High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers
Phase: PHASE2
Conditions: Alcohol Dependence, Nicotine Dependence
Sponsor: University of Virginia

Document Date: 4-4-2022
NCT01182766 
Title: New Treatment for Alcohol and Nicotine Dependence

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
1 
Version 9, April 4, 2022 
High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
 
A Phase II, 18-week, double-blind clinical trial with a 3-month follow-up, in which alcohol-
dependent smokers will receive brief behavioral compliance enhancement treatment (BBCET) 
plus a smoking self-help manual as their psychosocial treatment, and shall be randomized to get 
placebo, high-dose topiramate (up to 250 mg/day), or low-dose topiramate (up to 125 mg/day) to 
prevent relapse to heavy drinking and smoking. IND # 56,887. 
 
 
Site Principal Investigator:  
Nassima Ait-Daoud Tiouririne, M.D. 
University of Virginia 
Center for Addiction Research and Education 
1670 Discovery Drive, Suite 110 
Charlottesville, VA 22911 
Tel: (434) 243-0570  
Email: nat7b@virginia.edu 
 
Site Principal Investigator:  
Robert M. Anthenelli, M.D. 
Department of Psychiatry (0603) 
University of California, San Diego 
Biomedical Sciences Building 
9500 Gilman Drive 
La Jolla, CA 92093 
Tel: 858-552-8585, ext. 1530 
Email: robert.anthenelli@va.gov 
 
Site Principal Investigator:  
Paul M. Cinciripini, Ph.D. 
 
 
 
 
 
Department of Behavioral Science 
UT M.D. Anderson Cancer Center 
1155 Pressler 
Houston Texas, 77030 
 
 
 
 
 
Tel: 713-792-0919 
Email: pcinciri@mdanderson.org 
 
Significant Contributor:                  Bankole A. Johnson, D.Sc., M.D., Ph.D  
University of Maryland Baltimore 
Department of Psychiatry 
110 South Paca Street, Room 4N140 
Baltimore, MD 21201 
Tel: (410)328-6735 
 
Email: bjohnson@psych.umaryland.edu 
 
 
Sponsor: 
 
 
 
National Institute on Alcohol Abuse and Alcoholism 
National Institutes of Health 
Division of Treatment and Recovery Research 
5635 Fishers Lane 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
2 
Version 9, April 4, 2022 
Bethesda MD 20892 
 
NIAAA Project Officer: 
 
Joanne Fertig, Ph.D. Tel: (301) 443-0635 
 
 
 
 
 
Email: jfertig@mail.nih.gov 
 
Statistics Consultants: 
 
Lei Liu, Ph.D. 
University of Virginia 
 
 
 
 
 
PO Box 800717, Public Health Sciences, MSB 3181 
 
 
 
 
 
Charlottesville, VA 22908 
 
 
 
 
 
Tel: 434-982-3364 
Email: ll9f@Virginia.EDU 
 
Xin-Qun Wang, M.S. 
PO Box 800717, Public Health Sciences, MSB 3181 
 
 
 
 
 
Charlottesville, VA 22908 
Tel : 434-924-8519 
Email: xw9r@Virginia.EDU 
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
3 
Version 9, April 4, 2022 
TABLE OF CONTENTS 
 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS ............................................................................ 6 
2 
STUDY SCHEMA ...................................................................................................................... 8 
3 
STUDY SCHEDULE .................................................................................................................. 9 
4 
ABSTRACT ............................................................................................................................... 12 
5 
INTRODUCTION AND RATIONALE ................................................................................................... 15 
5.1 
General Rationale for the Pharmacological Treatment of comorbid alcohol and 
smoking dependence ......................................................................................................................15 
5.2 
Topiramate .....................................................................................................................16 
5.2.1 Chemistry ...................................................................................................................16 
5.2.2 Pharmacology ............................................................................................................17 
5.2.3 Pharmacokinetics (PK) ..............................................................................................19 
5.2.4 Adverse Effects ...........................................................................................................19 
5.2.5 Withdrawal .................................................................................................................19 
5.2.6 Possible Adverse Events from the Interaction Between Topiramate and Alcohol.....20 
5.2.7 Rationale for Study Design and Dose Regimen .........................................................20 
6 
STUDY OBJECTIVES ................................................................................................................................... 21 
6.1 
Primary Objective ..........................................................................................................21 
6.2 
Exploratory Objectives ..................................................................................................21 
7 
REGULATORY CONSIDERATIONS .................................................................................................... 22 
8 
STUDY SITES .................................................................................................................................................... 22 
9 
STUDY DESIGN ....................................................................................................................... 23 
10 SUBJECT SELECTION ................................................................................................................................ 24 
10.1 
Inclusion Criteria ...........................................................................................................24 
10.2 
Exclusion Criteria ..........................................................................................................24 
11 INVESTIGATIONAL PRODUCTS.......................................................................................................... 26 
11.1 
Topiramate and Matched Placebo Control 
26 
11.2 
Investigational Product Labeling 
27 
11.3 
Investigational Product Accountability 
27 
11.4 
Used/Unused Supplies 
27 
12 INTERVENTIONS .......................................................................................................................................... 27 
12.1 
Investigational Agents ...................................................................................................27 
12.2 
Brief Behavioral Compliance Enhancement Treatment (BBCET) ................................28 
13 STUDY PROCEDURES ................................................................................................................................ 29 
13.1 
Subject Recruitment .......................................................................................................29 
13.2 
Screening Assessments ..................................................................................................30 
13.3 
Subject Randomization ..................................................................................................30 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
4 
Version 9, April 4, 2022 
13.4 
Intervention Phase ..........................................................................................................31 
13.5 
One and three month follow-up visits ............................................................................32 
13.6 
Early Termination (ET)..................................................................................................32 
13.7 
Study Completion Referral to Treatment .......................................................................32 
13.8 
Management of Withdrawal ..........................................................................................32 
13.9 
Concomitant Medication Use ........................................................................................33 
13.10 
Safety Monitoring Plan ..................................................................................................33 
13.11 
Volunteer Discontinuation .............................................................................................37 
13.12 
Recommended Subject Compensation ..........................................................................37 
13.13 
Trial Registration ...........................................................................................................37 
14 ASSESSMENT METHODS ..................................................................................................... 37 
14.1 
AEs .................................................................................................................................37 
14.2 
Alcohol Breathalyzer .....................................................................................................38 
14.3 
Blood Chemistries, Hematology and Urine ...................................................................38 
14.4 
BBCET Session Compliance .........................................................................................38 
14.5 
Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR) ...............38 
14.6 
Wisconsin Smoking Withdrawal Scale ..........................................................................38 
14.7 
Positive Affect Negative Affect Schedule (PANAS) ....................................................39 
14.8 
The Center for Epidemiologic Studies Depression Scale (CES-D) ...............................39 
14.9 
Medical Outcomes Sleep Scale (MOS-Sleep) ...............................................................39 
14.10 
Drinker Inventory of Consequences (DrInC) ................................................................39 
14.11 
Fagerström Test for Nicotine Dependence ....................................................................40 
14.12 
Demographics ................................................................................................................40 
14.13 
Drug Accountability.......................................................................................................40 
14.14 
ECG................................................................................................................................40 
14.15 
Eligibilty Checklist ........................................................................................................40 
14.16 
Medical History .............................................................................................................40 
14.17 
Concomitant Medications ..............................................................................................40 
14.18 
TLFB ..............................................................................................................................41 
14.19 
Carbon Monoxide (CO) Level .......................................................................................41 
14.20 
Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)………… 41 
14.21 
Alcohol Craving Visual analog Scales ..........................................................................41 
14.22 
Nicotine Craving Visual analog Scales..........................................................................41 
14.23 
The Tobacco Use History Questionnaire .......................................................................42 
14.24 
Alcohol Use Disorders Identification Test (AUDIT) ....................................................42 
14.25 
Mini International Neuropsychiatric Interview (MINI) .................................................42 
14.26 
Salivary cotinine level....................................................................................................42 
14.27 
Physical Examination.....................................................................................................43 
14.28 
Vital Signs ......................................................................................................................43 
14.29 
Genotyping .....................................................................................................................43 
14.30    Baseline Drug Use and Other Drug Use ................................................................................. 43 
14.31  CONTRACEPTIVE METHOD  
 
 
 
 
 
 
 
  44 
15 ANALYTICAL PLAN .................................................................................................................................... 44 
15.1 
Outcome Measures.........................................................................................................44 
15.2 
Standard Drink and Drinking Day Definitions ..............................................................44 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
5 
Version 9, April 4, 2022 
15.3 
Statistical Hypotheses ....................................................................................................44 
15.4 
Subject Populations ........................................................................................................45 
15.5 
Sample Size Calculation ................................................................................................47 
15.6 
Additional Exploratory Analyses ...................................................................................48 
16 DATA MANAGEMENT……………………………………………………………………...48  
16.1 
Data Collection ..............................................................................................................49 
16.2 
Data Editing, Monitoring and Control ...........................................................................49 
16.3 
Study Documentation and Records Retention ...............................................................49 
16.4 
Confidentiality ...............................................................................................................50 
16.4.1 
Confidentiality of Data ..........................................................................................50 
16.4.2 
Confidentiality of Subject Records.........................................................................50 
17 PUBLICATIONS OF THE STUDY RESULTS ................................................................................... 50 
18 SIGNATURES........................................................................................................................... 52 
19 APPENDIX I: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................... 53 
20 APPENDIX II: CERTIFICATE OF CONFIDENTIALITY ........................................................... 59 
21 APPENDIX III: TABLE OF ALLOWED AND DISALLOWED CONCOMITANT 
MEDICATIONS ......................................................................................................................................................... 61 
22 APPENDIX IV: BBCET MANUAL .......................................................................................................... 61 
23 APPENDIX V: CLEARING THE AIR BOOKLET ........................................................................... 62 
24 APPENDIX VI: BLOOD COLLECTION FOR GENOTYPING ................................................. 62 
24    REFERENCES…………………………………………………………………………….….62 
 
 
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
6 
Version 9, April 4, 2022 
1  
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
Abbreviations 
Definition 
AA 
Alcoholics Anonymous 
AE 
Adverse Event 
AMPA 
APA 
AUD 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 
American Psychiatric Association 
Alcohol Use Disorder 
AUDIT 
Alcohol Use Disorders Identification Test 
BAC  
Breath Alcohol Content 
BBCET 
Brief Behavioral Compliance Enhancement Treatment 
BUN  
Blood Urea Nitrogen 
CBC 
Complete blood count 
CES-D 
The Center for Epidemiologic Studies Depression Scale 
CO 
Carbon Monoxide 
CIWA-AR  
Clinical Institute Withdrawal Assessment for Alcohol-revised  
CMDA  
Cortico-mesolimbic dopamine 
CNS 
Central Nervous System 
DDD 
Drinks per drinking day 
DrInC  
Drinker Inventory of Consequences 
DSMB  
Data and Safety Monitoring Board 
DSM-4  
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-4  
Diagnostic and Statistical Manual of Mental Disorders-5 
ECG  
Electrocardiogram 
ET 
Early Termination 
FDA 
FTND  
Food and Drug Administration 
Fagerström Test for Nicotine Dependence  
GABA 
γ-aminobutyric acid-A 
GGT 
γ-glutamyl transferase 
Heavy Drinking 
5 or more drinks per drinking day for men, 4 or more drinks per 
drinking day for women 
ID 
Identification 
IND  
Investigational New Drug  
IRB  
Institutional Review Board  
ITT 
Intention-to-Treat 
LDH 
Lactate Dehydrogenase 
MD 
Medical Doctor  
MINI 
Mini International Neuropsychiatric Interview 
MOS - Sleep 
Medical Outcomes Sleep Scale 
NIAAA 
National Institute on Alcohol Abuse and Alcoholism 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NP 
Nurse Practitioner 
PANAS 
Positive Affect Negative Affect Schedule 
PDA 
Percentage of Days Abstinent  
PHDD 
Percentage of  heavy drinking days 
PI 
Principal Investigator 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
7 
Version 9, April 4, 2022 
Abbreviations 
Definition 
PK 
Pharmacokinetics 
Q-LES-Q 
Quality of Life Enjoyment and Satisfaction Questionnaire 
SAE 
Serious Adverse Event  
SDU 
Standard Drink Units 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOP 
Standard Operating Procedure 
TARG 
Tobacco and Alcohol Research Group 
TLFB 
Timeline Followback  
TQD 
Target Quit Date 
UVa CLEAR 
University of Virginia Center for Leading Edge Addiction Research 
ULN 
Upper Limit Of Normal 
VTA 
WSWS 
Ventral tagmental area 
Wisconsin Smoking Withdrawal Scale 
 
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
8 
Version 9, April 4, 2022 
 
2  
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
9 
Version 9, April 4, 2022 
3  
STUDY SCHEDULE 
 
 
 
 
 
 
 
 
 
 
 
 
Screen 
Weeks 1 to 5 
(-5 to -1 weeks 
to TQD) 
Week 6 visit= TQD (0) 
Weeks 6 to 10 
(0 to +4 weeks 
from TQD) 
Weeks 10 to 18 
(+4 to +12 weeks 
from TQD) 
Week 19 
(+13 
weeks 
from TQD) 
Follow-Up 
Visit 
1 month 
Follow-Up 
Phone Call 
3 months 
Assessments 
X 
Weekly 
Weekly 
Biweekly 
X 
X 
X 
Psychosocial 
Intervention 
_____ 
Weekly 
Weekly 
Biweekly 
X 
______ 
______ 
Medication 
Dispensation 
_____ 
Weekly 
Weekly 
Biweekly 
______ 
______ 
______ 
Randomization 
Target Quit Date 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
10 
Version 9, April 4, 2022 
Table 1:  Time and Events Schedule 
Assessment 
Investigational Product Administration 
Study Week 
-4 
to 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
12 
14 
16 
18 
19/
ET 
F/U 
1 month 
F/U 
3 month 
(phone) 
Visit Number 
S 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Subject characteristics 
  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Informed consent 
x 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Use Disorders Identification 
Test (AUDIT) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fagerström Test for Nicotine 
Dependence 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Tobacco Use History Questionnaire 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Drug Use 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI for DSM-4, plus supplement 
x 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
Efficacy 
  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
Timeline follow-back* 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Carbon monoxide level 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Urinary cotinine level****  
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life Enjoyment and 
Satisfaction Questionnaire (Q-LES-
Q) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Alcohol Craving Visual Analog 
Scales 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Nicotine Craving Visual Analog 
Scales 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Salivary cotinine level 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Clinical Institute Withdrawal 
Assessment for Alcohol scale – 
Revised (CIWA-AR) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Wisconsin Smoking Withdrawal 
Scale 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Positive Affect Negative Affect 
Schedule (PANAS) 
x  
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
 
 
x 
x 
 
The Center for Epidemiologic 
Studies Depression Scale (CES-D) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Medical Outcomes Sleep Scale 
(MOS – Sleep) 
x  
x 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
 
Drinker Inventory of Consequences 
(DrInC) 
x 
x 
 
 
x 
 
x 
 
 
x 
 
x 
 
 
 
x 
 
 
Psychosocial intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief behavioral compliance 
enhancement treatment (BBCET) 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
11 
Version 9, April 4, 2022 
Assessment 
Investigational Product Administration 
Study Week 
-2 
to 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
12 
14 
16 
18 
19/ 
ET 
F/U 
1 month 
F/U 
3 month 
(phone) 
Visit Number 
S 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Subject characteristics 
  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Clearing the Air Booklet 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication compliance measures 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
BBCET session checklist 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Genotyping 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dispensing 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Drug Use 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam** 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Vital signs (blood pressure, heart 
rate, weight) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Electrocardiogram 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Breathalyzer (BAC) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Urine pregnancy test 
x 
x 
 
 
x 
  
 
x 
  
 
 x  
 
  
x 
 
x 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Blood chemistry 
x 
 
 
 
  
  
 
  
  
 
  
 
  
  
 
x 
 
 
Hematology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Urine Drug Screen*** 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
Urinalysis 
x 
 
 
 
 
  
 
 
  
 
  
 
  
  
 
 
 
 
Contraceptive method 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Key:   
S = screen is 30 days prior to visit #1 (weeks –4 to -1).  
Randomization will occur before week 1 of double-blind treatment. 
F/U = follow-up at months 1 and 3.   
*Timeline follow-back will quantify both smoking and drinking behavior. 
**Physical Exam may be done at screening or on or prior to visit 1. 
***If positive at screen subject will be advised to stop using and will be allowed one repeat urine drug screen. Must provide negative results prior to 
randomization. 
**** If subject registers a CO level of <10, a urinary cotinine will be administered. Subjects must have a cotinine level of >3at Screen and prior to  
Randomization to be eligible for study inclusion. 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
12 
Version 9, April 4, 2022 
 
4  
ABSTRACT 
 
Objectives 
Primary: The primary objectives of this study are to assess the efficacy of both low- and high-
dose topiramate in reducing the percentage of heavy drinking days (PHDD), while also 
increasing the continuous abstinence rate for smoking determined by a combination of self-report 
and carbon monoxide (CO) monitoring after the target quit date (TQD), and in the last 4 weeks 
of treatment. We propose that high-dose topiramate will be more efficacious than low-dose 
topiramate at reducing PHDD and increasing the continuous abstinence rate for smoking 
determined by a combination of self-report and CO monitoring after the TQD in the last 4 weeks 
of treatment after TQD. 
 
Secondary: Secondary objectives include assessing that both low- and high-dose topiramate will 
be more efficacious than placebo at improving quality of life and reducing alcohol and nicotine 
craving in the last 4 weeks of treatment after TQD; high-dose topiramate will be more 
efficacious than low-dose topiramate at improving quality of life and reducing craving after the 
TQD, and in the last 4 weeks of treatment;  
 
Exploratory: Improvements in quality of life and craving reductions will be predictably 
associated with reduced PHDD, increased continuous abstinence rates for smoking, or both, 
irrespective of treatment group. 
 
Study Design: Two hundred and ninety-four comorbid alcohol- and nicotine-dependent subjects 
who meet eligibility criteria will be randomized to 1 of 3 treatment groups — placebo, low-dose 
topiramate (up to 125 mg/day), or high-dose topiramate (up to 250 mg/day).  Randomization will 
be achieved using a block randomization procedure in which treatment groups will be stratified 
to achieve a balance on age of onset for alcoholism (less than 26 years old or 26 years and older), 
gender, and drinks per drinking day (DDD) (< 8 DDD or ≥ 8 DDD) and the number of cigarettes 
smoked (<20 or >20 cigarettes/day).   
 
Following randomization, subjects will participate in an 18-week, double-blind treatment period 
during which they also will receive weekly Brief Behavioral Compliance Enhancement 
Treatment (BBCET) and a self-help manual for smoking cessation.  Topiramate and matching 
placebo will be titrated for the first 5 weeks of the 18-week treatment period. The TQD will be at 
the beginning of the 6th week of treatment.  Subjects will be instructed not to attempt smoking or 
alcohol cessation prior to the TQD.  Setting a TQD at the end of medication titration enables 
stability of effects, comfort with the medication prior to attempting to cease alcohol and smoking 
consumption, and an appreciable buildup of medication.  
 
Study Pre-Screening Procedures: Potential subjects will call a study phone number, which will 
be set up for each participating site.  The intake interviewer will answer queries from the subject 
about the nature and demands of the study.  The interviewer will request permission from the 
potential subject to collect data that will be part of the telephone screening interview.  
Confirmation of consent will be completed by the subject providing his or her name and 
telephone number.  The telephone screening interview will include demographic data, physical 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
13 
Version 9, April 4, 2022 
status, psychiatric history, timeline follow back (TLFB) for alcohol and cigarettes, and questions 
to assess motivation to engage in treatment.  One such question to assess motivation will read as 
follows:  “Are you willing to quit both smoking and drinking 30 – 60 days into the study?”  
Subjects who answer “yes” and meet all additional eligibility criteria will be preferably 
scheduled for a screening visit within 30 days of the telephone screening interview.  
 
Study Screening Procedures: At the screening visit (visit S) subjects will be provided with 
information about the study, its rationale, risks, and potential benefits, and the role of the 
Institutional Review Board.  All questions pertinent to the study raised by the potential subject 
will be answered before consent is signed.  Those who complete all screening procedures and 
assessments and who are eligible for the study will be scheduled for a randomization visit (visit 
1). Those who complete the screening procedures, but who are not eligible for study inclusion 
will be provided with the address and telephone number of another treatment center or will be 
referred to other research studies at the research site. 
 
Study Duration: Each subject will remain in the study for 19 weeks including a follow up visit 
at 1 month and a follow up phone call at 3 months.  The expected ratio of intake screens to 
enrolled subjects is approximately 2:1.  Thus, the enrollment of 294 individuals will require 588 
intake sessions over approximately 54 months of recruitment.  Of the enrolled 294 individuals, 
the expected dropout rate is 30%; therefore, 206 individuals will be expected to complete all 18 
weeks of double-blind treatment.  
 
Sample Size:  Two hundred and ninety four (294) subjects will be randomized to one of 3 
groups, low-dose topiramate, high-dose topiramate or placebo control.  
 
Population: Entry into this study is open to treatment seeking men and women at least 18 years 
of age and to all racial and ethnic subgroups. A Diagnostic and Statistical Manual of Mental 
≥Disorders-5 (DSM-5) diagnosis of mild to severe alcohol use disorder is required and subjects 
must smoke an average of ≥ 5 cigarettes/day in the 30 days prior to randomization.   
 
Investigational Project:  Subjects will be randomized on Study Day 1 to one of the following 
three groups: 
 
1. Low-dose topiramate (up to 125 mg/day); or 
 
2. High-dose topiramate (up to 250 mg/day); or 
 
3. Identical matched placebo control. 
 
To mask the intervention groups, identical matched placebo will be provided.  
 
Dose titrations will be as follows: 
The titration scheme has been devised such that this process is completed for the low- or high-
dose topiramate groups, and matching placebo, at the end of week 5 (i.e., beginning of week 6).  
Both titration schemes are provided below.  
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
14 
Version 9, April 4, 2022 
 
 
Topiramate high-dose escalation schedule 
 
Week  A.M. Dose  
P.M. Dose  
Total Daily Dose 
1 
- 
50 mg 
50 mg 
2 
50 mg 
50 mg 
100 mg 
3 
75 mg 
75 mg 
150 mg 
4 
100 mg 
100 mg 
200 mg 
5 
125 mg 
125 mg 
250 mg 
6-18 
125 mg 
125 mg 
250 mg 
 
Topiramate low-dose escalation schedule 
 
Week  A.M. Dose  
P.M. Dose  
Total Daily Dose 
1 
- 
25 mg 
25 mg 
2 
25 mg 
25 mg 
50 mg 
3 
37.5 mg 
37.5 mg 
75 mg 
4 
50 mg 
50 mg 
100 mg 
5 
62.5 mg 
62.5 mg 
125 mg 
6-18 
62.5 mg 
62.5 mg 
125 mg 
 
 
Outcomes:  
Primary Efficacy Outcomes: The timeline follow-back (TLFB) method of measuring alcohol 
and cigarette consumption will be used to construct a retrospective index of smoking behavior 
during the 3-month period before enrolling in the study.  Thereafter, the consumption of alcohol 
or cigarettes between weekly visits will be recorded.[1]  Days abstinent will refer to the number 
of days on which the subject consumes no alcohol or cigarettes.  While subjects also will be 
provided with daily record cards as an aide-mémoire, only the TLFB data will be used in the 
efficacy analyses.  From these data, we will determine both the PHDD and the point prevalence 
smoking abstinence rates.  Self-reported reports of smoking cessation will be corroborated by 
measurement of breath CO level, and, when necessary, urinary cotinine level (see below).   
PHDD is calculated as days for which the number of drinks was five or greater for men and four 
or greater for women, divided by the number of study days. [73] 
 
Expired carbon monoxide (CO) level will be measured using a Bedfont CO monitor, and, when 
necessary, Accutest NicAlert strips Self-reported abstinence will be verified by expired CO 
samples of <10 ppm. Individuals who report smoking at screen and visit 1, but register less than 
10ppm on the CO monitor will be re-tested with a NicAlert cotinine strip. Urinary cotinine 
scores of 3 or higher indicate tobacco usage.  
 
Secondary Efficacy Outcomes:   
1. 
The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)  
2. 
The Alcohol Craving Visual Analog Scales  
3. 
The Nicotine Craving Visual Analog Scales  
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
15 
Version 9, April 4, 2022 
Exploratory Outcomes: 
 
Psychological Assessments: 
1. Fagerström Test for Nicotine Dependence  
2. Revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar),[2]  
3. Wisconsin Smoking Withdrawal Scale  
4. Positive Affect Negative Affect Schedule (PANAS) 
5. The Center for Epidemiologic Studies Depression Scale (CES-D) 
6. Medical Outcomes Sleep Scale (MOS-Sleep) 
7. The Drinker Inventory of Consequences (DrInC)[3] 
 
Study Retention and Compliance: 
1. Attendance at regularly scheduled clinic visits  
2. We shall assess compliance by comparing unused capsule count to dispensing logs and 
dosing records (number of capsules dispensed, number of capsules expected to be taken, 
versus the number returned).  
3. Brief behavioral compliance enhancement treatment (BBCET) 
Safety Assessments: 
1. 
Medical history 
2. Physical examination 
3. Vital signs 
4. ECG  
5. Blood chemistries and hematology 
6. Urine pregnancy test 
7. AEs 
8. Concomitant medication use 
9. Contraceptive method 
10. BAC 
 
 
 
 
 
5   
INTRODUCTION AND RATIONALE  
 
5.1 
General rationale for the pharmacological treatment of comorbid alcohol and 
smoking dependence: Advances in the neurosciences have shown that there are important 
neurochemical pharmacodynamic interactions between alcohol and nicotine that might summate 
to increase co-dependency on both.[11]  Further, there is evidence that pharmacokinetic factors 
associated with the absorption, distribution, and metabolism of both compounds might lead 
individuals to administer these compounds in such a way that the effects of one of these drugs 
serve to modulate the effects of the other.[12, 13]  Emerging genetic evidence also shows that an 
earlier onset of smoking is associated with greater likelihood of problem drinking, and fetal 
exposure to alcohol may increase susceptibility to smoking.[14, 15]  Nevertheless, despite this 
striking evidence for substantial neurochemical and biological overlap between alcohol and 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
16 
Version 9, April 4, 2022 
nicotine dependence, few clinical trials have addressed the possibility of using a common 
pharmacological approach to treat both disorders. 
 
Important neurochemical interactions exist between alcohol and nicotine that can serve to 
increase the reinforcing effects and, therefore, abuse liability of the combination.   
 
The reinforcing effects of both nicotine and alcohol are mediated through CMDA (cortico-
mesolimbic dopamine) pathways.[16-18]  While the primary action by which alcohol exerts its 
reinforcing effects is through the disinhibition of the inhibitory effects of γ-aminobutyric acid-A 
(GABAA) neurons in the ventral tegmental area (VTA) (for a review, see Johnson[19]), there is 
also evidence that alcohol might excite VTA neurons through nicotinic acetylcholine 
receptors.[12, 20]  Animal studies show that chronic nicotine intake can increase the likelihood 
of alcohol consumption.  For instance, chronic nicotine intake up-regulates nicotinic 
acetylcholine receptors,[21, 22] thereby increasing the sensitization of the CMDA system to 
alcohol.  Extended to humans, this would imply that smoking would be expected to enhance the 
pleasurable effects of consuming alcohol.  The results of patch clamp studies have, however, 
been utilized to understand further the neurochemical interactions between alcohol and nicotine.  
The acetylcholine receptor can generate two types of current — an α-bungarotoxin-sensitive 
current and an α-bungarotoxin-insensitive current — that originate from the α7- and α4β2-type 
subunits, respectively.[23, 24]  Narahashi et al.[25] have shown that alcohol potentiates the 
activity of the α4β2-type subunit at physiologically relevant doses and can offset nicotine’s 
ability to desensitize this subunit.  They propose that these effects of alcohol facilitate the 
recovery of acetylcholinergic currents from nicotine-associated desensitization, thereby serving 
to promote smoking behavior.  Importantly, however, other authorities have suggested that the 
principal site of alcohol-nicotine interactions might not be the α4β2-type subunit,[26] although 
the nicotinic acetylcholine receptor was still implicated by demonstration that mecamylamine, a 
non-competitive nicotinic acetylcholine receptor antagonist, suppresses alcohol consumption.[26, 
27]   
 
In sum, whatever the exact molecular pharmacological explanation for the interaction between 
alcohol and nicotine, the nicotinic acetylcholine receptor appears to be principally involved.  
Alcohol and nicotine appear to combine such that their ability on reinforcement mechanisms is 
additive.[28]  Thus, an important neuropharmacological approach toward simultaneous treatment 
of alcohol and nicotine dependence would be to administer a compound such as topiramate (see 
below) that has the potential to profoundly modulate CMDA function.  
 
 
 
 
 
5.2 
Topiramate 
 
5.2.1 Chemistry 
Topiramate has the following structural formula: 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
17 
Version 9, April 4, 2022 
 
5.2.2 Pharmacology 
 
Topiramate, a sulfamate-substituted fructopyranose derivative, might antagonize the reinforcing 
effects associated with the abuse liability of both nicotine and alcohol by modulation of CMDA 
function.[29]  As we have conceptualized previously,[4] topiramate could, theoretically, suppress 
the extracellular release of dopamine by facilitating contemporaneously the actions of the 
inhibitory neurotransmitter, GABA, through a non-benzodiazepine receptor site[30] in the VTA 
and nucleus accumbens and antagonizing the excitatory effects of AMPA and kainate glutamate 
receptors on A10 DA neurons at these same sites[29-35] (see figure below).  These effects of 
topiramate might be even more pronounced in the chronic compared with the acute condition 
because of its ability to decrease glutaminergic sensitization, thereby normalizing CMDA 
function.  Indeed, there is evidence that topiramate can attenuate nicotine-associated rises in 
nucleus accumbens release of DA.[36]  

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
18 
Version 9, April 4, 2022 
 
Further, there might be other effects of topiramate that may either independently or in 
combination serve to decrease alcohol and nicotine consumption.  For instance, due to 
topiramate’s ability to antagonize L-type calcium channel currents as well as decrease 
glutaminergic sensitization, it might enable individuals to withdraw more comfortably from 
either alcohol or nicotine.  Indeed, this potential effect, when coupled with the mild anxiolytic 
properties of topiramate, may serve to decrease the potential for protracted withdrawal upon 
ceasing alcohol or nicotine consumption, or both.   
Finally, topiramate might have an additional property that could make it an attractive anti-
smoking aid and, among those comorbid with alcohol dependence, could enhance the drive 
toward sobriety.  It is well recognized that the potential for weight gain upon stopping smoking 
is an important reason why some individuals,[37-39] particularly women,[40-44] fail to 
quit.  While the mechanism for this effect is unknown, female smokers concerned about gaining 
weight upon initiating abstinence appear more likely to drop out or to fail to comply successfully 
with treatment compared with those without such concerns.[41]  While some controversy exists 
in the literature about the importance of concern about weight gain as a barrier to smoking 
cessation, with notable discrepancies and criticisms of methodological approach, and suggestions 
that other factors such as self-efficacy might be equally important (for an overview, see Borrelli 
and Mermelstein[45]), topiramate might have utility as a putative pharmacological agent for 
smoking cessation, even among those with comorbid alcohol dependence, because there would 
be no fear of weight gain; indeed, some weight loss would be the expected result.  In this respect, 
it is of interest that topiramate has been shown to promote weight loss in both men and 
Schematic illustration of the effects of topiramate on alcohol and nicotine dependence.  The reinforcing effects 
of both alcohol and nicotine are mediated through activity at CMDA neurons.  Both alcohol and nicotine 
enhance VTA DA neuronal function via the stimulation of nicotinic acetylcholine receptors.  Alcohol also exerts 
an additional effect to promote increased CMDA activity by disinhibiting the inhibitory effects of GABA 
neurons in the VTA and nucleus accumbens (N Acc.).  Topiramate antagonizes the ability of alcohol and 
nicotine to increase CMDA activity by facilitating GABA suppression of VTA and N Acc. neurons and 
antagonizing the excitatory effects of AMPA and kainate glutamate (GLU) receptors at these same receptor 
sites.  Line weights (i.e., heavy, medium, and thin) denote relative strengths of neuronal activity.  VP = ventral 
pallidum.

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
19 
Version 9, April 4, 2022 
women.[46]  Hence, it is reasonable for us to expect that these anti-weight-gain effects of 
topiramate might enhance its utility as an aid to smoking cessation even among those with 
comorbid alcohol dependence.  Taken together, the foregoing would suggest that topiramate is a 
promising agent for the treatment of both nicotine and alcohol dependence. 
 
5.2.3 Pharmacokinetics (PK) 
The sprinkle formulation of topiramate is bioequivalent to the immediate release tablet 
formulation and, therefore, may be substituted as a therapeutic equivalent. 
Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 
hours following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet 
formulation is about 80% compared to a solution. The bioavailability of topiramate is not 
affected by food. 
The pharmacokinetics of topiramate are linear with dose proportional increases in plasma 
concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination 
half-life is 21 hours after single or multiple doses. Steady state is thus reached in about 4 days in 
patients with normal renal function. Topiramate is 15-41% bound to human plasma proteins over 
the blood concentration range of 0.5 -250 μg/mL. The fraction bound decreased as blood 
concentration increased. 
5.2.4 Adverse Effects  
Topiramate at the dosage that will be prescribed in this proposal is well tolerated.  The most 
common adverse events (AEs) that we observed in our alcohol treatment study were transient 
tingling, psychomotor slowing, weight loss, and dizziness.  We acknowledge that other central 
nervous system adverse events have been reported by others, such as ataxia, speech disorders and 
related speech problems, cognitive slowing, mood disturbance, and nystagmus (eyes jumping), 
but these would appear to be more manifest at higher doses than what we have proposed.  A rarer 
adverse event of topiramate is kidney stone, which was not seen in any of our previous studies.  
Topiramate has weak carbonic anhydrase properties.  Thus, topiramate’s concurrent use with 
other carbonic anhydrase inhibitors, such as acetazolamide and zonisamide, may increase the risk 
of kidney stone formation and should, therefore, be avoided.  Topiramate may be associated with 
the development of metabolic acidosis.  
 
Psychological risks can include distress and heightened sensitivity, which can occur as part of 
the behavioral treatments, clinical interviews, or completing self-reported ratings and 
questionnaires.  While the possibility of such events is low, we will monitor these situations and 
provide an appropriate level of support.  Such events will be documented fully in the case 
records. 
5.2.5 Withdrawal  
Antiepileptic drugs are usually withdrawn gradually to minimize the potential of increased 
seizure frequency. In our experience, we have not used a taper phase with topiramate. We have 
completed multiple trials using topiramate and have never experienced a single seizure, and 
carefully screen for possible seizure risk.  

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
20 
Version 9, April 4, 2022 
5.2.6 Possible adverse events from the interaction between Topiramate and Alcohol  
In one clinical trial with alcohol-dependent adults, the following adverse events were observed 
with those who took topiramate: paresthesia (abnormal skin sensations), taste perversion, 
anorexia, and difficulty with concentration. 
 
5.2.7 Rationale for Study Design and Dose Regimen 
Study Design: 
Two principal reasons support combining psychosocial management with pharmacotherapy for 
comorbid alcohol dependence and smoking.  These include: 1) pharmacological agents alone are 
not considered to compose a comprehensive treatment program, and 2) the operative research 
question is whether the pharmacological agents add to the success of psychosocial management.  
For psychosocial management in this proposal, we plan to use a combination of brief behavioral 
compliance enhancement treatment (BBCET) plus a self-help manual for smoking cessation.  
The rationale for this choice is straightforward.  In studies where psychosocial treatments have 
been provided for the independent treatment of alcohol dependence or smoking behavior, the 
general trend has been from intensive psychotherapies to briefer treatments because these are 
more generalizable to clinical practice.  Furthermore, psychosocial treatments that promulgate 
the strategy of brief advice and education have been shown to be effective treatment for both 
alcohol dependence[4, 5] and smoking behavior.[47-53]  It is, therefore, reasonable to propose 
the use of BBCET, which emphasizes brief advice, compliance, motivation, and education for 
the treatment of comorbid alcohol dependence and smoking behavior (see Appendix IV).  
Additionally, to ensure that there is a focus to promote smoking cessation, we will provide the 
self-help booklet, Clearing the Air: Quit Smoking Today,[54] at randomization (see Appendix 
V).   
 
For this project, the educational component of BBCET will be expanded to include information 
about the hazards not only of excessive alcohol consumption but also of smoking.  We can 
readily accomplish this goal as BBCET has already been adapted not only for the treatment of 
alcohol dependence but also for the treatment of stimulant dependence in NIH-funded studies 
that we have led.  BBCET will be delivered in 15- to 30-minute sessions, which will emphasize 
that compliance with the medication and the treatment program are critical elements for reducing 
alcohol and nicotine intake.  Whilst BBCET is a minimal intervention, it is clearly not a “no-
treatment” condition, and will be combined with the self-help pamphlet to further facilitate 
smoking cessation.  The tenets of BBCET were modeled on a development of the clinical 
management condition in the NIMH collaborative trial on depression — essentially a compliance 
management intervention that was found to be a rather significant intervention that compared 
well with other more sophisticated psychotherapies.[56]  An added purpose of providing BBCET 
with the self-help pamphlet rather than a formal intensive psychotherapy is to ensure the delivery 
of adequate treatment while minimizing the potential for a large psychosocial treatment effect to 
mask our ability to detect any pharmacotherapy response in this initial proof-of-concept study.  
Importantly, the BBCET program has been developed into a standardized manual with well-
established supervised training procedures through didactic and videotaped sessions.  All 
BBCET practitioners will be certified to perform this intervention in the trial and will be 
monitored regularly.  
 
Dose Regimen: 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
21 
Version 9, April 4, 2022 
In patients with epilepsy, the package insert and clinical expertise recommends the dose for 
topiramate monotherapy in adults and children 10 years of age and older is 400 mg/day in two 
divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal 
dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. 
 
The recommended total daily dose for the treatment for prophylaxis of migraine headache is 100 
mg/day administered in two divided doses.  
 
Topiramate high-dose escalation schedule 
 
Week  A.M. Dose  
P.M. Dose  
Total Daily Dose 
1 
- 
50 mg 
50 mg 
2 
50 mg 
50 mg 
100 mg 
3 
75 mg 
75 mg 
150 mg 
4 
100 mg 
100 mg 
200 mg 
5 
125 mg 
125 mg 
250 mg 
6-18 
125 mg 
125 mg 
250 mg 
 
Topiramate low-dose escalation schedule 
 
Week  A.M. Dose  
P.M. Dose  
Total Daily Dose 
1 
- 
25 mg 
25 mg 
2 
25 mg 
25 mg 
50 mg 
3 
37.5 mg 
37.5 mg 
75 mg 
4 
50 mg 
50 mg 
100 mg 
5 
62.5 mg 
62.5 mg 
125 mg 
6-18 
62.5 mg 
62.5 mg 
125 mg 
 
Safety Considerations: 
Although topiramate is generally well tolerated, its side effect profile coincides with that of 
alcohol. Therefore, monitoring of CNS effects, and also laboratory values (hepatic function, 
hematology) will be performed.  
 
6 
STUDY OBJECTIVES 
6.1  
Primary Objective 
The primary objectives of this study will be the PHDD for the drinking outcome and the 
continuous abstinence rate for the smoking outcome (during the last 4 weeks of treatment, i.e., 
weeks 15–18 inclusive), respectively.  The secondary efficacy variables will be quality of life 
and measures of alcohol and nicotine craving.   
 
6.2 
Exploratory Objectives 
Additional objectives will include:  
 
1. Measures of drinking severity (i.e., DDD) and abstinence (i.e., percentage of days abstinent; 
PDA) averaged across either the entire double-blind period or the last 4 weeks of treatment.  

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
22 
Version 9, April 4, 2022 
 
2. Smoking measures including the point prevalence abstinence rate and the CO level over either 
the entire double-blind period or the last 4 weeks of treatment.  
 
3. Measures of nicotine and alcohol withdrawal, and negative affect as described previously. 
 
7 
REGULATORY CONSIDERATIONS 
We have filed for an Investigational New Drug (IND) extension as we have previously used 
topiramate in alcoholics, of which many were cigarette smokers as well.  All investigators will 
obtain Institutional Review Board (IRB) approval before initiating the study at their site. 
 
8 
STUDY SITES 
This project will be conducted at three different sites: the University of Virginia, the University 
of California, San Diego, and the University of Texas-M.D. Anderson Cancer Center.  The 
principal investigators at each of these sites have agreed to engage in this collaborative effort, 
each bringing expertise in medication development for alcohol and tobacco research, and 
expecting to produce a synergy of creativity and productivity that will be of invaluable benefit to 
the research being conducted. 
 
Dr. Nassima Ait-Daoud Tiouririne is the contact PI for this project, and the University of 
Virginia Center for Leading Edge Addiction Research (UVa CLEAR) will be the coordinating 
site.  UVa CLEAR is designed to foster mutually trusting, fully collaborative, and highly 
productive partnerships among the different academic centers.  Working together, the partnering 
sites will develop a system of operation that will be administered through a steering committee 
using a mixed matrix model.  This model is exceptional for developing programs where 
substantial overlap and shared decision making are critical to success.  Subsumed under the 
steering committee will be the research core with its four groups of focus: the research 
development group, the data management group, the statistical group, and the research and 
dissemination group (see figure below).   
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
23 
Version 9, April 4, 2022 
 
 
9 
STUDY DESIGN 
Two hundred and ninety-four comorbid nicotine-dependent subjects with mild to severe alcohol 
use disorder who meet eligibility criteria will be randomized to 1 of 3 treatment groups — 
placebo, low-dose topiramate (up to 125 mg/day), or high-dose topiramate (up to 250 mg/day).  
Randomization will be achieved using a block randomization procedure in which treatment 
groups will be stratified to achieve a balance on age of onset for alcoholism (less than 26 years 
old or 26 years and older), gender, and drinks per drinking day (DDD) (<8 DDD or ≥8 DDD) 
and the number of cigarettes smoked (<20 or >20 cigarettes/day).   
 
Following randomization, subjects will participate in an 18-week, double-blind treatment period 
during which they also will receive weekly BBCET, and a self-help manual for smoking 
cessation.  Topiramate and matching placebo will be titrated for the first 5 weeks of the 18-week 
treatment period. The TQD will be at the beginning of the 6th week of treatment.  Subjects will 
be instructed not to attempt smoking or alcohol cessation prior to the TQD.  Setting a TQD at the 
end of medication titration enables stability of effects, comfort with the medication prior to 
attempting to cease alcohol and smoking consumption, and an appreciable buildup of 
medication.  However, in cases where individuals either quit smoking or alcohol consumption 
prior to the TQD, counseling will be directed at helping them maintain their abstinence and 
reengaging their efforts in the event of relapse.  If an individual finds that he or she cannot quit 
TARG Research Core 
Research 
Development 
Group 
Data 
Management 
Group 
Statistical 
Group 
Dr. Nassima Ait-Daoud 
Dr. Bankole Johnson 
Dr. Paul Cinciripini 
Dr. Robert Anthenelli 
Michelle Storer 
Eva Jenkins-Mendoza 
 Jennifer Ferguson 
Dr. Maher Karam-Hage 
 
Dr. Lee Ritterband 
Tracie Kostelac  
Thomas Blom 
Rudel Rymer 
 
Dr. Lei Liu 
Xin-Qun Wang 
Dr. Jason Robinson 
 
Research 
Dissemination 
Group 
Dr. Nassima Ait-Daoud 
Dr. Bankole Johnson 
Dr. Paul Cinciripini 
Dr. Robert Anthenelli 
Dr. Maher Karam-Hage 
Robert Cormier 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
24 
Version 9, April 4, 2022 
smoking and/or consuming alcohol completely following the TQD, he or she shall remain in the 
study and counseling will be directed at the continued setting of reduction goals, with cessation 
as the ultimate target.  
 
10 
SUBJECT SELECTION 
10.1 
Inclusion Criteria 
1) Males and females who have given written informed consent 
2) Subjects must be at least 18 years of age or older 
3) Subjects must weigh at least 40 kg  
4) Good physical health as determined by a physical examination, an electrocardiogram (ECG) 
within normal limits, and laboratory screening tests within acceptable parameters (see 
exclusion criteria below) 
5) DSM-5 diagnosis of mild to severe alcohol use disorder   
6) Record an expired CO level of ≥ 10 ppm or a urinary cotinine level of > 3at screening and 
prior to randomization 
7) Smoking an average of ≥ 5 cigarettes/day in the 30 days prior to randomization 
8) Currently drinking at least 8 standard drink units (SDUs) per week in the 30 days prior to 
randomization for women and at least 15 SDUs per week in the 30 days prior to 
randomization for men 
9) Subjects must provide evidence of stable residence in the last month prior to enrollment in 
the study, and have no plans to move in the next 9 months.  Stable residence is a domicile in 
which an individual can operate as if it were his or her own homestead and does not include 
shelters or halfway houses 
10) The pregnancy test for females of child-bearing potential at screen and prior to 
randomization must be negative.  Additionally, women of child-bearing potential must be 
using an  acceptable form of contraception.  These include, but are not limited to: oral 
contraceptives, hormonal (levonorgestrel) or surgical implants, or barrier plus spermicide 
11) Literate in English and able to read, understand, and complete the rating scales and 
questionnaires accurately, follow instructions, and make use of the behavioral treatments  
15)  Willing to participate in a treatment program for nicotine and alcohol dependence 
 
10.2 
Exclusion Criteria 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
25 
Version 9, April 4, 2022 
1) 
Any current axis I DSM-4 psychiatric disorder (except for alcohol and nicotine addiction) 
that warrants treatment or would preclude safe participation in the protocol, including 
schizophrenia or other psychosis, bipolar disorder, major depression as assessed by the 
MINI, bulimia/anorexia nervosa, and dementia 
2) 
Other neurological or psychiatric disorders, such as: 
1. 
Dependence on any substances except nicotine, alcohol and caffeine 
3) 
Organic brain disease 
1. 
Risk of severe alcohol withdrawal as evidenced by history of alcohol 
withdrawal seizures, illusions/hallucinations, or delirium tremens. 
4) 
Seizure disorders, epilepsy, severe head injury or coma 
5) 
History of suicide attempts (5 years prior to screening) as assessed by the MINI and/or 
current suicidal ideation/plan as assessed by the MINI 
6) 
Serious medical illnesses including but not limited to: 
1. 
Uncontrolled severe hypertension 
2. 
Kidney stones 
3. 
Significant unstable heart disease, including myocardial infarction  
4. 
Unstable angina 
5. 
Clinically significant cardiovascular abnormality (ECG) 
6. 
Disease of the gastrointestinal system, liver, or kidneys that could result in 
altered metabolism, excretion of the study agent or absorption 
7. 
History of major gastrointestinal tract surgery (e.g., gastrectomy, gastrostomy, 
bowel resections) 
8. 
Current or historical diagnosis of chronic disease of the gastrointestinal tract 
(e.g., ulcerative colitis, regional enteritis, or gastrointestinal bleeding) 
9. 
Serious, potentially life-threatening, or progressive medical illness other than 
addiction that may compromise subject safety or study conduct 
7) 
Severe or life-threatening adverse reactions to medications (including topiramate) in the past 
or during this clinical trial 
8) 
Currently on active treatment with topiramate 
9) 
Receipt of a drug with known potential for toxicity to a major organ system within 30 days 
prior to study entry (e.g., isoniazid, methotrexate) 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
26 
Version 9, April 4, 2022 
10) 
Female subjects who are pregnant, lactating, or not adhering to an acceptable form of 
contraception at any time during the study 
11) 
Concomitant (within 2 weeks of randomization) pharmacotherapy with anticonvulsants, 
psychomotor stimulant-type medications, and specific anridepressants like Elavil, Endep. 
Wellbutrin, and MAOIs. 
12) 
Use within 2 weeks of randomization of St. John’s Wort, yohimbine, ginkgo biloba, 
horehound, or any other central nervous system active herbal preparations 
13) 
Use of any opiate substitutes (such as methadone, LAAM, buprenorphine) within 1 month 
preceding screening 
14) 
Exclusive use of tobacco products other than cigarettes, such as (but not limited to) cigars, 
chew, snuff, or pipe in the 30 days prior to screening and not agreeing to abstain from these 
products during the study , if concomitantly using them with smoking. 
15) 
Nicotine replacement treatment (NRT) or participation in an NRT program or any other 
treatment for nicotine dependence in the last 30 days prior to screening   
16) 
Elevation of liver enzymes serum glutamic oxaloacetic transaminase (SGOT), serum 
glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), or lactate dehydrogenase 
(LDH) greater than four times the upper limit of the normal range  
17) 
Electroconvulsive therapy within the 3 months preceding screening 
18) 
Members of the same household 
19) 
Before double-blind randomization, urine positive for opiates, THC, cocaine, amphetamines, 
barbiturates, benzodiazepines, methadone, methamphetamines, phencyclidine, or 
propoxyphene/norpropoxyphene 
20) 
Any circumstance or condition that in the opinion of the investigator would compromise the 
individual’s ability to adhere to the protocol and complete the study 
21) 
Received inpatient or outpatient treatment for alcohol dependence within the last 30 days 
prior to screen 
 
11 
INVESTIGATIONAL PRODUCT 
11.1   Topiramate and Matched Placebo Control 
Greenpark Compounding Pharmacy (Houston, TX) will purchase 100-mg tablets of topiramate. 
They will grind the tablets into a fine powder and make capsules with the appropriate dosage 
strength.  Placebo capsules will contain spray dried lactose, and a small amount will also be 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
27 
Version 9, April 4, 2022 
added to the topiramate capsules. Medication will be packaged by Greenpark and distributed to 
the study sites.   
 
11.2   Investigational Product Labeling 
All medication will be dispensed as labeled medication in bottles.  Each subject will be assigned 
a study number, which will be placed on his or her case records and on each of the medication 
bottles.  The bottles also will be labeled with the subject’s study treatment week number  
and there will be space on the label for the subject’s initials and identification number as well as 
the date dispensed..  These procedures are designed to avoid mis-assignment of medication.  
Each medication bottle will be preprinted with the protocol title, the site number and name, the 
week number, the number of capsules the bottle contains, the dosing directions, the expiration 
date and bottle number.  
 
11.3   Investigational Product Accountability 
The site PI or designated study personnel will maintain a log of all investigational products 
dispensed to the subject, each time investigational product is dispensed.  Bottles of topiramate or 
placebo for each subject will be inventoried and accounted for throughout the trial. The site PI or 
his/her staff will count the bottles returned and record the bottle count on the appropriate drug 
accountability form. Subject compliance with investigational product will be assessed by 
comparing unused tablet count to dispensing logs and dosing records.  If the bottle is not 
returned, the subject will also be asked to report daily drug self administration. 
 
11.4 
Used/Unused Supplies 
At the end of the study, all unused investigational products will be inventoried. Each site will be 
responsible for the destruction of any unused investigational product.  
 
12 
INTERVENTIONS 
12.1 
Investigational Agents 
Topiramate will be self administered by subjects in a dosing regimen of one capsule in the 
evening beginning on Day 1, Week 1 and then moving to one capsule in the morning and one 
capsule in the evening beginning on Day 8, Week 2 and continuing through Day 126, of Week 
18. 
 
The titration scheme has been devised such that this process is completed for the low- or high-
dose topiramate groups, and matching placebo, at the end of week 5 (i.e., beginning of week 6).  
Both titration schemes are provided below:  
 
Topiramate high-dose escalation schedule 
 
Week  A.M. Dose  
P.M. Dose  
Total Daily Dose 
1 
- 
50 mg 
50 mg 
2 
50 mg 
50 mg 
100 mg 
3 
75 mg 
75 mg 
150 mg 
4 
100 mg 
100 mg 
200 mg 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
28 
Version 9, April 4, 2022 
5 
125 mg 
125 mg 
250 mg 
6-18 
125 mg 
125 mg 
250 mg 
 
 
Topiramate low-dose escalation schedule 
 
Week  A.M. Dose  
P.M. Dose  
Total Daily Dose 
1 
- 
25 mg 
25 mg 
2 
25 mg 
25 mg 
50 mg 
3 
37.5 mg 
37.5 mg 
75 mg 
4 
50 mg 
50 mg 
100 mg 
5 
62.5 mg 
62.5 mg 
125 mg 
6-18 
62.5 mg 
62.5 mg 
125 mg 
 
 
Missed Doses. If a subject misses a week or more of investigational products, the product may be 
re-introduced with the A.M. dose for two days, then only the P.M. dose for the following two 
nights and by day 5 both doses should be taken, if tolerated. If a subject misses up to 6 
consecutive days’ doses, s/he will be instructed to start taking the investigational product at the 
last dose that s/he was taking before stopping. If the subject realizes he/she missed the AM dose 
and it is after 12pm then the subject should not take missed AM dose. A missed AM dose can be 
taken anytime before 12pm of the same day. If the subject realizes he/she missed the PM dose 
and it is the next day then the subject should not take missed PM dose. A missed PM dose can be 
taken before 24:00 (midnight) of the same day. 
 
Medication Management. Pills may be taken with or without food. If a subject cannot tolerate a 
dose, the dose will be de-escalated to the next lower tolerated dose and a new kit will be ordered 
from Greenpark Compounding Pharmacy. Until the new kit arrives, subjects will take only one 
of their two daily pills.  On an as needed basis and with the judgment of the site PI, both doses 
can be moved to the PM to manage sedation. 
 
Placebo Control:  Subjects assigned to the placebo group will receive the same number of 
matched placebo capsules on the same schedule as the topiramate high-dose and low-dose 
groups.  
 
In the case of drug related AEs, discontinuation of the investigational product altogether may be 
necessary. In such a situation, the research physician will evaluate the subject to determine 
whether the investigational product should be discontinued immediately, or should be dose 
reduced. If a woman becomes pregnant, she will be instructed to immediately stop taking 
investigational products without any dose tapering.  
 
12.2 
Brief Behavioral Compliance Enhancement Treatment (BBCET) 
The BBCET is a brief (15 to 30 minutes per session) standardized treatment program to be used 
in conjunction with a pharmacological intervention for the treatment of alcohol dependence.[57] 
The purpose of the treatment is to increase and enhance compliance with the investigational 
products and other aspects of the treatment regimen. Each session addresses subject issues 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
29 
Version 9, April 4, 2022 
related to the personal barriers of compliance, focuses on how medication can assist the subject 
in achieving goals related to the control of drinking and smoking, and, if necessary, addresses 
management of side effects. The treatment emphasizes the role of medication and setting 
drinking and smoking goals. Sessions will be audiotaped and 10% of tapes will be centrally 
reviewed by staff at University of Virginia Health System. Subjects may decline to have their 
sessions audiotaped.  
 
Research staff involved in counseling the subjects will be trained to deliver BBCET and will 
have to pass a certification procedure ratified by Dr. Ait-Daoud (Overall PI) or a designee.  
Training will include didactic meetings with the therapy supervisor, reading assignments, and 
review of at least one training case.  Dr. Ait-Daoud or a designee also will also conduct any 
additional training sessions, as needed.  To monitor and prevent practitioner deviation from the 
protocol, about 10% of the recorded sessions will be selected at random for evaluation of quality 
and adherence to manual guidelines.  Monthly conference calls to discuss issues with the 
BBCET will be used as another measure to monitor protocol adherence and to take necessary 
steps to correct any deviation from the allowed procedure.  Supervision of practitioners at all 
sites will be coordinated through Dr. Ait-Daoud or a designee at the University of Virginia 
(UVa).  Practitioners will remain blind to the subjects’ medication condition. 
 
A subject checklist and survey form will be designed to measure the type and amount of treatment 
received.  This checklist, administered at the end of every session, also will serve as an index of 
treatment acceptability and perceived helpfulness.   
 
Subjects who cannot tolerate the medication or who need to reduce or stop the medication for other 
reasons will still be allowed to take part in the BBCET and other aspects of the study. 
 
13 
STUDY PROCEDURES 
13.1 
Subject Recruitment 
Subjects will be recruited at the research centers at UVa and in San Diego and Houston.  
Recruitment strategies vary across each site based on their local population, however, standard 
tactics will be used (i.e., flyers, newspaper advertisements, radio advertisements, internet 
advertisements). Local IRBs will approve all advertising materials used for subject recruitment.  
 
Interested candidates responding to recruitment materials by telephone will be asked a 
standardized set of questions about their drinking and smoking behavior without revealing the 
entry criteria into the study and will be asked if they are seeking treatment and are available for 
approximately 8 months. Candidates will additionally be asked if they are willing to quit both 
smoking and drinking within the next 30 to 60 days.   
 
 
Candidates who report drinking and smoking consistent with the entry criteria, confirm their 
willingness to quit smoking and drinking, and appear to be available and interested in the study 
will meet with the investigator or designated investigational staff within 30 days after the initial 
inquiry to start the informed consent process and assessment process.  
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
30 
Version 9, April 4, 2022 
13.2 
Screening Assessments 
At the first screening visit candidates will meet with either the Principal Investigator (PI), or a 
study staff member designated to obtain informed consent to receive an explanation of the study 
purpose and requirements. If still interested after receiving an explanation of the study, the 
candidate will be given an opportunity to review, inquire about, and sign the study informed 
consent form approved by the local site’s IRB. Subjects must have a breath alcohol content 
(BAC) of 0.000 when signing the informed consent document. Repeat measurements of BAC are 
permitted at the discretion of the investigator. Subjects will be given a copy of the signed 
informed consent.  
 
Interested candidates must be at least 18 years of age and have been determined during the 
screening process to have a DSM-5 diagnosis of mild to severe alcohol use disorder.  Subjects 
must also report to be smoking an average of >5 cigarettes a day in the 30 days prior to 
randomization, which will be collected through the Tobacco Use History Questionnaire and the 
TLFB.  Female subjects must be drinking 8 or more standard drink units (SDUs) per week and 
male subjects 15 or more SDUs per week during the 30 days prior to randomization, as assessed 
by the TLFB. Repeat measurements of CO at screening and visit 1 will be permitted at the 
discretion of site investigators. Subjects will be allowed to smoke prior to testing of CO levels. 
A CO level  ≥10, or a urinary cotinine level of  ≥3 using a NicAlert cotinine screen strips must 
be achieved at screening and visit 1 to be randomized into the study. Subjects will be allowed to 
smoke prior to testing of CO levels. 
 
In the medical history, all female subjects will be asked about their child-bearing potential. 
Women of child-bearing potential must have a negative pregnancy test and must agree to use an 
acceptable method of birth control for the duration of the study. Medical history will be taken 
including the age at which the subject started drinking alcohol regularly (age of onset).  
 
A physical exam will be performed including the subject’s weight. Vital signs will be taken, an 
ECG will be performed, and the subject will be queried on medication use in the 90 day period 
prior to signing consent. Subjects will be instructed that no new prescription/non-prescription 
medications are to be taken between the start of screening and randomization without informing 
the study staff. The subject’s demographics will also be collected at this visit. 
 
A urine drug test will be performed using a point of care test strip. Blood will be collected for 
hematology, chemistry and optional genotyping assessments. Urine will also be collected for 
urinalysis. Saliva will also be collected for cotinine level. 
 
The MINI will be performed to assess diagnoses of psychiatric disorders in accordance with 
DSM-4 criteria. At screening the following questionnaires will be administered: Fagerström Test 
for Nicotine Dependence, AUDIT, CIWA-AR, Q-LES-Q, The Alcohol Craving Visual Analog 
Scales, The Nicotine Craving Visual Analog Scales, Wisconsin Smoking Withdrawal Scale, 
PANAS, CES-D, MOS-Sleep, Baseline Drug Use, and DrInC. Screening may be completed in a 
single visit or over two visits (e.g., a hematology or chemistry test needs to be repeated).  
 
Subjects will be required to provide the name, phone number, and address of up to three contact 
persons who are likely to know their whereabouts. 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
31 
Version 9, April 4, 2022 
 
13.3 
Subject Randomization 
Prior to randomization, data essential for eligibility will be reassessed. Drinking and smoking 
requirements during the time period between the screening visit and visit 1 will be reassessed. 
All essential data for assignment to a treatment group will be collected by the study staff on the 
randomization form. 
 
Assignment to a stratum during randomization will be based on the following:  age of onset (≤25 
or >25), drinks per drinking day (DDD) during the 90 days prior to screening (<8 or ≥8), average 
number of cigarettes smoked per day during the 90 days prior to screening, and gender.  
Calculations will be made using the formulas below. 
 
90 Day SDU Total   = Drinks per Drinking Day (DDD) 
                    # Drinking Days 
  
 
 
       90 Day Cigarette Total =  Average # Cigarettes per Day 
 
 
         90 Days 
 
13.4 
Intervention Phase 
Subjects will be seen in person at the clinical site for  17 visits (screening, intervention phase and 
the one month follow-up visit) and will complete the three month follow-up visit over the phone. 
All subject clinic visits will be collected on source documents and entered into an electronic 
database, or entered directly into an electronic database and printed out and placed in the source 
documentation binder. Clinic visits should be scheduled on the same day of the week that the 
subject was randomized, if possible, but a 3-day window is allowed.  In the event of a missed 
visit, subjects will have until the end of the same week to reschedule an appointment or if the 
subject is unable to visit the clinic then the visit may be conducted over the telephone.     
 
If the subject comes to a visit outside the allowed window, assessments scheduled for this visit 
will be conducted and data will be recorded as if it were for that week’s scheduled visit and 
recorded as an unscheduled visit. At each of the clinic visits during the intervention phase, 
subjects will receive a brief session with one or more study staff members who will 
systematically assess AEs since the last visit, take vital signs, measure weight, conduct a BBCET 
session, administer questionnaires, ask about concomitant medication use and contraceptive 
method, and assess drinking and smoking using the TLFB. A new supply of investigational 
product will be given and the medication bottle(s) from the previous period will be collected.  
Blood will be collected for chemistries and hematology and a physical exam and 
electrocardiogram will be performed at Week 19 (visit 15). Women of child bearing potential 
will have a repeat pregnancy test during Weeks 1, 4, 7, 10, 16 and 19. An alcohol breathalyzer 
will be administered at each visit to determine if the subject has a BAC < 0.020 to complete the 
visit. A urine drug test will be performed intermittently throughout the study. If the subject 
misses a visit in which safety measures were collected, the safety measures should be collected at 
the next in-clinic visit. 
 
The following assessments will be administered at each study visit during the intervention phase 
(Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18 and 19): Q-LES-Q, Alcohol Craving Visual 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
32 
Version 9, April 4, 2022 
Analog Scale, Nicotine Craving Visual Analog Scale, CIWA-AR, Wisconsin Smoking 
Withdrawal Scale, and CES-D. In addition the PANAS assessment will be administered at Week 
1, 3, 5, 7, 9 and 19 and the MOS-Sleep assessment will be administered at Week 1, 5, 9, 12, 16 
and 19. The DrInC will be administered at Week 1, 4, 6, 9, 12 and 19. 
 
CO levels will be measured at each visit during the study. 
 
Salivary cotinine level is obtained before randomization and also at visit 15. In addition, in the 
event that a subject is unable to attend visit 15, they may be asked to provide a cotinine sample, 
via mail, which will be used to verify abstinence. In such a case, a saliva collection kit and 
instructions will be mailed to the subject with a prepaid return address envelope.  
 
 13.5 One and three month follow-up visits  
At the end of the treatment period, subjects will be scheduled to attend a follow-up assessment 
session at one month post-treatment and take part in a follow-up phone call at  three months 
post-treatment.  
 
The following assessments will be administered at the one month follow-up visit: Fagerström 
Test for Nicotine Dependence, Q-LES-Q, The Alcohol Craving Visual Analog Scales, The 
Nicotine Craving Visual Analog Scales, CIWA-AR, Wisconsin Smoking Withdrawal Scale, 
PANAS, and CES-D. In addition, TLFBs for smoking and alcohol consumption and BAC and 
CO level will be collected at this visit.  During the 3 month follow-up phone call, the CIWA-AR 
will be administered and TLFBs for smoking and alcohol use will be performed.  
 
13.6 
Early Termination (ET) 
If a subject wishes to withdraw from the study before completing all study visits during the 
treatment phase then the study staff will schedule an early termination visit. The early 
termination visit will include all procedures and assessments of visit number 15 (week 19). 
 
13.7 
Study Completion Referral to Treatment 
At the last contact with a study staff member, subjects who request ongoing care will be given a 
referral to an alcohol treatment facility or may be given a list of alcohol treatment facilities to 
contact.  
 
13.8 
Management of Withdrawal 
Persons drinking at the level required for study entry may experience moderate to severe 
withdrawal symptoms if they stop drinking abruptly or if they attempt to taper their drinking, 
including shakes or tremors, chills, nausea and/or vomiting, agitation, sleeplessness, seizures, 
and delirium (disorientation, altered sensorium, and hallucinations). In addition to being 
distressing to the subject, these symptoms may become severe enough to require hospitalization 
in order to be managed safely. If the subject requires assistance with withdrawal between the 
consent and randomization visit or takes any benzodiazepines during this time period, they will 
be given appropriate treatment referrals. Any subject who is treated for withdrawal with 
medication between consent and randomization is no longer eligible to participate in the study. If 
management of alcohol withdrawal during the study is necessary, the subject will be referred to a 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
33 
Version 9, April 4, 2022 
health care facility. Persons who are at risk for severe alcohol withdrawal will be excluded from 
the study. 
 
At every in clinic visit subjects will be assessed for the emergence of withdrawal symptoms 
using a modified self-report version of the CIWA-AR and will be asked about changes in their 
health and drinking status.  If the subject is experiencing withdrawal symptoms that would be 
equal to or greater than a total score of 10, or if their score on any individual item exceeds 
predetermined thresholds specific to each item on the CIWA-AR scale, and depending upon the 
situation, the clinic personnel will promptly speak to the subject to further assess their status. 
 
Continuation of the investigational products while the subject undergoes detoxification is up to 
the discretion of the investigator. 
 
13.9 
Concomitant Medication Use 
Subjects who enter this study can be on psychotropic medication if they are deemed stable 
enough to participate. We also will avoid the prescription of medications with even minimal 
potential interactions with topiramate.  It is, however, recognized that concomitant medication 
may be prescribed or self-administered to treat minor physical ailments during the study.  Such 
appropriate medications will be allowed and documented in the concurrent medications section, 
and the physical ailment recorded in the adverse events section of the subject’s study book.  A 
list of disallowed concomitant medications will be compiled and placed in the appendix section 
of each case study book for easy reference (see Appendix III, Table of Disallowed 
Concomitant Medications). 
 
 
13.10 Safety Monitoring Plan  
In compliance with the National Institutes of Health (NIH) policy for protection of human 
subjects in clinical studies, a Data and Safety Monitoring Plan (DSMP) previously approved by 
the NIH will be implemented at each site.  The Data and Safety Monitoring Board (DSMB) for 
this study will be at the lead site, the University of Virginia. This DSMP serves to protect the 
health and safety of human subjects and provide information relevant to subjects’ continuation in 
clinical studies and will consist of the following elements: 
 
 a) Responsibilities of the principal investigator (PI) 
These responsibilities include:  
 
1. Reporting immediately to the Institutional Review Board (IRB) any severe adverse 
reaction or serious problem, whether anticipated or unanticipated;  
2. Reporting immediately to the IRB the death of a subject, regardless of cause;  
3. Reporting promptly to the IRB any significant findings that become known in the course 
of the research and that might affect the willingness of subjects to participate in the study, 
including such items as changes in available standard of care, any interim analyses such 
as DSMB reports, and results of any monitoring visits by the institution or external 
regulatory bodies;  
4. Ensuring that only persons formally approved by the IRB enroll subjects;  

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
34 
Version 9, April 4, 2022 
5. Protecting the confidentiality of all personal identifiable information collected, and 
training one’s staff and collaborators on policies and procedures for ensuring 
confidentiality of this information;  
6. Submitting any change(s) to the protocol and/or consent document(s) to the IRB for 
review and approval prior to the implementation of the change(s);  
7. Submitting a progress report: federal regulations require IRB review of ongoing projects 
no less than once a year;  
8. Notifying the IRB when the study has been completed and submitting a final report. 
  
b) Institutional Review Board (IRB) responsibilities 
The IRB reviews all human subject research conducted by faculty, staff, and students, regardless 
of the location of the research activity, source of funding, and whether the research is exempt 
under the Code of Federal Regulations for Protection of Human Subjects (45 CFR 46).  
 
A guarantee that all human subject research will be reviewed by the IRB has been given to the 
Department of Health and Human Services (DHHS) in a Multiple Project Assurance (M-1403).  
The Multiple Project Assurance covers the universities at each participating site.  The intent of 
the institutional policy to review all human subject research irrespective of location, source of 
funding, and exempt status is to foster high ethical standards in the conduct of research and to 
assure that uniform criteria are applied to protect the human subjects who take part in research.  
 
The IRB reviews research in accordance with current DHHS and FDA regulations.  The main 
purpose of the IRB is to protect the rights and welfare of human subjects who take part in 
research.   
 
c) Data and Safety Monitoring Board (DSMB) 
The DSMB group will be centralized at UVa. One member from each site will be included on a 
yearly DSMB teleconference. The DSMB will include relevant experts with supervisory capacity 
and the ability to enforce such actions as may be deemed necessary.  The DSMB will also have 
one lay member.  The DSMB will meet regularly to review progress pursuant to presentation of a 
summary report from the principal investigator ensuring that policies on the identification and 
reporting of adverse events to the appropriate regulatory bodies, which can include the local IRB, 
the FDA, and the project officer at the NIH, have been implemented diligently and promptly.  
Prompt and due diligence reporting of serious adverse events (i.e., within 24 hours during the 
week and on the next working day following a weekend) to the regulatory bodies remains the 
express duty of the principal investigator.  The DSMB will retain the right to make independent 
representation to the regulatory bodies if there has been a failure or lapse in reporting by the 
principal investigator.  The DSMB also will have the capacity to instruct the principal 
investigator to pause or terminate pursuance of research if regulatory body guidelines are 
contravened.  The DSMB will provide regular independent reports to the IRB concerning the 
protection of human subjects in this study.  These DSMB procedures have been approved 
previously by the NIH for our ongoing clinical studies.   
 
Frequency of data and safety monitoring reviews:  This team has extensive experience with 
clinical trials using topiramate and with the recruitment and retention of alcohol- and nicotine–

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
35 
Version 9, April 4, 2022 
dependent subjects.  In the past, such trials have been conducted with minimal risks to 
participants.  Therefore, the DSMP will include two items: 
 
1. The research staff at each site involved in the study will meet weekly to discuss progress 
on the study and to address any issues with the research procedures and database.   
2.  Once a year thereafter, the safety data described in the above section will be reviewed by 
the DSMB.  The executive secretary will then generate a report that is sent to the PI.  The 
report will summarize the Board’s review of cumulative serious and unexpected adverse 
events. 
 
Content of data and safety monitoring report:  The PI will be responsible for monitoring the 
safety and efficacy of this trial, executing the DSMP, providing the DSMB with the needed 
information, and complying with the reporting requirements.  The overall PI will provide a 
summary of the data and safety monitoring report to the NIAAA on an annual basis as part of the 
progress report.  
 
d) Confidentiality 
Extensive procedures in compliance with FDA regulations on Good Clinical Practice will be 
implemented for this trial to protect subject confidentiality and database integrity.   
Briefly, besides the consent form that contains identifiers, all other data will be coded using a 
code number and initials.  The consent form is stored in a secure location with limited access.  
Security procedures are implemented to ensure that only authorized personnel can enter study 
data.   
 
e) Emergency procedures 
On the day of randomization, participants are given an emergency notification card.  The 
emergency notification card has a 24-hour emergency number by which to contact a PI study 
staff member in case of an after-hours emergency.   
 
f) Emergency breaking of the study blind 
The decision to break the study blind for an individual subject lies with the study principal 
investigator (or a designated co-investigator if a PI is not available) at each site and Dr. Nassima 
Ait-Daoud Tiouririne. Breaking the study blind will be resorted to only in cases of a life-
threatening emergency when knowledge of the treatment arm investigational agent will influence 
clinical management. A designated study staff member will contact Dr. Nassima Ait-Daoud 
Tiouririne (cell: 434-284-1709, pager: 434-924-0000, #2186) in the event that the site PI believes 
the blind needs to be broken. Once permission has been granted by Dr. Ait-Daoud, a designated 
staff member at UVa will match up the pill bottle number for the subject with the master list of 
dose conditions to disclose which medication the subject was assigned.  
 
g) Subject withdrawal 
An investigator may terminate a subject if he or she deems it clinically appropriate or for any of 
the following reasons: 1) significant side effects from the medication, 2) serious or unexpected 
adverse events, 3) inability to comply with the study protocol, 4) protocol violation, or 5) serious 
inter-current illness.  A subject may withdraw from the study anytime he or she wishes.  In the 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
36 
Version 9, April 4, 2022 
event that a subject is discontinued from receiving the research medication, he or she will be 
allowed to continue the psychosocial interventions with the approval of the investigator.   
 
 
Any subject who discontinues prematurely, regardless of the reason, will be requested to return 
for a final visit to perform the necessary procedures and obtain data for the end-of-study/early-
termination visit. 
 
h) Adverse event reporting 
In accordance with FDA reporting requirements, all adverse events (AEs) occurring during the 
course of the clinical trial will be collected, documented, and reported by the investigator or sub-
investigators at each site. Policies established by the local IRB at each site will be followed with 
regard to reporting AEs. 
 
 
An adverse event is any untoward, unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease, temporally associated with the use of the product under 
investigation, whether or not related to the product under investigation. 
 
An unexpected adverse event is any adverse drug experience, the nature, specificity, or severity 
of which is not consistent with the investigator's brochure, package insert or the general 
investigational plan. 
 
For this study, AEs will include events reported by the subject, as well as clinically significant 
abnormal findings on physical examination or laboratory evaluation.  A new illness, symptom, 
sign, or clinically significant clinical laboratory abnormality, or a worsening of a pre-existing 
condition or abnormality, is considered an AE.  Stable chronic conditions, such as arthritis, that 
are present prior to clinical trial entry and do not worsen are not considered AEs.  All AEs, 
including clinically significant abnormal findings on laboratory evaluations, regardless of 
severity, will be followed by study investigators until there is a satisfactory resolution.  AEs may 
be reported up to 4 weeks following completion of, or termination from, the study. UVa will 
submit all AEs to FDA. 
 
i) Serious adverse events 
Serious and unexpected adverse experiences or death occurring during the course of a research 
project, regardless of cause, must be reported to the IRB immediately according to institutional 
guidelines (i.e., within 24 hours).  In addition, all sites must report all SAEs to UVa within 24 
hours. Nassima Ait-Daoud Tiouririne, of UVa, is the IND holder and therefore responsible for 
reporting all SAEs to the FDA. 
 
The FDA reporting requirements are similar.  The FDA defines a “serious adverse experience” 
as any unfavorable event associated with the use of the drug, whether or not it is considered 
drug-related.  
 
 “Serious” means an adverse experience that is life-threatening, is permanently or severely 
disabling, or requires an emergency room visit or inpatient hospitalization.  “Unexpected” means 
an adverse experience that is not listed in the current labeling or investigational use data.  This 
includes an event that may be symptomatically and pathophysiologically related to an adverse 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
37 
Version 9, April 4, 2022 
reaction listed in the labeling or protocol, but that differs because of greater severity or 
specificity.  Serious and unexpected adverse experiences include: 
  
1- Any unexpected event, injury, toxicity, or sensitivity reaction or any unexpected 
incidence or severity associated with clinical use, and  
2- Any unusual failure of the drug to exhibit its expected pharmacological activity.  
 
It is the responsibility of the investigator to inform UVa of the investigation and the FDA of the 
occurrence of unanticipated adverse reactions, death, or serious adverse experiences.  
 
In the event that either a study subject withdraws from the study or an investigator decides to 
discontinue the subject from the study due to a serious adverse event, the subject will have 
follow-up monitoring until the problem prompting the SAE has resolved or stabilized with no 
further change expected, or until it is discovered to be clearly unrelated to study medication, or 
until it progresses to death. 
 
13.11 Volunteer Discontinuation 
The investigators will follow the protocol to identify and intervene with subjects experiencing 
clinical deterioration during study participation. Potential protocol discontinuations will be 
reported to the overall PI, Nassima Ait-Daoud Tiouririne.  
 
13.12 Recommended Subject Compensation 
Subjects will be compensated for travel expenses and for time contributed to this research study 
in the form of vouchers, retail scrip, or cash. Compensation amounts will be in accordance with 
each local site’s IRB recommendations. Subjects will be compensated regardless of whether they 
continue to receive the investigational product, if they attend visits.  This compensation is for 
time and expenses incurred for study participation (e.g., gasoline, public transportation).  
Compensation for all completed visits, procedures and assessments may be up to $510.  
 
13.13 Trial Registration 
This trial will be registered on the National Library of Medicine’s Clinical Trials Registry on the 
World Wide Web at http://www.clinicaltrials.gov. 
 
14 
ASSESSMENT METHODS 
Table 1 summarizes the timing of the clinical activities and assessments to be conducted over 
the entire study period. These include the PANAS, Q-LES-Q, The Alcohol Craving Visual 
Analog Scales, The Nicotine Craving Visual Analog Scales, Wisconsin Smoking Withdrawal 
Scale, CES-D, MOS-Sleep, DrInC, CIWA-AR, Other Drug Use, and Fagerström Questionnaires. 
 
14.1 
AEs 
AEs will be assessed starting after the subject takes the first dose of investigational product. AEs 
assessed in the clinic will use an opened ended question: “How have you been feeling since your 
last visit?” If an AE is reported that requires medical attention, it should be reported to the 
medical team for evaluation and follow-up.  

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
38 
Version 9, April 4, 2022 
 
14.2 
Alcohol Breathalyzer 
An alcohol breathalyzer will be administered at consent, at screening, and at every in-clinic visit 
as a safety measure. Acceptable BAC levels at consent and screening is equal to 0.000 and less 
than or equal to 0.020 for in-clinic visits.  
 
14.3 
Blood Chemistries, Hematology and Urine 
Blood chemistry and hematology will be performed to confirm the subjects’ physical health.  
These tests will include: complete blood count (CBC), sodium, potassium, chloride, calcium, 
phosphorus, total protein, albumin, globulin, glucose, total bilirubin, alkaline phosphatase, 
albumin/globulin ratio, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic 
pyruvic transaminase (SGPT), γ-glutamyl transferase (GGT),  blood urea nitrogen (BUN), 
creatinine, uric acid, and lactate dehydrogenase.  
 
Urine will be collected for routine urinalysis.  Women of child-bearing potential will receive a 
urine pregnancy test as scheduled in Table 1.  Additionally, women of child-bearing potential 
participating in this study will be required to use an acceptable form of contraception, which 
includes but is not limited to the oral contraceptive pill, barrier (diaphragm and condom) plus 
spermicide, or hormonal or surgical implants.    
 
An onsite urine drug screen will be performed at the screening visit to clear each subject for 
randomization.  This UDS must be negative for all drugs.  If a patient tests positive for a drug, he 
or she will be permitted one repeat urine drug screen prior to randomization.    At site PIs’ 
discretion, should a patient test positive again during the repeat UDS, he or she may rescreen 
(including re-consenting) 30 days from the end of the original 14 day period for randomization, 
which began when the informed consent was signed at the first screen visit.  Urine drug screens 
will be repeated intermittently throughout the study.   
 
14.4   BBCET Session Compliance 
 
The BBCET session checklist is an instrument for provider assessments of session activities that 
was developed by the BBCET provider in our ongoing clinical trials.  The checklist contains key 
interventions specific to the treatment.  The rationale for the use of a BBCET session checklist is 
to provide a reminder of the key elements of the intervention and to provide an estimate of the 
overall level of treatment-specific intervention to each of the subjects in the study.    
 
14.5 
Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR) 
The CIWA-AR, a reliable and well-validated 10-item scale, will be used weekly to assess the 
severity of alcohol withdrawal symptoms. The CIWA-AR has been used both in clinical and 
research applications and has demonstrated both reliability and validity.  
 
14.6   Wisconsin Smoking Withdrawal Scale  
This questionnaire will be used weekly to assess the severity of nicotine  withdrawal symptoms. 
It is a 28-item scale divided into 7 subscales related to smoking cessation: sadness, sleep, hunger, 
craving, concentration, anxiety, and anger.   
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
39 
Version 9, April 4, 2022 
14.7   Positive Affect Negative Affect Schedule (PANAS) 
The 20-item PANAS is a psychometric scale developed to measure the largely independent 
constructs of positive and negative effect, both as states and traits.[58]  Subjects will be asked to 
describe different feelings and emotions during the past week. 
 
14.8 
The Center for Epidemiologic Studies Depression Scale (CES-D) 
The CES-D[59] was developed to measure symptoms of depression in community populations. 
The scale has been used in many research studies as a screen for the presence of depressive 
illness. When the scale was developed items were selected to represent the major components of 
depression on the basis of the clinical literature and factor analytic studies. Components include 
the following: depressed mood, feelings of hopelessness, feelings of worthlessness, loss of 
appetite, poor concentration, and sleep disturbance.  
 
The measurement of mood is particularly important to both alcohol and nicotine studies.  With 
respect to alcohol, abrupt cessation of intake in dependent individuals can be associated with 
mood disturbance including depression, anxiety, confusion, and irritability.  Likewise, abrupt 
smoking cessation among those dependent on nicotine can be associated with negative affect[60] 
including depression and anxiety.  Furthermore, because the FDA has included the monitoring of 
depression and suicidality for all individuals receiving an anticonvulsant (including topiramate), 
we have included specific measurement of those parameters using the CES-D.  
 
14.9   Medical Outcomes Sleep Scale (MOS-Sleep) 
Abrupt cessation of either alcohol or nicotine in dependent individuals can be associated with 
sleep disturbance, and overall improvement in clinical condition might be associated with 
improved sleep. Therefore, sleep behavior will be measured explicitly. 
 
The MOS-Sleep is a self-report questionnaire consisting of 12 items to provide information 
across sleep dimensions.[61]  The scale assesses the following sleep constructs: initiation (2 
items), maintenance (2 items), respiratory problems (2 items), quantity (1 item), perceived 
adequacy (2 items), and somnolence (3 items).  Subjects report the amount of time it took to fall 
asleep and the number of hours they slept each night over the past week.  Subjects answer 10 
additional questions on a 6-point Likert scale ranging from 1 = all of the time to 6 = none of the 
time.  
 
14.10   Drinker Inventory of Consequences (DrInC) 
The DrInC[3] contains 50 items assessed on a 3-point scale ranging from “never” (0 points)  to 
“daily or almost daily” (3 points).  These 50 items are further subdivided into 6 subscales: 
physical consequences (8 items; maximum score = 24); intrapersonal consequences (8 items; 
maximum score = 24); social responsibility consequences (7 items; maximum score = 21); 
interpersonal consequences (10 items; maximum score = 30); impulse control consequences (12 
items; maximum score = 36), and control items (5 items; maximum score = 15), as well as a total 
consequences scale (45 items; maximum score = 135).  The total consequences scale is the sum 
of all the subscales except for the control items subscale.  A lower score indicates reduced 
adverse consequences of drinking as compared with a higher score.  The control items subscale 
is the sum of 5 reverse-scored validity items. 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
40 
Version 9, April 4, 2022 
14.11   Fagerström Test for Nicotine Dependence 
The Fagerström Test for Nicotine Dependence[62] will be used to assess the behaviors 
associated with dependence on nicotine in potential study participants.  The Fagerström Test for 
Nicotine Dependence will be administered at screening, and will, also, be repeated at the end of 
the double-blind phase and during the one month follow-up to ascertain behavioral consequences 
associated with nicotine dependence. 
 
 
14.12  Demographics 
Patient demographics will be collected for all subjects who sign a consent form. The subject’s 
date of consent, date of birth, gender, race, marital status, education, employment status, income 
level and ethnicity will be recorded. 
 
14.13   Drug Accountability 
Drug accountability will be performed by recording the number of capsules dispensed and the 
number of capsules returned at clinic visits. The amount dispensed, daily dose prescribed, and 
amount returned will be reconciled and recorded at each visit. If the subject reports missing 
capsules that were not taken, this data will also be recorded and used to calculate total drug 
exposure. If the bottle was not returned, then the subject’s self report of drug administration will 
be reported. 
 
14.14  ECG 
A 12-lead ECG will be obtained during screening and at visit 15. All 12-lead ECGs will be 
evaluated for HR, rhythm, and QTc intervals. Any abnormalities will be noted and an assessment 
of clinical significance will be done by a study physician or a qualified licensed medical 
provider. 
 
14.15   Eligibility Checklist 
The Eligibility Checklist which includes all inclusion and exclusion criteria will be reviewed in 
stages as follows: 1) after screening measures are completed and before scheduling the Study 
Day 1 visit and 2) prior to randomization on Study Day 1. If the subject was found not to be 
eligible at either of these timepoints, the reason(s) will be recorded. This data will be included in 
the study database for all subjects who signed the informed consent. 
 
14.16   Medical History 
A medical history will be taken on all potential study subjects to assure medical fitness and will 
be used to supplement the physician’s general inquiry and physical examination.  
 
14.17   Concomitant Medications 
All medications (prescribed and over the counter medications plus herbal remedies) taken by the 
subject 90 days prior to the start of screening, during the screening period, and while taking 
investigational products will be recorded. Medications taken after the start of screening must be 
pre-approved by the study physician whenever possible to avoid interactions with the 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
41 
Version 9, April 4, 2022 
investigational products. All medications reported by the subject or prescribed by the study 
physician will be recorded.  
 
14.18 Timeline Follow-Back (TLFB) 
The TLFB method of measuring alcohol and cigarette consumption will be used to construct a 
retrospective index of smoking and drinking behavior during the 3-month period before enrolling 
in the study.  Thereafter, the consumption of alcohol or cigarettes between weekly visits will be 
recorded.[1]  Days abstinent will refer to the number of days on which the subject consumes no 
alcohol or cigarettes.  While subjects also will be provided with daily record cards as an aide-
mémoire, only the TLFB data collected by a designated study staff member will be used in the 
efficacy analyses.  From these data, we will determine both the PHDD and the point prevalence 
and continuous smoking abstinence rates.  Self-reported reports of smoking cessation will be 
corroborated by measurement of breath CO level (see below).   
 
Each site will receive training from the coordinating site, UVa, on how to administer the TLFB. 
 
14.19   Carbon Monoxide (CO) Level 
 
Expired carbon monoxide (CO) level will be measured using a Bedfont CO monitor.  Self-
reported abstinence will be verified by expired CO samples of <10 ppm.  This will be measured 
at every in-clinic visit. 
 
14.20   Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) 
The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)[64] is composed of 93 
items, each containing responses on a 5-point scale that can range from 1 (“not at all or never”) 
to 5 (“frequently or all the time”).  Ninety-one of these items are grouped into 8 summary scales.  
Five of the 8 summary scales are scored for all subjects and include: physical health/activities 
(13 items, maximum score = 65); subjective feelings (14 items, maximum score = 70); leisure 
time activities (6 items, maximum score = 30); social relationships (11 items, maximum score = 
55), and general activities (14 items, maximum score = 70).  The other 3 summary scales are 
scored when applicable, and these include: work (13 items, maximum score = 65); household 
duties (10 items, maximum score = 50), and school/course work (10 items, maximum score = 
50).  We measured satisfaction with medication and overall life satisfaction and contentment on 
individual item scales, each with a maximum score of 5.   
 
14.21  Alcohol Craving Visual Analog Scales 
The Alcohol Craving Visual Analog Scales will comprise 4 items on which subjects will be 
asked to rate themselves on how they feel “right now” by placing a mark along a 100-mm line 
anchored on the left by “not at all” and on the right by “extremely”.  These items include: “Right 
now I crave a drink”; “Right now I have a strong urge to have a drink”; “Right now I want to 
have a drink”; and “Right now I could refuse to have a drink”.  Scales of this type have been 
validated in a previous alcohol study by Johnson et al.[65]  Whilst we are cognizant that other 
standardized measures of alcohol craving could have been collected (e.g., Obsessive Compulsive 
Drinking Scale,[66]) we chose the scale above because it also was validated and would 
correspond and be directly comparable to the nicotine craving measure described below. 
 
14.22   Nicotine Craving Visual Analog Scales 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
42 
Version 9, April 4, 2022 
The Nicotine Craving Visual Analog Scales will comprise 4 items on which subjects will be 
asked to rate themselves on how they feel “right now” by placing a mark along a 100-mm line 
anchored on the left by “not at all” and on the right by “extremely.”  These items include: “Right 
now, I crave a cigarette”; “Right now, I have a strong urge to have a cigarette”; “Right now, I 
want to have a cigarette”; and “Right now, I could refuse to have a cigarette”.  These scales are 
a derivative of those used in alcohol research by Johnson et al.[65] 
 
14.23   The Tobacco Use History Questionnaire  
This will be administered at screen.  This self-report instrument provides data primarily on past 
cessation attempts, years smoking, other tobacco use, and past methods of cessation, and will be 
used to describe the past smoking behavior of the participants and to determine desire to quit. 
 
14.24   Alcohol Use Disorders Identification Test (AUDIT)[67] 
The Alcohol Use Disorders Identification Test (AUDIT)[67] is a well-validated measure of 
ascertaining the extent of alcohol-related problems.   
 
14.25   Mini International Neuropsychiatric Interview (MINI) 
The Mini International Neuropsychiatric Interview is a short 15 minute structured clinical 
interview. It is used for multi-site clinical trials and epidemiological studies to determine 
diagnoses of psychiatric disorders according to DSM-4 or ICD-10. The MINI we use will 
diagnose psychiatric disorders other than alcohol use disorder based on DSM-4 criteria.  
However, a DSM-5 diagnosis of mild to severe alcohol use disorder is required to be eligible for 
the study.  In order to ascertain that a subject meets this criterion, if the subject answers “yes” to 
question I1 on the MINI, providers will proceed to ask the subject questions in both section I2 
and I3.  In addition, a supplemental sheet with an additional DSM-5 craving question will be 
added to the MINI.  This sheet will also contain directions for scoring:  all items coded YES will 
receive a score of one, including questions in I2, I3, and the supplemental craving question, and 
excluding question I 3 c. (regarding legal consequences).  The total score will then be used to 
determine the severity grade of the subject’s alcohol use disorder.  Severity grades include “no 
diagnosis” (a score of 0 to 1), “mild alcohol use disorder” (2 to 3), “moderate alcohol use 
disorder” (4 to 5), and “severe alcohol use disorder” (6 or greater).   
 
The use of DSM-5 criteria rather than DSM-4 reflects a desire on the part of the research team to 
embrace the future of the Diagnostic and Statistical Manual and to be at the forefront of use of 
these carefully researched, revised guidelines. By including in one spectrum criteria formerly 
divided into two distinct, but clearly related, groups and by judging the results using a severity 
grade, we feel we will have a more accurate picture of a subject’s disorder and his or her 
suitability for participation.  With this change, subjects who met one or two criteria in the former 
dependence section and also met one or more criteria in the abuse portion—and formerly would 
have failed to meet study inclusion criteria—will now be judged in a more overarching manner 
with an eye to the various ways the disorder may express itself.  As we have included minimum 
use levels as part of our inclusion criteria, we feel that the modifications in the DSM-5 will 
prevent us from excluding those who are good candidates for the treatment proposed.  
 
14.26   Salivary Cotinine Level 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
43 
Version 9, April 4, 2022 
Cotinine is the primary metabolite of nicotine and has a half-life of about 19 hours.[68]  Salivary 
cotinine level will be used as an additional objective measure of tobacco exposure for those who 
are still smoking.  We propose the use of 15 ng/ml of saliva cotinine as a cut-off level to 
segregate non-smokers (≤15 ng/ml) from smokers (>15 ng/ml).  The SRNT Subcommittee on 
Biochemical Verification[69] and Seccareccia et al.[70] both recommend that a cut-off level of 
cotinine (15 ng/ml) be utilized for saliva, serum, or plasma samples. 
 
Each site will collect saliva samples on all subjects before randomization and at visit 15. In the 
event that a subject is unable to attend  visit 15, they may be asked to provide a cotinine sample, 
via mail, which will be used to verify abstinence. In such a case, a saliva collection kit and 
instructions will be mailed to the subject with a prepaid return address envelope.  
 
Samples will be sent to a specialty lab where cotinine analysis will be performed on those who 
report abstinence. All sites will use the same saliva cotinine collection kits to maintain 
uniformity across the study. 
 
14.27 Physical Examination 
A physical examination of the oral cavity, head, eyes, ears, nose, and throat, cardiovascular 
system, lungs, abdomen, extremities, skin, neurological system, neck, lymph nodes, 
musculoskeletal system and general appearance will be performed.  
 
14.28 Vital Signs  
Vital signs to be assessed include sitting heart rate, respirations, temperature, and blood pressure. 
Weight will also be recorded at every visit in which vital signs are measured and height will be 
gathered at visits during which an ECG is performed. 
 
14.29 Genotyping 
It has been proposed recently that a single nucleotide polymorphism (SNP) variant of the 
glutamate receptor GluR5 gene (GRIK1) might predict adverse events to topiramate.  
Specifically, the SNP in intron 9 of the GRIK1 gene (rs2832407) appears to be particularly 
associated with adverse events.[71]  Whilst it would not be reasonable to exclude participants 
from the study based upon the findings of a single unconfirmed report, because of the need to 
increase the generalizability of topiramate use, should this study demonstrate efficacy, we 
propose to type this SNP.  Collecting DNA also will provide us with genetic samples that may be 
utilizable as science advances to understand further the neurobiology of excessive alcohol intake 
or smoking, and related behaviors. 
 
Each site will collect blood samples for DNA extraction and genotyping. Samples will be 
collected for genotyping from subjects who consented to genetic testing. Samples will be shipped 
to University of Texas-MDACC where the DNA extraction and genotyping procedures will take 
place. The blood collection for genotyping protocol can be found in Appendix VI. 
 
14.30  Baseline Drug Use and Other Drug Use  
The Baseline Drug Use form will be used at screen to assess current and lifetime drug use.  The 
Other Drug Use form will be used at visits 1-15 and at the one month follow-up visit to record 
any new drug use since the participant’s last visit. 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
44 
Version 9, April 4, 2022 
 
14.31  Contraceptive Method 
The Contraceptive Method form will be used at screen and during visits 1-15.  The form will 
record contraceptive method for females of childbearing potential or why the participant cannot 
bear children.  For male participants, the form will be marked “Not Applicable” at the screening 
visit. 
 
15 
ANALYTICAL PLAN 
15.1 
Outcome Measures 
The primary efficacy variables will be the PHDD for the drinking outcome and the continuous 
abstinence rate for the smoking outcome (during the last 4 weeks of treatment, i.e., weeks 15–18 
inclusive), respectively.  The secondary efficacy variables will be quality of life and measures of 
alcohol and nicotine craving. Exploratory outcomes include measures of dependence, and 
measures of nicotine and alcohol withdrawal including negative effect, as noted below:   
 
1. 
Fagerström Test for Nicotine Dependence  
2. 
Revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-
Ar) [2]  
3. 
Wisconsin Smoking Withdrawal Scale  
4. 
Positive Affect Negative Affect Schedule (PANAS) 
5. 
The Center for Epidemiologic Studies Depression Scale (CES-D) 
6. 
Medical Outcomes Sleep Scale (MOS-Sleep) 
7. 
The Drinker Inventory of Consequences (DrInC)[3] 
 
Additional exploratory outcome variables will include other: 1) measures of drinking severity 
(i.e., DDD) and abstinence (i.e., percentage of days abstinent; PDA) averaged across either the 
entire double-blind period or the last 4 weeks of treatment, and 2) smoking measures including 
the point prevalence abstinence rate and the CO level over either the entire double-blind period 
or the last 4 weeks of treatment. 
 
15.2 
Standard Drink and Drinking Day Definitions 
Drinking days are defined as the number of days in which the subject reported consumption of at 
least one standard drink. The data given by the subjects on amount and type of alcoholic 
beverage(s) consumed will be converted to SDUs (standard drink units). The following SDU 
formulas and conversions will be used: 
(# of Drinks) x (oz drink) x (% alcohol) x 2  = Daily SDU 
 
30 Day SDU Total   x   7  = Weekly SDU 
        30 
 
 
15.3 
Statistical Hypotheses 
Primary Outcomes: 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
45 
Version 9, April 4, 2022 
1. Both low- and high-dose topiramate will be more efficacious than placebo at reducing the 
percentage of heavy drinking days (PHDD) and increasing the continuous abstinence rate 
for smoking determined by a combination of self-report and CO monitoring after the 
TQD, and in the last 4 weeks of treatment. 
2. High-dose topiramate will be more efficacious than low-dose topiramate at reducing 
PHDD and increasing the continuous abstinence rate for smoking determined by a 
combination of self-report and CO monitoring after the TQD, and in the last 4 weeks of 
treatment. 
 
Secondary Outcomes: 
3. Both low- and high-dose topiramate will be more efficacious than placebo at improving 
quality of life and reducing craving, after the TQD, and in the last 4 weeks of treatment. 
4. High-dose topiramate will be more efficacious than low-dose topiramate at improving 
quality of life and reducing craving, nicotine and alcohol withdrawal symptoms and 
negative affect after the TQD, and in the last 4 weeks of treatment. 
 
5. Exploratory Outcomes:Both low- and high-dose topiramate will be more efficacious 
than placebo at improving nicotine and alcohol withdrawal symptoms and negative affect 
in the last 4 weeks of treatment after the TQD. 
6. Improvements in quality of life and craving reductions will be predictably associated with 
reduced PHDD, increased continuous abstinence rates for smoking, or both, irrespective 
of treatment group. 
 
15.4 
Subject Populations  
The ITT population will be used for the primary analysis and is defined as the subjects who are 
randomized into the study. The evaluable population is defined as those subjects randomized to 
the study who completed at least 6 consecutive weeks of maintenance investigational product 
administration with a dose of at least 50 mg per day for at least 5 days of each 7-day weekly 
period. The safety population includes all subjects who received at least one dose of 
investigational product.  
 
Analysis:  Data will be summarized with respect to the primary and secondary outcome 
measures, demographics, and baseline characteristics.  In general, quantitative variables will be 
summarized with standard descriptive statistics (e.g., range, quartiles, means, standard 
deviations), while frequency tables will summarize categorical variables.  Group comparison for 
quantitative variables will be performed using standard two-sample t-tests or analysis of variance 
as appropriate.  Highly skewed variables may be transformed prior to inferential comparison, or 
non-parametric methods may be used if needed.  Group comparison for categorical variables will 
be analyzed with two-sample comparisons of proportions, or chi-square tests as appropriate. 
 
The primary efficacy variables will be the PHDD for the drinking outcome and the continuous 
abstinence rate for the smoking outcome (during the last 4 weeks of treatment, i.e., weeks 15–18 
inclusive), respectively.  The secondary efficacy variables will be quality of life and measures of 
alcohol and nicotine craving.   
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
46 
Version 9, April 4, 2022 
Exploratory outcome variables will include other: 1) measures of drinking severity (i.e., DDD) 
and abstinence (i.e., percentage of days abstinent; PDA) averaged across either the entire double-
blind period or the last 4 weeks of treatment, and 2) smoking measures including the point 
prevalence abstinence rate and the CO  level over either the entire double-blind period or the last 
4 weeks of treatment; 3) psychological assessments including measures of nicotine and alcohol 
withdrawal (WSWS, MOS-Sleep, CIWA-Ar), negative affect (PANAS, CES-D), dependence 
(FTND), drinking behavior (DrInC) and compliance (BBCET). 
 
The general approach to statistical analyses will be the same as what we utilized in our previous 
studies.[4, 5]  All randomized subjects will be included in the analysis using the intent-to-treat 
principle.  Statistical analyses will be conducted using SAS 9.1 (SAS Institute Inc., Cary, 
NC).[6]  
 
Primary Outcomes Analytical Models: 
We will use generalized linear models (GLM) to estimate treatment effects on PHDD and 
logistic regression for abstinence. We will adjust for baseline covariates on the same drinking or 
smoking variables.  For the drinking and smoking variables, that baseline is the averaged value 
for the 90-day period prior to the screening visit.  Other potential covariates shall include age, 
gender, and ethnicity.  We also will consider the treatment period up to the TQD as an additional 
set of covariates for analyses that focus on the last 4 weeks of treatment.  The residuals from our 
analyses will be checked for normality by computing their skewness and kurtosis and will be 
checked for homogeneity of variance by plotting them in a histogram and against predicted 
outcomes.  Standard transformations will be employed to improve the distributions when 
required (i.e., square root or log transformation). 
 
If, however, there is a differential attrition rate (i.e., if dropout is informative), we shall consider 
other approaches to handle repeated-measures data that can be adopted to obtain valid results.[7, 
8]   
 
Exploratory Analytical Models: 
We also will use the more advanced two-part random-effects model[9, 10] to analyze the daily 
drinking and smoking record.  Such a model can simultaneously characterize the frequency (odds 
of daily drinking or smoking being zero) and quantity (number of drinks on a drinking day or 
number of cigarettes smoked on a smoking day) of drinking and smoking outcomes, 
respectively.  It is more efficient and can tackle non-normality in the drinking or smoking level.  
We also are interested in trajectory analysis of different treatments over time to capture 
differences in these outcomes.  Such analysis is more clinically intuitive and could be more 
powerful than the analysis based on endpoint.  
 
The Kaplan-Meier survival method will be used to compare time to achieve continuous 
abstinence between the treatment groups.  Homogeneity between different arms will be tested 
with the log-rank test.  Additionally, we will use the Cox proportional-hazards model to estimate 
the relative likelihood (i.e., magnitude of the treatment response) between the treatment groups 
for achieving continuous periods of abstinence.  For the Cox regression model, potential 
confounding variables such as age of onset for alcoholism (less than 26 years old or 26 years and 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
47 
Version 9, April 4, 2022 
older), gender, weight, and baseline smoking level will be considered as potential covariates for 
inclusion in the final analytic model.   
 
If the saliva cotinine level satisfactorily achieves criteria for normality as longitudinal data, we 
will compare the groups using a mixed-effects linear model, accounting for a three-group design 
as well as the repeated measure of weeks (when appropriate).  Otherwise, salivary cotinine level 
will be dichotomized as negative if ≤15 ng/ml and positive if >15 ng/ml and analyzed using the 
generalized linear mixed models. 
 
 
Logistic regression analysis will be used to compare point prevalence abstinence rates for the 
topiramate vs. placebo groups.  We will determine point prevalence abstinence rates by a report 
of not smoking (0 cigarettes/day) for the entire period prior to a particular visit and an expiratory 
CO of <10 ppm at the present visit. 
 
15.5 
Sample Size Calculation 
We did two sets of power analysis to account for the drinking and smoking endpoints in our 
proposed study.  Importantly, because smoking outcomes are based mostly on dichotomous 
variables, power estimates for these outcomes drive the numbers needed for this comorbid 
alcohol- and nicotine-dependent cohort.  Hence, it is important to have adequate power for the 
smoking outcomes even though this will result in a superfluous level of power for the drinking 
outcomes.  
 
First, for the smoking outcomes, we did a power analysis by comparing the two-sample 
difference in nicotine abstinence using SAS Proc POWER.  We have estimated power based 
upon our ability to detect a difference in the percentage of smoking abstinence between the 
treatment groups.  Because the comparisons of the topiramate groups with one another (i.e., high 
vs. low) and with placebo are experimental, we chose to calculate power to detect the effect size 
of therapeutic treatments typical of the smoking cessation literature.  We chose to calculate 
power based on our estimates of the percentage of smoking abstinence in the pivotal study by 
Jorenby et al.,[72] where bupropion was compared with placebo in a 9-week randomized, 
controlled clinical trial.  In that study, the TQD occurred at the end of the first week of double-
blind treatment.  As a conservative measure, we have accepted the subject numbers for these two 
groups for the present study to represent the comparison of the low-dose topiramate vs. placebo 
or the high-dose vs. low-dose topiramate.  Thus, we have assumed that the difference between 
low-dose topiramate and placebo would be similar to that between high- and low-dose 
topiramate.  Since there are 3 pairwise comparisons between the three arms, we will adopt 
Bonferroni’s adjustment and take alpha level as 0.05/3 = 0.017.  
 
From Figure 1 in Jorenby et al.,[72] the continuous prevalence rate of smoking abstinence at 18 
weeks is approximately 10% for placebo and 28% for bupropion.  Using these numbers, we find 
that 98 subjects in each arm (294 in total) are needed to achieve a power of 0.80.  If we observe a 
similar effect to that in the preliminary study we will be operating under even increased power.  
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
48 
Version 9, April 4, 2022 
For the drinking outcome, we based the power calculation from data obtained in a previous 
multi-site randomized controlled trial of topiramate for the treatment of alcohol dependence.[5]  
We observed that the slope of PHDD for the topiramate group declined faster than that for the 
placebo group by 0.014 per week, with a standard error of 0.003.  We anticipate that the weekly 
PHDD will have this similar variability in the proposed trial.  We have assumed that the low and 
high doses of 
topiramate will have a 
similar trajectory but 
with the high dose 
being more efficacious.  
 
The null hypothesis is 
that there is no 
difference in the 
declining rate in weekly 
PHDD between low-
dose topiramate, high-
dose topiramate, and 
the placebo group.  
Power was then 
obtained by the 
probability that the non-
centrality parameter is 
greater than the critical value in the F-distribution with the numerator and denominator degrees 
of freedom from the mixed-model results.  Since there are 3 pairwise comparisons between the 
three arms, we will use Bonferroni’s adjustment and take alpha level as 0.05/3 = 0.017.  We find 
that 76 subjects in each of the treatment arms (a total of 228 subjects in 3 arms) will yield a 
power of 80%.  Hence, this study will be operating under increased power for the primary 
efficacy variable on drinking outcome.  The technical details of the power calculations for mixed 
models can be found in Littell et al.[73] (Chapter 12).  The figure above shows the power curve 
for different sample sizes. 
Since we already accounted for dropout in the mixed model for the multi-site study, no 
additional measure to address the attrition rate is necessary as long as the weekly dropout rate 
(i.e., not the total dropout) in the present study is similar to that in the previous trial.  
After considering both sample sizes, we chose the larger value, 98 subjects in each group, as our 
final sample size.  It can fulfill our need to test our primary hypothesis. 
 
15.6 
Additional Exploratory Analyses 
Data will be collected in this study for scientific use and not as primary or secondary outcome 
measures.  Additional post hoc analysis may be performed to evaluate other confounding factors 
on outcomes such as depression or patterns of alcohol use at baseline prior to randomization 
(visit 1) and after interventions.  
 
16 
DATA MANAGEMENT 
 
0.6
0.7
0.8
0.9
1
61
63
65
67
69
71
73
75
77
79
81
83
85
87
89
Sample Size
Power

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
49 
Version 9, April 4, 2022 
16.1 
Data Collection 
Database and statistical functions for this project will be managed at each center by an 
experienced core group.  Collected pen-and-paper-completed data will be entered into an 
electronic web-based database in a timely manner The database group at each site will follow 
compliance with all FDA database and statistical procedures.  The database and statistical 
procedures will be supervised by the statistical team at UVa. 
  
16.2 
Data Editing, Monitoring and Control 
Data collected for this study will be entered into a secure web-based database provided by 
DatStat (Seattle, WA). DatStat ensures the privacy of data by utilizing industry best practices for 
security such as password protection, data encryption, and secure networks. The transfer of 
survey data is accomplished using the internet with a secure connection via the secure sockets 
layer (SSL). All surveys hosted with DatStat are encrypted using 128-bit SSL Technology 
(Secure Socket Layer) that is equivalent to the industry standard for securely transmitting credit 
card information over the Internet. This technology encrypts participant responses. Thus, all 
responses are instantly encrypted and remain so until they are received at the DatStat database. 
 
All data will be stored at DatStat and will be backed up on a daily basis and held in a tightly 
secured facility. All DatStat servers that are used for data collection are highly fault tolerant and, 
to this end, are equipped with redundant, hot-pluggable power supplies, redundant network 
interfaces, and RAID 1/5 hot-pluggable disk storage. Most customer applications are deployed 
under the Linux operating system using Apache server technology. Servers are stored in a 
locked, well-ventilated room in locked server cabinet/racks. The server room is in a building 
with 24/7 alarm security. Any building compromise will sound the alarm and generate a call to 
the building supervisor and police, who will subsequently notify DatStat personnel of the 
intrusion.  All primary servers are plugged into a monitored uninterruptible power supply (UPS) 
offering a minimum of 30 minutes of battery power in the event of a power outage. At least one 
additional server is available at all times to handle the off-chance of a major server crash. 
 
The overall study coordinator will be in charge of monitoring data entry at all study sites. This 
includes coordinating trainings, and completing monitoring visits with audits. 
 
16.3 
Study Documentation and Records Retention 
Study documentation includes all data correction forms, workbooks, source documents, 
monitoring logs and appointment schedules, Sponsor and investigator correspondence and 
regulatory documents (e.g., signed protocol and amendments and IRB correspondence and 
approved consent form and signed informed consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Accordingly, source documents include, but are not limited to, laboratory reports, ECG tracings, 
progress notes, hospital charts or pharmacy records and any other similar reports or records of 
any procedure performed in accordance with the protocol.  Whenever possible, the original 
recording of an observation should be retained as the source document; however, a photocopy is 
acceptable provided that it is a clear, legible, and exact duplication of the original document. 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
50 
Version 9, April 4, 2022 
 
Government agency regulations and directives require that the investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. These documents must be retained for 
the length of time that the IND is open and for an additional 2 years after the IND is closed.  
 
The likelihood of information from our clinic being disseminated without the subject’s consent 
to an outside source is remote.  No information about a subject is disclosed without his or her 
written authority.  At each site, source documents are kept at a secure location in locked files.  
Access to these files is restricted to known personnel.   
 
16.4 
Confidentiality 
16.4.1 
Confidentiality of Data 
Particular attention is drawn to the regulations promulgated by the FDA under the Freedom of 
Information Act providing, in part, that proprietary information furnished to clinical investigators 
and IRBs will be kept confidential by the FDA only if maintained in confidence by the clinical 
investigator and IRB. 
 
By signing this protocol the investigator affirms to UVa that information furnished to the 
investigator by UVa will be maintained in confidence and such information will be divulged to 
the IRB or similar or expert committee; affiliated institution; and employees only under an 
appropriate understanding of confidentiality with such board or committee, affiliated institution 
and employees. 
 
16.4.2 Confidentiality of Subject Records 
To maintain subject confidentiality, all laboratory specimens, reports and other records will be 
identified by a coded study subject number only. Research and clinical records will be stored in a 
locked cabinet. Only research staff will have access to the records. Subject information will not 
be released without written permission, except as necessary for monitoring by representatives of 
UVa. Upon approval of the study by an IRB, an application will be filed with UVa for a 
Certificate of Confidentiality. 
 
The use and procedure for applying for a Certificate of Confidentiality are provided in Appendix 
II. 
 
17 
PUBLICATIONS OF THE STUDY RESULTS 
The role of Tobacco and Alcohol Research Group (TARG) (diagram below) is to assist the PI 
and co-investigators in data dissemination and manuscript preparation and publication.  This 
group will create a database of measures and possible manuscripts, identify the authors to be 
involved in each manuscript, and review manuscripts before submission.   
 
The statistical group will provide ongoing statistical support to carry out the research project and 
to develop and apply innovative methods in study design and statistical analysis.  Thus, the 
group will provide statistical support to investigators in statistical analysis and interpretation, and 
in the preparation of abstracts, presentations, and manuscripts.  The group consists of 
biostatisticians who are members of the Division of Biostatistics and Epidemiology in the 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
51 
Version 9, April 4, 2022 
Department of Public Health Sciences at the University of Virginia, and who have established 
expertise in a wide range of statistical areas.  Their areas of strength include experimental 
designs, dose finding, clinical trials, longitudinal analysis, and survival analysis (particularly in 
dealing with non-classical analyses such as those involving dependent censoring).   
 
 
 
TARG Research Core 
Research 
Development 
Group 
Data 
Management 
Group 
Statistical 
Group 
Dr. Nassima Ait-Daoud 
Dr. Bankole Johnson 
Dr. Paul Cinciripini 
Dr. Robert Anthenelli 
Michelle Storer 
Eva Jenkins-Mendoza 
Jennifer Ferguson 
Dr. Maher Kara-Hage 
 
Dr. Lee Ritterband 
Tracie Kostelac  
Thomas Blom 
Rudel Rymer 
 
Dr. Lei Liu 
Xin-Qun Wang 
Dr. Jason Robinson 
 
Research 
Dissemination 
Group 
Dr. Nassima Ait-Daoud 
Dr. Bankole Johnson 
Dr. Paul Cinciripini 
Dr. Robert Anthenelli 
Dr. Maher Kara-Hage 
Robert Cormier 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
52 
Version 9, April 4, 2022 
18 
SIGNATURES 
 
INVESTIGATORS 
I agree to conduct this clinical study in accordance with the design and specific provisions of this 
protocol; deviations from the protocol are acceptable only with a mutually agreed upon protocol 
amendment with IRB approval. I also agree to report all information or data in accordance with 
the protocol, and in particular I agree to report any serious adverse experiences as defined in 
section 13.10 i  and Appendix I of this protocol. 
 
Typed Name  
 
      
Signature 
 
 
 
Date 
 
Nassima Ait-Daoud Tiouririne, M.D  _________________________          __________________ 
Site Principal Investigator 
 
 
Robert M. Anthenelli, M.D 
  
_________________________          _________________ 
Site Principal Investigator 
 
Paul M. Cinciripini, Ph.D. 
  
_________________________          _________________ 
Site Principal Investigator 
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
53 
Version 9, April 4, 2022 
19 
APPENDIX I 
 
Instructions for Evaluating and Reporting AEs and SAEs 
 
A. GENERAL INSTRUCTIONS 
 
1. 
Record AEs beginning the day of randomization (subject will take the first dose of 
investigational product that evening). 
 
2. 
Report the severity of the event following the guidance in section B below. 
  
3. 
Report the relatedness of the event to the investigational product administration according 
to the guidance in section C. 
 
B. DEFINITIONS – ADVERSE EVENT, UNEXPECTED ADVERSE EVENT AND 
SEVERITY OF EVENTS 
 
Adverse event (AE):  An adverse event is any untoward, unfavorable or unintended sign 
(including an abnormal laboratory finding), symptom, or disease, temporally associated with the 
use of the product under investigation, whether or not related to the product under investigation. 
 
Unexpected adverse event:  Any adverse drug experience, the nature, specificity, or severity of 
which is not consistent with the investigator's brochure, package insert or the general 
investigational plan. 
 
Mild:  
 
Awareness of symptom, but easily tolerated. 
 
Moderate: 
Discomfort enough to cause interference with usual activity. 
 
Severe: 
Incapacitating with inability to work or do usual activity. 
 
Life-threatening: 
At imminent risk of death without intervention. 
 
C.  DEFINITIONS – RELATEDNESS OF EVENTS 
 
 
The study physician is responsible for defining, in his/her best judgment, the relationship of the 
AE/SAE to the investigational products. The degree of certainty for which the AE/SAE is 
attributed to the investigational product or alternative causes (e.g., natural history of the 
underlying disease, concomitant therapies, etc.) should be determined by how well the 
experience can be understood in terms of one or more of the following: 
 
• Exposure:  Is there evidence that the subject was actually exposed to the investigational 
product?  
 
• Timing of the study drug/placebo:  Did the AE/SAE follow in a reasonable temporal 
sequence from administration of the investigational product? 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
54 
Version 9, April 4, 2022 
 
• Consistency with study drug profile:  Known pharmacology and toxicology of the study 
drug in animals and man; reaction of similar nature having been previously described with 
the investigational product. 
 
• Alternative explanations for the AE such as concomitant medications, concurrent illness, 
non-medicinal therapies, diagnostic tests, procedures or other confounding findings. 
 
• Response to discontinuation of the study investigational product. 
Terms and definitions to be used in assessing the investigational product relationship to the 
AE/SAE are: 
 
• Unknown: 
Use this category only if the cause of the AE/SAE is not possible to determine 
 
• Not Related:   
The subject did not receive the investigational product, the temporal sequence of the AE/SAE 
onset relative to administration of the investigational product is not reasonable, or there is 
another obvious cause of the AE/SAE. 
 
• Remotely (Unlikely) Related:   
There is evidence of exposure to the investigational product or there is another more likely 
cause of the AE/SAE. 
 
• Possibly Related:  
There is evidence of exposure to the investigational product, the temporal sequence of the 
AE/SAE onset relative to administration of the investigational product is reasonable, but the 
AE/SAE could have been due to another equally likely cause. 
 
• Probably Related:  
There is evidence of exposure to the investigational product, the temporal sequence of the 
AE/SAE onset relative to administration of the investigational product is reasonable, and the 
AE/SAE is more likely explained by the investigational product than by any other cause. 
 
• Definitely Related:  
There is evidence of exposure to the investigational product, the temporal sequence of the 
AE/SAE onset relative to administration of the investigational product is reasonable, the 
AE/SAE is more likely explained by the investigational product than by any other cause, and 
the AE/SAE shows a pattern consistent with previous knowledge of the investigational 
product or investigational product class. 
 
D.  DEFINITIONS FOR ADVERSE EVENT REPORTS 
 
A serious adverse event is defined as one that satisfies any of the following criteria: 
• results in death, 
• is immediately life-threatening, 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
55 
Version 9, April 4, 2022 
• requires in-patient hospitalization, or prolongation of existing hospitalization, 
• results in persistent or significant disability or incapacity, 
• is a congenital abnormality or birth defect, or 
• is an important medical event that may jeopardize the subject, or may require medical 
intervention to prevent one of the outcomes listed above. 
 
 
SAEs are further explained as follows: 
• any death resulting from an AE occurring during the trial period or within 14 days after the 
last dose of the trial drug. 
• the subject must have been at an immediate risk of dying from the AE as it occurred. This 
does not include events that might have caused death if they had occurred in a more serious 
form (e.g., drug-induced hepatitis that resolves without hepatic failure). 
• any AE resulting in hospital admission and usually an overnight stay. Prolongs 
hospitalization means delayed planned or anticipated discharge date (again usually by at least 
one overnight stay). This does not include hospitalization for elective surgery for a condition 
that was present prior to trial entry and whose clinical course has not changed after exposure 
to the trial drug. 
• any AE resulting in impairment, damage or disruption in the subject's body function, 
structure or both, physical activities or quality of life. 
• any AE resulting in a condition which requires medical or surgical intervention to prevent 
permanent impairment of a body function or permanent damage to a body structure of the 
subject. Examples of this can include procedures such as blood transfusion or catheterization. 
However, discontinuation of the trial drug, or routine administration of prescription 
medications or changes in their dosages, should not be considered as medical intervention. 
• if there are suspicions that exposure of either parent to the trial drug resulted in an adverse 
outcome in the offspring. 
 
Guide to Interpreting the Causality Question 
• Time Course. Exposure to suspect drug. Has the subject actually received the suspect drug? 
• Did the AE occur in a reasonable temporal relationship to the administration of the suspect 
drug? 
• Consistency with known drug profile. Was the AE consistent with the previous knowledge of 
the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological class? 
OR could the AE be anticipated from its pharmacologic properties? 
• De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose of 
the suspect drug?  
• No alternative cause. The AE cannot be reasonably explained by another etiology such as the 
underlying disease, other drugs, other host or environmental factors.  
• Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped?  
• Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.  
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
56 
Version 9, April 4, 2022 
A "reasonable possibility" could be considered to exist for an AE where one or more of these 
factors exist. 
 
In contrast, there would not be a "reasonable possibility" of causality if none of the above criteria 
apply or where there is evidence of exposure and a reasonable time course but any dechallenge 
(if performed) is negative or ambiguous or there is another more likely cause of the AE. 
 
 
 
In difficult cases, other factors could be considered such as: 
• Is this a recognized feature of overdose of the drug? 
• Is there a known mechanism? 
 
Ambiguous cases should be considered as being a "reasonable possibility" of a causal 
relationship unless further evidence becomes available to refute this. Causal relationship in cases 
where the disease under study has deteriorated due to lack of effect should be classified as no 
reasonable possibility. 
 
Life threatening 
 
"Life-threatening" means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the subject's 
death. "Life-threatening" does not mean that had an AE occurred in a more severe form it might 
have caused death (e.g., hepatitis that resolved without hepatic failure). 
 
Hospitalization 
 
Out-patient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
 
Important medical event or medical intervention 
 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
 
Examples of such events are: 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
57 
Version 9, April 4, 2022 
• Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment. 
• Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with N-
acetylcysteine. 
• Intensive treatment in an emergency room or at home for allergic bronchospasm. 
• Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization. 
• Development of drug dependency or drug abuse. 
 
E.  SPECIFIC INSTRUCTIONS – LABORATORY/ECG ADVERSE EVENT 
 
A laboratory or ECG AE is any clinically significant worsening in a test variable that occurs 
during the course of the study, whether or not considered to be investigational product related. For 
each such change, provide the information requested on date of test, severity, likelihood of a 
relationship to investigational product, change in investigational product dosage due to the AE, and 
treatment required. 
 
All laboratory AEs should be specified as an increased or decreased test result (e.g. “increased 
glucose”, “decreased potassium”) or as a term that implies an abnormality (e.g., hypercalcemia, 
azotemia, hypokalemia, or bradycardia). Any abnormal laboratory value that is considered 
clinically significant will be recorded as such on the clinical laboratory form in the source 
document along with a comment providing justification for that determination. 
 
F. 
SERIOUS ADVERSE EVENT AND UNEXPECTED ADVERSE EVENT 
REPORTING 
 
24 hour Reporting Requirements 
 
Serious and unexpected adverse experiences or death occurring during the course of a research 
project, regardless of cause, must be reported to the IRB immediately according to institutional 
guidelines (i.e., within 24 hours).  In addition, all sites must report all SAEs to UVa within 24 
hours. Nassima Ait-Daoud Tiouririne, of UVa, is the IND holder and therefore responsible for 
reporting all SAEs to the FDA. 
 
Upon receipt of a report of adverse experience or report of death, the IRB will decide whether 
further investigation of the event is required.  In some cases, an investigator may be required to 
suspend a study pending the outcome of IRB review.  It is the responsibility of the investigator to 
inform the sponsor of the investigation and the FDA of the occurrence of unanticipated adverse 
reactions, death, or serious adverse experiences.  
 
 
 
In the event that either a study subject withdraws from the study or an investigator decides to 
discontinue the subject from the study due to a serious adverse event, the subject must have 
appropriate follow-up medical monitoring.  If the subject is hospitalized, medical monitoring will 
consist of not less than daily evaluation by physical examination, vital signs, laboratory 
evaluations, and, if applicable, ECG monitoring for significant treatment emergent abnormalities.  
Monitoring will continue until the problem prompting hospitalization has resolved or stabilized 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
58 
Version 9, April 4, 2022 
with no further change expected, or until it is discovered to be clearly unrelated to study 
medication, or until it progresses to death. 
 
The following information with the initial report of an SAE or unexpected AE must be provided 
to the IND holder, Nassima Ait-Daoud Tiouririne: 
 
• Name of person reporting the SAE/unexpected AE 
• Subject's I.D. number 
• Name of the PI and institution 
• Date the subject signed informed consent 
• Date first dose of investigational product was ingested 
• Description of the SAE/unexpected AE 
• Date and time of Onset 
• Date/time of administration of last dose of investigational product prior to the 
SAE/unexpected AE 
• Severity of the SAE/unexpected AE 
• Investigator's assessment of the relationship of the SAE/unexpected AE to investigational 
product (related, possibly related, probably related, unlikely related, not related) 
• Any action taken with the investigational product, alteration to protocol defined schedule, 
diagnostics, and treatments secondary to the SAE/unexpected AE. 
 
Follow-Up of All AEs/SAEs 
 
All adverse medical events must be followed until they are resolved, or until all attempts to 
determine the resolution of the AE/SAE are exhausted. This may require an extended 
hospitalization period or a change in status from outpatient to inpatient.   
 
All AEs must be recorded on the adverse event log.    Anticipated adverse experiences are AEs 
that have been anticipated in the protocol, such as reactions to drugs, and do not have to be 
reported to the IRB unless they are unexpectedly serious, life-threatening, or fatal. 
 
Each week, each site PI must review the adverse event log completed for the previous week for 
any events that were reported as continuing.  All AEs, including clinically significant abnormal 
findings on laboratory evaluations, regardless of severity, will be followed by study investigators 
until there is a satisfactory resolution.  AEs may be reported up to 4 weeks following completion 
of, or termination from, the study. 
 
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
59 
Version 9, April 4, 2022 
20 
APPENDIX II: Certificate of Confidentiality 
 
 
The only people who will know the identity of the subjects are members of the research team 
and, if appropriate, the physicians and nurses.  No information about the subjects, or provided by 
the subjects during the research, will be disclosed to others without the subjects’ written 
permission, except if necessary to protect subjects’ rights or welfare. 
 
When the results of the research are published or discussed in conferences, no information will 
be included that would reveal subjects’ identity.  Authorized representatives of the FDA and 
NIAAA study monitors may need to review records of individual subjects.  As a result, they may 
know subjects’ names, but they are bound by rules of confidentiality not to reveal their identity 
to others.  The results of this study including laboratory results and clinical information collected 
during this study will be submitted to the FDA and may be used for research purposes.  The 
results of this study may be published but will not personally identify any subjects.  All records 
will be kept in locked storage locations that will be accessible only to authorized study 
personnel.  
 
UVa will apply for a Certificate of Confidentiality for all participating sites. 
 
This Certificate of Confidentiality helps researchers protect the privacy of subjects in health 
research projects against compulsory legal demands (e.g., court orders and subpoenas) that seek 
the names or other identifying characteristics of research subjects.  The certificate was developed 
to protect against the involuntary release of personally identified research information of a 
sensitive nature sought through any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings.  This authority was granted under the Comprehensive Drug 
Abuse Prevention and Control Act of 1970, Public Law No. 91-513, Section 3(a).  
 
This certificate is necessary for investigators to avoid being required to involuntarily disclose 
personally identifiable research information about individual study subjects. Under this statute: 
 
"The Secretary [of the Department of Health and Human Services] may authorize persons 
engaged in biomedical, behavioral, clinical, or other research (including research on mental 
health, and on the use and effect of alcohol and other psychoactive drugs) to protect the privacy 
of individuals who are the subject of such research by withholding from all persons not 
connected with the conduct of such research the names or other identifying characteristics of 
such individuals. Persons so authorized to protect the privacy of such individuals may not be 
compelled in any Federal, State, or local civil, criminal, administrative, legislative, or other 
proceedings to identify such individuals" (Public Health Service Act 301 (d), 42 U. S. C. 241  
(d), as amended by Public Law No. 100-607, Section 163 (November 4, 1988)).” 
 
Accordingly, this special privacy protection can be granted only to research (i.e., a systematic 
investigation, designed to develop or contribute to generalizable knowledge). It is granted only 
when the research is of a sensitive nature where the protection is judged necessary to achieve the 
research objectives. 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
60 
Version 9, April 4, 2022 
The study subjects should be informed that a Certificate is in effect, and be given a fair and clear 
explanation of the protection it affords, including the limitations and exceptions. This 
information will be included in the informed consent. Please see below some suggested wording: 
 
“We have received a Certificate of Confidentiality from the NIAAA, which will help us protect 
your privacy. The Certificate protects against the involuntary release of information about your 
participation in this study. The researchers involved in this project cannot be forced to disclose 
your identity or your participation in this study in any legal proceedings at the federal, state, or 
local level, regardless of whether they are criminal, administrative, or legislative proceedings. 
However, you or the researcher may choose to voluntarily disclose the protected information 
under certain circumstances. For example, if you or your guardian requests disclosure of your 
participation, the researchers will provide research data. The Certificate does not protect against 
that voluntary disclosure. 
 
Furthermore, federal agencies may review our records under limited circumstances, such as a 
DHHS request for information for an audit or program evaluation or a Food and Drug 
Administration request under the Food, Drug and Cosmetics Act.”  
          
 
 
 
 
  
“A Certificate of Confidentiality has been obtained from the Federal Government for this study 
to help insure your privacy. This Certificate means that the researchers cannot be forced to tell 
people who are not connected with the study, including courts, about your participation, without 
your written consent. If we see [learn] something that would immediately endanger you, your 
child, or others, we may discuss it with you, if possible, or seek help.” 
 
Study subjects will be notified that a Certificate has expired if they are recruited to the study 
after the expiration date of the Certificate and an extension of the Certificate's coverage has not 
been granted. 
 
If the research scope of a project covered by a Certificate should change substantially, the PI will 
request an amendment to the Certificate; however, the NIAAA Certificate Coordinator may 
require a new Certificate depending on the extent of the change in scope.  An extension of 
coverage must be requested if the research extends beyond the expiration date of the original 
Certificate, as research information collected after the expiration of a Certificate is not protected 
from compelled release. 
 
A Certificate of Confidentiality is a legal defense against a subpoena or court order, and is to be 
used by the researcher to resist disclosure. The researcher should seek legal counsel from his or 
her institution if legal action is brought to release personally identifying information protected by 
a certificate. The Office of General Counsel for DHHS is willing to discuss the regulations with 
the researcher's attorney. 
 
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
61 
Version 9, April 4, 2022 
  
21 
 APPENDIX III: Table of Disallowed Concomitant Medications* 
 
Drug Class 
• 
Opioid Analgesics (1) 
•  
• 
Psychomotor stimulant-type medications (e.g. Adderall®, Ritalin®) 
• 
Opiate substitutes (e.g. methadone, LAAM, buprenorphine) 
• 
Drugs with known potential for toxicity to a major organ system  (e.g. 
isoniazid, methotrexate) 
• 
Anticonvulsants 
•  
•  
• 
Anti-dependence (e.g., Chantix®, Wellbutrin® NRT, acamprosate, or 
naltrexone, antabuse ) 
• 
Carbonic anhydrase inhibitors 
• 
Dietary supplements and Herbal remedies  (2) 
• 
Nicotine replacement 
• 
The medication being studied 
 
 
Definitions 
Chronic use: 4/7 days per week or more, for a month or more.  Additionally, the medication must have 
been started and stabilized for at least 2 weeks prior to study enrollment.  Periodic or episodic use: 3/7 
days per week or less, or more frequent use for less than a month’s duration. 
 
 
 
*This table is to be used as a guideline. The physician at each site may use their clinical judgment based 
on each drugs individual profile to allow or disallow medications listed or not listed specifically in this 
table. 
 
 
 
Key 
 
 
1. Episodic use of narcotic pain relievers are allowable. 
2. Supplements with CNS action including pro-metabolic supplements/anorexics, and those having an 
effect on mood (e.g. St. John’s Wort, yohimbine, ginkgo biloba, horehound) are not allowed.  Vitamins 
at therapeutic doses will be permitted. 
Note:  
• 
Specific antidepressant like Elavil, Endep, Wellbutrin, and other MAOIs will not be allowed. 
• 
Antipsychotics will be allowed as precautionary medications as long as they are prescribed for sleep, 
anxiety, or mood stabilization. 
• 
Anxiolytics and withdrawal agents will be allowed if they are prescribed short term by a provider for 
anxiety. 
 
 
22 
 
 
 
APPENDIX IV 
BBCET Manual 
(Attached as separate document) 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
62 
Version 9, April 4, 2022 
23 
 
 
 
APPENDIX V 
Clearing the Air Booklet 
(Attached as separate document) 
 
 
24  
APPENDIX VI: Blood Collection for Genotyping* 
 
 
1. PROCEDURES 
 
A. Blood Collection: 
• Collect 2 yellow top tubes (BD vaccutainer tubes containing ACD buffer) from each 
subject that consented to genetic testing, using standard phlebotomy techniques.  
• Label each tube with subject ID#, date, visit#, and study ID. 
• The 2 tubes should contain 8-10ml of whole blood. 
• After collection, invert the tubes 5-10 times to mix blood with the ACD buffer that 
was in the tube. 
 
B. Storage 
• Within two hours of blood collection, transfer blood from yellow top tubes (2) to 
cryovials (2) using a pipette (Prior to transfer, invert the tubes to mix the contents). 
• Label each cryovial with subject ID#, date, visit#, and study ID. 
• Store each cryovial in separate cryovial boxes at -800C until shipment (i.e. Subject A 
has two cryovials, cryovial 1 placed in cryovial box ‘A’ and cryovial 2 placed in 
cryovial box ‘B’). 
 
C. Shipping 
• Shipments to University of Texas-MDACC should be made every 6 months or when 
cryovial boxes reach full capacity. 
o Cryoival box ‘A’ and cryovial box ‘B’ should be in separate shipments in case 
of any lost or damaged boxes. 
• Shipments should be overnight and on a Monday, Tuesday, Wednesday or Thursday. 
• Each site will follow their local IRB’s rules and regulations regarding the shipment of 
biological materials (i.e. the use of dry ice). 
• University of Texas-MDACC study coordinator should be notified when shipments 
are en route. 
 
* DNA Extraction and Genotyping will be done at University of 
Texas-MDACC. 
 
 
 
 
 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
63 
Version 9, April 4, 2022 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
References  
 
1. 
Sobell, L.C. and M.B. Sobell, Timeline follow-back: a technique for assessing self-
reported alcohol consumption, in Measuring alcohol consumption: psychosocial and 
biochemical methods, R.Z. Litten and J.P. Allen, Editors. 1992, Humana Press Inc.: 
Totowa, NJ. p. 41-72. 
2. 
Sullivan, J.T., et al., Assessment of alcohol withdrawal: the revised clinical institute 
withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict, 1989. 84: p. 1353-
1357. 
3. 
Miller, W.R., J.S. Tonigan, and R. Longabaugh, The drinker inventory of consequences 
(DrInC): an instrument for assessing adverse consequences of alcohol abuse, in Project 
MATCH Monograph Series, NIH Publication No. 95-3911, M.E. Mattson and L.A. 
Marshall, Editors. 1995, National Institutes of Health: Rockville, MD. 
4. 
Johnson, B.A., et al., Oral topiramate for treatment of alcohol dependence: a randomised 
controlled trial. Lancet, 2003. 361: p. 1677-1685. 
5. 
Johnson, B.A., et al., Topiramate for treating alcohol dependence: a randomized 
controlled trial. JAMA, 2007. 298(14): p. 1641-1651. 
6. 
SAS Institute Inc., SAS version 9.1. 2003, SAS Institute Inc.: Cary, NC. 
7. 
Wulfsohn, M.S. and A.A. Tsiatis, A joint model for survival and longitudinal data 
measured with error. Biometrics, 1997. 53: p. 330-339. 
8. 
Liu, L., Joint modeling longitudinal semi-continuous data and survival, with application 
to longitudinal medical cost data. Stat Med, 2009. 28: p. 972-986. 
9. 
Olsen, M.K. and J.L. Schafer, A two-part random-effects model for semicontinuous 
longitudinal data. J Am Stat Assoc, 2001. 96: p. 730-745. 
10. 
Tooze, J.A., G.K. Grunwald, and R.H. Jones, Analysis of repeated measures data with 
clumping at zero. Stat Methods Med Res, 2002. 11: p. 341-355. 
11. 
Littleton, J. and H. Little, Interactions between alcohol and nicotine dependence: a 
summary of potential mechanisms and implications for treatment. Alcohol Clin Exp Res, 
2002. 26: p. 1922-1924. 
12. 
Blomqvist, O., et al., Mecamylamine modifies the pharmacokinetics and reinforcing 
effects of alcohol. Alcohol Clin Exp Res, 2002. 26: p. 326-331. 
13. 
Seaton, M.J. and E.S. Vesell, Variables affecting nicotine metabolism. Pharmacol Ther, 
1993. 60: p. 461-500. 
14. 
Prendergast, M.A., et al., Ethanol and nicotine: a pharmacologic balancing act? Alcohol 
Clin Exp Res, 2002. 26: p. 1917-1918. 
15. 
Lê, A.D., Effects of nicotine on alcohol consumption. Alcohol Clin Exp Res, 2002. 26: p. 
1915-1916. 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
64 
Version 9, April 4, 2022 
16. 
Wise, R.A. and M.A. Bozarth, A psychomotor stimulant theory of addiction. Psychol 
Rev, 1987. 94: p. 469-492. 
17. 
Hemby, S.E., B.A. Johnson, and S.I. Dworkin, Neurobiological basis of drug 
reinforcement, in Drug addiction and its treatment: nexus of neuroscience and behavior, 
B.A. Johnson and J.D. Roache, Editors. 1997, Lippincott-Raven: Philadelphia. p. 137-
169. 
18. 
Hemby, S.E., Neurobiology of alcoholism, in Handbook of clinical alcoholism treatment, 
B.A. Johnson, P. Ruiz, and M. Galanter, Editors. 2003, Lippincott Williams & Wilkins: 
Baltimore, MD. p. 10-18. 
19. 
Johnson, B.A., Progress in the development of topiramate for treating alcohol 
dependence: from a hypothesis to a proof-of-concept study. Alcohol Clin Exp Res, 2004. 
28: p. 1137-1144. 
20. 
Blomqvist, O., et al., Accumbal dopamine overflow after ethanol: localization of the 
antagonizing effect of mecamylamine. Eur J Pharmacol, 1997. 334: p. 149-156. 
21. 
Collins, A.C., Interactions of ethanol and nicotine at the receptor level. Recent Dev 
Alcohol, 1990. 8: p. 221-231. 
22. 
Ksir, C., et al., Exposure to nicotine enhances the behavioral stimulant effect of nicotine 
and increases binding of [3H]acetylcholine to nicotinic receptors. Neuropharmacology, 
1985. 24: p. 527-531. 
23. 
Albuquerque, E.X., et al., Properties of neuronal nicotinic acetylcholine receptors: 
pharmacological characterization and modulation of synaptic function. J Pharmacol Exp 
Ther, 1997. 280: p. 1117-1136. 
24. 
Changeux, J.P., et al., Brain nicotinic receptors: structure and regulation, role in 
learning and reinforcement. Brain Res Brain Res Rev, 1998. 26: p. 198-216. 
25. 
Narahashi, T., et al., Mechanisms of alcohol-nicotine interactions: alcoholics versus 
smokers. Alcohol Clin Exp Res, 2001. 25(5 Suppl ISBRA): p. 152S-156S. 
26. 
Lê, A.D., et al., Involvement of nicotinic receptors in alcohol self-administration. Alcohol 
Clin Exp Res, 2000. 24: p. 155-163. 
27. 
Smith, B.R., et al., Exposure to nicotine enhances acquisition of ethanol drinking by 
laboratory rats in a limited access paradigm. Psychopharmacology, 1999. 142: p. 408-
412. 
28. 
Tizabi, Y., et al., Effects of combined systemic alcohol and central nicotine 
administration into ventral tegmental area on dopamine release in the nucleus 
accumbens. Alcohol Clin Exp Res, 2002. 26: p. 394-399. 
29. 
Moghaddam, B. and M.L. Bolinao, Glutamatergic antagonists attenuate ability of 
dopamine uptake blockers to increase extracellular levels of dopamine: implications for 
tonic influence of glutamate on dopamine release. Synapse, 1994. 18: p. 337-342. 
30. 
White, H.S., et al., Topiramate modulates GABA-evoked currents in murine cortical 
neurons by a nonbenzodiazepine mechanism. Epilepsia, 2000. 41 (suppl 1): p. S17-S20. 
31. 
Weiss, F. and L.J. Porrino, Behavioral neurobiology of alcohol addiction: recent 
advances and challenges. J Neurosci, 2002. 22: p. 3332-3337. 
32. 
Kohl, R.R., et al., Ethanol and negative feedback regulation of mesolimbic dopamine 
release in rats. Psychopharmacology, 1998. 139: p. 79-85. 
33. 
Dodd, P.R., et al., Glutamate-mediated transmission, alcohol, and alcoholism. 
Neurochem Int, 2000. 37: p. 509-533. 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
65 
Version 9, April 4, 2022 
34. 
Breese, C.R., R. Freedman, and S.S. Leonard, Glutamate receptor subtype expression in 
human postmortem brain tissue from schizophrenics and alcohol abusers. Brain Res, 
1995. 674: p. 82-90. 
35. 
Skradski, S. and H.S. White, Topiramate blocks kainate-evoked cobalt influx into 
cultured neurons. Epilepsia, 2000. 41(suppl 1): p. S45-S47. 
36. 
Schiffer, W.K., et al., Topiramate selectively attenuates nicotine-induced increases in 
monoamine release. Synapse, 2001. 42: p. 196-198. 
37. 
Weekley, C.K., 3rd, R.C. Klesges, and G. Reylea, Smoking as a weight-control strategy 
and its relationship to smoking status. Addict Behav, 1992. 17: p. 259-271. 
38. 
Jeffery, R.W., et al., Reconciling conflicting findings regarding postcessation weight 
concerns and success in smoking cessation. Health Psychol, 2000. 19: p. 242-246. 
39. 
Russ, C.R., et al., Weight gain as a barrier to smoking cessation among military 
personnel. Am J Health Promot, 2001. 16: p. 79-84. 
40. 
Pomerleau, C.S., A.N. Zucker, and A.J. Stewart, Characterizing concerns about post-
cessation weight gain: results from a national survey of women smokers. Nicotine Tob 
Res, 2001. 3: p. 51-60. 
41. 
Meyers, A.W., et al., Are weight concerns predictive of smoking cessation? A prospective 
analysis. J Consult Clin Psychol, 1997. 65: p. 448-452. 
42. 
Pirie, P.L., D.M. Murray, and R.V. Luepker, Gender differences in cigarette smoking and 
quitting in a cohort of young adults. Am J Public Health, 1991. 81: p. 324-327. 
43. 
Glasgow, R.E., et al., Concern about weight gain associated with quitting smoking: 
prevalence and association with outcome in a sample of young female smokers. J Consult 
Clin Psychol, 1999. 67: p. 1009-1011. 
44. 
Pomerleau, C.S., et al., Short-term weight gain in abstaining women smokers. J Subst 
Abuse Treat, 2000. 18: p. 339-342. 
45. 
Borrelli, B. and R. Mermelstein, The role of weight concern and self-efficacy in smoking 
cessation and weight gain among smokers in a clinic-based cessation program. Addict 
Behav, 1998. 23: p. 609-622. 
46. 
McElroy, S.L., et al., Topiramate in the treatment of binge eating disorder associated 
with obesity: a randomized, placebo-controlled trial. Am J Psychiatry, 2003. 160: p. 255-
261. 
47. 
Slama, K., et al., The effectiveness of two smoking cessation programmes for use in 
general practice: a randomised clinical trial. BMJ, 1990. 300: p. 1707-1709. 
48. 
Demers, R.Y., et al., The impact of physicians' brief smoking cessation counseling: a 
MIRNET study. J Fam Pract, 1990. 31: p. 625-629. 
49. 
Orleans, C.T., et al., Self-help quit smoking interventions: effects of self-help materials, 
social support instructions, and telephone counseling. J Consult Clin Psychol, 1991. 59: 
p. 439-448. 
50. 
Pederson, L.L., J.M. Wanklin, and N.M. Lefcoe, The effects of counseling on smoking 
cessation among patients hospitalized with chronic obstructive pulmonary disease: a 
randomized clinical trial. Int J Addict, 1991. 26: p. 107-119. 
51. 
Rollnick, S., C.C. Butler, and N. Stott, Helping smokers make decisions: the 
enhancement of brief intervention for general medical practice. Patient Education 
Counseling, 1997. 31: p. 191-203. 
52. 
Glasgow, R.E., et al., A brief smoking cessation intervention for women in low-income 
planned parenthood clinics. Am J Public Health, 2000. 90: p. 786-789. 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
66 
Version 9, April 4, 2022 
53. 
Wadland, W.C., B. Soffelmayr, and K. Ives, Enhancing smoking cessation of low-income 
smokers in managed care. J Fam Pract, 2001. 50: p. 138-144. 
54. 
National Cancer Institute, Clearing the air: quit smoking today. NIH publication 03-
1647. 2003, Washington, D.C.: National Institutes of Health. 
55. 
Fiore, M.C., Treating tobacco use and dependence: an introduction to the US Public 
Health Service Clinical Practice Guideline. Respir Care, 2000. 45: p. 1196-1199. 
56. 
Imber, S.D., et al., Mode-specific effects among three treatments for depression. J 
Consult Clin Psychol, 1990. 58: p. 352-359. 
57. 
Johnson, B.A. Pills for the pharmacogenetic treatment of alcohol dependence. In the 
NIAAA-sponsored symposium (organized by Willenbring M): Update on genetics and 
neuroscience. Presentation at the American Society of Addiction Medicine annual 
meeting, New Orleans, Louisiana. 2009. 
58. 
Watson, D., L.A. Clark, and A. Tellegen, Development and validation of brief measures 
of positive and negative affect: the PANAS scales. J Pers Soc Psychol, 1988. 54: p. 1063-
1070. 
59. 
Radloff, L.S., The CES-D Scale: a self-report depression scale for research in the 
general population. Appl Psychol Meas, 1977. 1: p. 385-401. 
60. 
Ait-Daoud, N., et al., Treating smoking dependence in depressed alcoholics. Alcohol Res 
Health, 2006. 29(3): p. 213-220. 
61. 
Stewart, A.L. and J.E. Ware, eds. Measuring functioning and well-being: the medical 
outcomes study approach. 1992, Duke University Press: Durham, NC. 235-246, 399-400. 
62. 
Heatherton, T.F., et al., The Fagerström Test for Nicotine Dependence: a revision of the 
Fagerström Tolerance Questionnaire. Br J Addict, 1991. 86: p. 1119-1127. 
63. 
Endicott, J., et al., Quality of Life Enjoyment and Satisfaction Questionnaire: a new 
measure. Psychopharmacol Bull, 1993. 29: p. 321-326. 
64. 
Johnson, B.A., et al., Attenuation of some alcohol-induced mood changes and the desire 
to drink by 5-HT3 receptor blockade: a preliminary study in healthy male volunteers. 
Psychopharmacology, 1993. 112: p. 142-144. 
65. 
Moak, D.H., R.F. Anton, and P.K. Latham, Further validation of the Obsessive-
Compulsive Drinking Scale (OCDS): relationship to alcoholism severity. Am J Addict, 
1998. 7: p. 14-23. 
66. 
Bohn, M.J., T.F. Babor, and H.R. Kranzler, The Alcohol Use Disorders Identification 
Test (AUDIT): validation of a screening instrument for use in medical settings. J Stud 
Alcohol, 1995. 56: p. 423-432. 
67. 
Benowitz, N.L., The use of biologic fluid samples in assessing tobacco smoke 
consumption. NIDA Res Monogr, 1983. 48: p. 6-26. 
68. 
SRNT Subcommittee on Biochemical Verification, Biochemical verification of tobacco 
use and cessation. Nicotine Tob Res, 2002. 4: p. 149-159. 
69. 
Seccareccia, F., et al., Serum cotinine as a marker of environmental tobacco smoke 
exposure in epidemiological studies: the experience of the MATISS project. Eur J 
Epidemiol, 2003. 18: p. 487-492. 
70. 
Ray, L.A., et al., A preliminary pharmacogenetic investigation of adverse events from 
topiramate in heavy drinkers. Exp Clin Psychopharmacol, 2009. 17: p. 122-129. 
71. 
Jorenby, D.E., et al., A controlled trial of sustained-release bupropion, a nicotine patch, 
or both for smoking cessation. N Engl J Med, 1999. 340: p. 685-691. 
72. 
Littell, R.C., et al., SAS for mixed models. 2nd edition. 2006, Cary, NC: SAS Institute Inc. 

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers 
67 
Version 9, April 4, 2022 
 73.       Johnson, B. A., Ait-Daoud, N., Bowden, C. L., DiClemente, C. C., Roache, J. D., Lawson, K., ... & 
Ma, J. Z. (2003). Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. The 
Lancet, 361(9370), 1677-1685.