  Study medication (topiramate or placebo), laboratory testing, and all clinic visits 
will be provided to you free of charge for the duration of your participation in the study. 
What happens if I am injured from being in the study?  
We will offer you the care needed to treat injuries directly resulting from taking part in this research.  
We may bill your insurance company or other third parties, if appropriate, for the costs of the care 
you get for the injury, but you may also be responsible for some of them. 
There are no plans for the University of Pennsylvania to pay you or give you other compensation 
for the injury.  You do not give up your legal rights by signing this form.   
If you think you have been injured as a result of taking part in this research study, tell the person in 
charge of the research study as soon as possible.  The researcher’s name and phone number are 
listed above in this form. 
 
When is the Study over?  Can I leave the Study before it ends? 
You are free to stop taking part in this study at any time.  If you choose to stop before the end of 
the study, the principal investigator may ask you to continue to take the study medication for a little 
while on a reduced schedule.  A reduced schedule will lessen your symptoms of withdrawal from 
the study medication.  Symptoms of withdrawal may include headaches, mood swings and/or 
nausea.  
If you decide to withdraw your participation, we ask that you let us know by calling the study Staff 
at (215) 746-1987.  We will ask that you return to the clinic to complete all final study procedures.  
We will also call you at the planned end of the study to collect some final information.   
This study is expected to end after all participants have completed all visits, and all information has 
been collected.  This study may also be stopped at any time by the principal investigator or the 
Food and Drug Administration without your consent because: 1) the principal investigator believes 
that your medical care could be improved with another therapy, 2) you become pregnant, 3) you 
experience a significant illness or unacceptable side effects from the study drug, or 4) you fail to 
follow the study schedule (i.e., do not come to the clinic when scheduled, or do not take your study 
medication).  The study principal investigator or the Food and Drug Administration may also decide 
to stop the study.   There may also be other reasons that are not specified here.  Such an action 
would not require your consent, but you will be informed if such a decision is made and the reason 
for the decision. 
If your participation in the study is stopped for any reason, you may be asked to come back to the 
clinic to be interviewed and to have final tests of your blood.  At that time you will be asked to 
return all unused medication or empty medication bottles. You will no longer receive free study 
medication. 
If you decide to participate in the study, you are free to leave the study at any time.  Withdrawal will 
not interfere with your future care.   
 
Who can see or use my information?  How will my personal information 
be protected?   
We will do our best to make sure that the personal information obtained during the course of this 
research study will be kept private.  However, we cannot guarantee total privacy.  Your personal 


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information may be given out under certain circumstances described below.  If information from this 
study is published or presented at scientific meetings, your name and other personal information 
will not be used. If this study is being overseen by the Food and Drug Administration, they may 
review your research records.   
 
To further help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
United States Department of Health and Human Services (DHHS).  
We cannot be forced (for example by court order or subpoena) to disclose information that may 
identify you in any federal, state, local, civil, criminal, legislative, administrative, or other 
proceedings. The researchers will use the Certificate to resist any demands for information that 
would identify you, except to prevent serious harm to you or others, and as explained below.  
You should understand that a Certificate of Confidentiality does not prevent you, or a member of 
your family, from voluntarily releasing information about yourself, or your involvement in this study.  
If an insurer or employer learns about your participation, and obtains your consent to receive 
research information, then we may not use the Certificate of Confidentiality to withhold this 
information. This means that you and your family must also actively protect your own privacy.  
You should understand that we will in all cases, take the necessary action, including reporting to 
authorities, to prevent serious harm to yourself, children, or others (for example, in the case of child 
abuse or neglect). 
 
The following procedures will be used to protect the confidentiality of your data:   
The study staff (principal investigator, research coordinator, co-investigators, etc.) will keep all 
study records (including any codes to your data) locked in a secure location.   Research records 
will be labeled with a code.  The code will be derived from a 3-digit number identifying the study, 
followed by a 3-digit number that is a sequential indicator of the number of patients that have been 
enrolled in the study.  A master key that links names and codes will be maintained in a separate 
and secure location.  All electronic files (e.g., database, spreadsheet, etc.) containing identifiable 
information will be password protected.  Any computer hosting such files will also have password 
protection to prevent access by unauthorized users.  Data that will be shared with others will be 
coded as described above to help protect your identity.  Any lab results will be stored in your 
research record only. 
All information related to your participation in this study will be kept in a research record, apart from 
your medical record. The research record will be labeled with a code and kept locked in a file 
cabinet in one of the study offices.  Only researchers officially appointed to work on this project and 
agencies or departments with responsibility for research compliance will have access to your 
information while it is stored in an identifiable format.   
We intend to run tests on your DNA sample in order to examine the genetic moderators of 
response to treatment with topiramate.  Once the sample is taken it will become the property of the 
University of Pennsylvania.  It will be stored in the laboratory of Dr. Kranzler or a study co-
investigator.  During the study, the sample will be stored under a code that only the principal 
investigator can link to your name. 
Upon completion of the study, the DNA blood sample will be kept in storage for up to 20 years to 
permit complete analysis of the sample.  However, the sample will forever be separated from your 
identity.  There will be no way, not even through codes, to link the sample back to you.  These “de-
identified” samples may be shared with other researchers and used in other projects. 
If you choose to withdraw from the study after your DNA sample has been obtained, we will 
destroy all records in our research files connecting your identity with your sample(s). In this way, 
the samples could only be studied anonymously from this point forward. We will not destroy the de-
identified sample. 


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You will not be told during the study whether you are taking topiramate or placebo. However, when 
you complete the 6-month follow-up visit for the study, you will be eligible to receive that 
information.  If you choose (after completing the 6-month follow-up), the research pharmacy will 
mail you a letter telling you which medication you were taking (topiramate or inactive placebo).  
Study staff (study physicians, nurses, and research assistants) will remain blinded. 
You will not be told the results of the genetic testing.  If you would like a copy of the overall results 
of the study once it is completed, you may request from the principal investigator a copy of the 
article that the researchers write describing the study. 
In addition to the research we intend to do, it is possible that unexpected and/or unrelated 
information will be discovered that is not the focus of this study.  This information will not be 
disclosed to you.    
    
Electronic Medical Records and Research Results  
What is an Electronic Medical Record?  
An Electronic Medical Record (EMR) is an electronic version of the record of your care within a 
health system. An EMR is simply a computerized version of a paper medical record. This study 
does not use an EMR and will not enroll you into the University of Pennsylvania Health System. 
  
In the event of your needing medical care within the University of Pennsylvania Health System 
either as a result of participating in this study or at the recommendation of the study team, the fact 
that you are a research study participant may be identified in an Electronic Medical Record created 
and maintained by UPHS. 
  
Once placed in your EMR, the fact that you have participated in research (with the only details of 
your participation being those needed to care for you medically) will be accessible to appropriate 
UPHS workforce members that are not part of the research team.  Information within your EMR 
may also be shared with others who are determined by UPHS to be appropriate to have access to 
your EMR (e.g. health insurance company, disability provider, etc)." 
 
Who can I call with questions, complaints or if I’m concerned about my 
rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this research study or 
if you have any questions about your rights as a research subject, you should speak with the 
Principal Investigator listed on page one of this form.  If a member of the research team cannot be 
reached or you want to talk to someone other than those working on the study, you may contact 
the Office of Regulatory Affairs with any question, concerns or complaints at the University of 
Pennsylvania by calling (215) 898-2614. 
 
When you sign this form, you are agreeing to take part in this research study. This means 
that you have read the consent form, your questions have been answered, and you have 
decided to volunteer.  Your signature also means that you are permitting the University 
of Pennsylvania to use your personal health information collected about you for research 
purposes within our institution. You are also allowing the University of Pennsylvania to 
disclose that personal health information to outside organizations or people involved with 
the operations of this study. 
A copy of this consent form will be given to you.  
 


Version 18: 2/19/2019                                                                           Topiramate-Genetics Study  
 
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Agreeing to be audio taped is not a requirement to participate in the study.  Please initial your 
decision: 
 
Yes, you agree that we can tape record your counseling sessions: __________ 
 
No, you do not agree that we can tape record your counseling sessions: ______ 
 
Agreeing to receive a debriefing letter for the UPenn investigational pharmacy is not a requirement 
to participate in the study.  Please initial your decision: 
 
Yes, you wish to receive the de-briefing letter from the UPenn Pharmacy: __________ 
 
No, you do not wish to receive the de-briefing letter from the UPenn Pharmacy: ______ 
 
 
________________________       ___________________________ 
_________ 
Name of Subject (Please Print)  Signature of Subject  
 
                Date 
 
 
________________________ 
_____________________________ 
_________ 
Name of Person Obtaining  
Signature                                  
 
     Date 
Consent (Please Print)