Genetically Informed Smoking Cessation Trial
Phase: PHASE4
Conditions: Smoking Cessation
Sponsor: Washington University School of Medicine

Genetically Informed Smoking Cessation Trial Study Protocol 
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GENETICALLY INFORMED SMOKING CESSATION 
TRIAL 
STUDY PROTOCOL 
TABLE OF CONTENTS 
A 
INTRODUCTION .............................................................................................................................................. 3 
A1 
STUDY ABSTRACT......................................................................................................................................... 3 
A2 
PRIMARY HYPOTHESIS .................................................................................................................................. 3 
A3 
PURPOSE OF THE STUDY PROTOCOL ............................................................................................................. 4 
B 
BACKGROUND ................................................................................................................................................. 4 
B1 
PRIOR LITERATURE AND STUDIES ................................................................................................................. 4 
B2 
RATIONALE FOR THIS STUDY ........................................................................................................................ 4 
C 
STUDY OBJECTIVES ....................................................................................................................................... 5 
C1 
PRIMARY AIM ............................................................................................................................................... 5 
C2 
SECONDARY AIM .......................................................................................................................................... 5 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES .......................................................................... 5 
D 
STUDY DESIGN ................................................................................................................................................. 7 
D1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................................ 7 
D2 
SUBJECT SELECTION AND WITHDRAWAL ...................................................................................................... 7 
2.a 
Inclusion Criteria ..................................................................................................................................... 7 
2.a 
Exclusion Criteria .................................................................................................................................... 8 
2.b 
Ethical Considerations ............................................................................................................................ 8 
2.c 
Subject Recruitment Plans and Consent Process ..................................................................................... 8 
2.d 
Randomization Method and Blinding ...................................................................................................... 9 
2.e 
Risks and Benefits .................................................................................................................................... 9 
2.f 
Early Withdrawal of Subjects ..................................................................................................................... 11 
2.g 
When and How to Withdraw Subjects .................................................................................................... 12 
2.h 
Data Collection and Follow-up for Withdrawn Subjects ....................................................................... 12 
D3 
STUDY DRUG .............................................................................................................................................. 13 
3.a 
Description ............................................................................................................................................ 13 
3.b 
Treatment Regimen ................................................................................................................................ 13 
3.c 
Method for Assigning Subjects to Treatment Groups ............................................................................ 13 
3.d 
Preparation and Administration of Study Drug ..................................................................................... 14 
3.e 
Subject Compliance Monitoring ............................................................................................................ 14 
3.f 
Prior and Concomitant Therapy ................................................................................................................ 14 
3.g 
Packaging .............................................................................................................................................. 14 
3.h 
Blinding of Study Drug .......................................................................................................................... 14 
3.i 
Receiving, Storage, Dispensing and Return ............................................................................................... 14 
E 
STUDY PROCEDURES .................................................................................................................................. 15 
E1 
SCREENING FOR ELIGIBILITY ...................................................................................................................... 15 
E2 
SCHEDULE OF MEASUREMENTS .................................................................................................................. 16 
E3 
INITIAL VISIT AND VISIT 1 .......................................................................................................................... 16 
E4 
VISIT 2-9 ..................................................................................................................................................... 17 
4.a 
Safety and Compliance Monitoring ....................................................................................................... 17 
4.b 
Medical Monitoring ............................................................................................................................... 18 
4.c 
Definitions of Adverse Events ................................................................................................................ 19 

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4.d 
Classification of Events ......................................................................................................................... 19 
4.e 
Data Collection Procedures for Adverse Events ................................................................................... 20 
4.f 
Reporting Procedures ................................................................................................................................ 20 
4.g 
Adverse Event Reporting Period ............................................................................................................ 20 
4.h 
Post-study Adverse Event ....................................................................................................................... 20 
E5 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ........................................................................ 20 
F 
STATISTICAL PLAN ...................................................................................................................................... 22 
F1 
SAMPLE SIZE DETERMINATION AND POWER ................................................................................................... 22 
F2 
INTERIM MONITORING AND EARLY STOPPING ................................................................................................ 22 
F3 
ANALYSIS PLAN .............................................................................................................................................. 22 
F4 
STATISTICAL METHODS .................................................................................................................................. 23 
F5 
MISSING OUTCOME DATA ............................................................................................................................... 24 
F6 
UNBLINDING PROCEDURES ............................................................................................................................. 24 
G 
DATA HANDLING AND RECORD KEEPING ........................................................................................... 24 
G1 
CONFIDENTIALITY AND SECURITY .............................................................................................................. 24 
G2 
TRAINING .................................................................................................................................................... 25 
G3 
CASE REPORT FORMS AND SOURCE DOCUMENTS ....................................................................................... 25 
G4 
RECORDS RETENTION ................................................................................................................................. 26 
G5 
PERFORMANCE MONITORING ...................................................................................................................... 26 
H 
STUDY MONITORING, AUDITING, AND INSPECTING ........................................................................ 26 
H1 
STUDY DATA SAFETY AND MONITORING PLAN .......................................................................................... 26 
H2 
COUNSELING MONITORING PLAN ............................................................................................................... 27 
H3 
AUDITING AND INSPECTING ........................................................................................................................ 28 
I 
STUDY ADMINISTRATION .......................................................................................................................... 29 
I1 
ORGANIZATION AND PARTICIPATING CENTERS ............................................................................................... 29 
I2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ............................................................................................ 29 
I3 
COMMITTEES ................................................................................................................................................... 29 
I4 
SUBJECT STIPENDS OR PAYMENTS .................................................................................................................. 29 
I5 
STUDY TIMETABLE .......................................................................................................................................... 29 
J 
PUBLICATION PLAN .................................................................................................................................... 30 
K 
ATTACHMENTS ............................................................................................................................................. 30 
K1 
INFORMED CONSENT ................................................................................................................................... 30 
K2 
BASELINE INTERVIEW ................................................................................................................................. 30 
K3 
FOLLOW UP INTERVIEW .............................................................................................................................. 30 
K4 
BECK DEPRESSION INVENTORY .................................................................................................................. 30 
K5 
BECK ANXIETY INVENTORY ....................................................................................................................... 30 
K6 
INITIAL CONTACT LETTER .......................................................................................................................... 30 
K7 
SCREENING LOG ......................................................................................................................................... 30 
K8 
CONTACT FORM .......................................................................................................................................... 30 
K9 
PATCH USE INSTRUCTION/PILL USE INSTRUCTION ..................................................................................... 30 
K10 
DETAILED STATISTICAL ANALYSIS PLAN (SAP) .......................................................................................... 30 
K11 
SMOKING CESSATION COUNSELING GUIDE ................................................................................................. 30 
L 
REFERENCES .................................................................................................................................................. 30 
 

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A Introduction 
 
A1 Study Abstract 
This is a randomized controlled trial examining the effects of one experimental factor 
(combination Nicotine Replacement Therapy (NRT) vs. varenicline vs. placebo for 3 months) 
and one non-experimental participant characteristic: CHRNA5 genotypes associated with high, 
intermediate, and low risk levels for nicotine dependence and smoking cessation failure. Based 
on the frequency distribution of these genotypes, there will be sufficient numbers of each 
genetic group represented in the active and placebo arm. All patients will receive intensive 
smoking cessation counseling. We will examine the main effects of medication (combination 
NRT vs. varenicline vs. placebo) and genotype (high, intermediate, and low risk), as well as the 
pharmacogenetic interaction between genotype and medication on the primary cessation 
outcome (abstinence at end of treatment, ABST_EOT) and other outcomes (abstinence at 6 
months). We chose the primary efficacy measure of abstinence at 3 months (EOT) because 
preliminary data (Chen et al., 2012) suggest the genetic effects on cessation take place in the 
early cessation stage. Our hypothesis is that NRT significantly increases smoking abstinence in 
patients possessing high-risk haplotypes, but not amongst patients without such haplotypes.  
 
This experiment will answer the following questions:  
1) Is there a genotype X Pharmacotherapy (cNRT vs. placebo) interaction with regard to 
abstinence?  
2) Is there a genotype X Pharmacotherapy (varenicline vs. placebo) interaction with regard to 
abstinence?  
 
 
This study has been designed following the guidelines and recommendations for conducting 
and reporting the results of clinical trials as described in the CONSORT (Consolidated 
Standards of Reporting Trials) statement. In addition, the design and methodology of the study 
are consistent with current guidelines and recommendations provided by the clinical trial experts 
in smoking cessation (Society for Research on Nicotine and Tobacco recommendations for 
follow-up procedures). 
A2 Primary Hypothesis 
Hypothesis #1 is to examine whether medication effect (cNRT vs. placebo) varies with CHRNA5 
(i.e. a genotype X medication interaction). A series of logistic regression models will be used to 
examine main effects of genotype (rs16969968) and medication before testing genotype x 
medication interactions, with sex, age, and study cohort as covariates using logistic regression 
models.  
 
Hypothesis #2 is to examine whether medication effect (varenicline vs. placebo) varies with 
CHRNA5 (i.e. a genotype X medication interaction). A series of logistic regression models will 
be used to examine main effects of genotype (rs16969968) and medication before testing 
genotype x medication interactions, with sex, age, and study cohort as covariates using logistic 
regression models.  

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A3 Purpose of the Study Protocol 
This experiment will answer the following questions:  
1) Is there a genotype X Pharmacotherapy (cNRT vs. placebo) interaction with regard to 
abstinence?  
2) Is there a genotype X Pharmacotherapy (varenicline vs. placebo) interaction with regard to 
abstinence?  
 
B Background 
 
B1 Prior Literature and Studies 
In a general population sample of smokers seeking to quit, we recently discovered that genetic 
markers in the CHRNA5 gene predict cessation success and response to pharmacotherapy. 
Patients with the high-risk variants had a 3-fold enhanced response to pharmacotherapy as 
compared to those with the low-risk and intermediate-risk variants. This information can be             
used to separate patients who are at serious risk of smoking relapse without pharmacotherapy 
from those who are likely to be able to quit on their own and thus not benefit from the 
medication (Chen et al, 2012). These results have been replicated in the large 
Pharmacogenetics of Nicotine Addiction Treatment (PNAT) consortium (Bergen et al, 2012). To 
address the current barriers to pharmacotherapy use which lead to failed smoking cessation in 
these patients, this genetically informed treatment study will investigate how genetic information 
can be used to personalize cessation pharmacotherapy to maximize efficacy for patients. 
 
B2 Rationale for this Study 
Our overarching goal is to identify the most appropriate genetically informed smoking cessation 
treatments for smokers hoping to quit. 
Our recent finding suggests that the effect of pharmacotherapy on cessation varies with 
genotype (nicotinic receptor gene, CHRNA5): pharmacotherapy significantly increases 
abstinence amongst individuals with the high-risk genetic variants, but provides little benefit to 
individuals with the low-risk variants. The genotype is useful to predict relapses and response to 
medication (Chen et al, 2012). Weighing both risk and efficacy on cessation success we will 
identify smokers who are more likely to relapse, and need pharmacotherapy in order to attain 
optimal outcomes versus those who will receive little benefit from pharmacotherapy. This work 
can lead to personalized treatment that promotes long term cessation success by focusing 
pharmacotherapy use on those who can benefit from it. 
 
 
 

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C Study Objectives 
 
C1 Primary Aim 
Specific Aim 1: To recruit 822 participants who are active smokers in a smoking cessation trial. 
All patients will be randomized to combination NRT (Nicotine Replacement Therapy) with 
nicotine patch and lozenge, or varenicline, or placebo for 3 months. All patients will receive 
intensive smoking counseling. These patients will be assessed in person at baseline, 3 months 
(if biochemical verification of abstinence is needed), 6 months (if biochemical verification of 
abstinence is needed), and by telephone at the last day pre-quit, quit date, 1 week, 2 weeks, 4 
weeks, 3 months (if biochemical verification of abstinence is not needed), 6 months (if 
biochemical verification of abstinence is not needed) and 1 year after the quit date.  
 
Specific Aim 2: To determine if the effect of cessation pharmacotherapy (combination Nicotine 
Replacement Therapy (NRT) vs. varenicline vs. placebo for 3 months) on abstinence varies 
significantly with genotype. We will examine the association between two genetic variants in the 
CHRNA5 gene and treatment on smoking cessation success (abstinence at end of treatment 
(ABST_EOT)). We will test the main effects of pharmacotherapy and genotype, as well as the 
interaction between them. Secondary cessation outcomes include abstinence at 6 months and 1 
year.  
 
C2 Secondary Aim 
To study the effect of other genetic or environmental risk factors on smoking cessation in this 
population. 
 
C3 Rationale for the Selection of Outcome Measures 
We will conduct a randomized controlled smoking cessation trial of 822 participants to examine 
the association between the genetic variants (CHRNA5), treatment, and cessation success 
(abstinence at end of treatment (ABST_EOT)). We will evaluate secondary cessation outcomes 
(abstinence at 6 months and 1 year). 
Primary Outcome Measure: 7-day point prevalence abstinence [Time Frame: Week 12]  
The definition of this measure requires: (a) no self-reported smoking (not even a puff of a 
cigarette) for at least the 7 days prior to the assessment, and (b) CO biochemical verification of 
abstinence. 
 
Secondary Outcome Measures: Continuous Abstinence (11 weeks) [Time Frame: 12 weeks 
with the first 1 week initial grace period] 
The definition of this measure requires: Not taking even 1 cigarette puff from target quit date to 
end of treatment with the first 1 week initial grace period. 
 
7-day point prevalence quit rate [Time Frame: Week 24] 
The definition of this measure requires: (a) no self-reported smoking (not even a puff of a 
cigarette) for at least the 7 days prior to the assessment, and (b) biochemical verification of 
abstinence. 

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Number of days to lapse and relapse [Time Frame: Assessed from the target quit day through 
52 weeks.]  
The number of days to lapse is defined as the number of days from the target quit date until the 
participant reports smoking (even a single puff). The number of days to relapse is defined as the 
number of days from the target quit day until the first of seven consecutive days of smoking. 
 
Initial Cessation [Time Frame: Assessed for the first seven days after the target quit date.]  
Defined as at least 1 day of abstinence during the first 7 days after the target quit day. 
 
Longitudinal models of abstinence outcomes across multiple time points [ Time Frame: 0-52 
Weeks ] 
The definition of this measure requires; no self-reported smoking (not even a puff of a cigarette) 
for at least 7 days prior to the assessment. 
Longitudinal models of smoking quantity in cigarettes per day outcomes across multiple time 
points. [ Time Frame: 0-52 Weeks ]The definition of this measure requires self-reported 
cigarettes per day. 
Medication adherence [ Time Frame: Pre-quit week to Week 12 ]Adherence is the proportion of 
expected medication (varenicline, patch, lozenge) taken as advised during pre-quit week to 
week 12 
Side effects [ Time Frame: Pre-quit week to Week 12 ]  
All reported side effects (occurring>4%) will be summarized and presented for the study. In 
addition, the investigators will further identify a pre-specified set of key side effects as being 
related to drug agonist effects (e.g., nausea, vomiting, racing heart, headache, and sleep 
disturbance). These will be analyzed as rate of occurrence during the period of medication use. 
 
Withdrawal [ Time Frame: Pre-quit week to Week 4 ] 
Withdrawal severity is assessed by Wisconsin Smoking Withdrawal Scale (WSWS) overall 
withdrawal scores, craving, and negative affect scores. 
 

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D Study Design  
 
D1 Overview or Design Summary 
This is a rs16969968 based stratified randomized controlled trial design examining the effects of 
one experimental factor (combination NRT vs. varenicline vs. placebo for 3 months) and one 
non-experimental participant characteristic: CHRNA5 genotypes associated with high, 
intermediate, and low risk levels for nicotine dependence and cessation failure. Based on the 
frequency distribution of these genotypes, there will be sufficient numbers of each genetic 
groups represented in the active and placebo arm. We will examine the main effects of 
medication (cNRT vs placebo as well as varenicline vs. placebo) and genotypes (high, 
intermediate, and low risk), as well as the pharmacogenetic interaction between the genotypes 
and medication on the primary cessation outcome (abstinence at end of treatment, ABST_EOT) 
and other outcomes (abstinence at 6 months and 1 year). We choose the primary efficacy 
measure of abstinence at 3 month (EOT) because our preliminary data from the UW-TTURC 
trial suggest the genetic effects on cessation take place in the early cessation stage. Our 
hypothesis is that NRT significantly increases smoking abstinence in patients possessing high-
risk genotypes, but not amongst patients without such genotypes. 
This experiment will achieve Aims 1 and 2 by answering the following questions:  
1) Is there a genotype X Pharmacotherapy (cNRT vs. placebo) interaction with regard to 
abstinence?  
2) Is there a genotype X Pharmacotherapy (varenicline vs. placebo) interaction with regard to 
abstinence?  
 
D2 Subject Selection and Withdrawal  
Some subjects for this study have participated in the previous study: the Collaborative Genetic 
Study of Nicotine Dependence (COGEND). Subjects who participated in COGEND must have 
provided a DNA sample. Subjects must have given permission to share data and to be 
contacted for future studies for both COGEND. Subjects must have active nicotine dependence. 
We are expanding enrollment opportunities to the community, by recruiting from the volunteers 
for health program, and smokers interested in smoking cessation in the local community. These 
participants must give permission to share data. When participants agree to be part of this study 
he/she gives up any property rights he/she may have in the blood and data. Cells from the blood 
will be used to develop cell lines.  DNA and plasma will then be extracted from these cell lines 
and used for research purposes. We will use the blood sample (DNA, plasma, cell lines from 
blood), and data for other research projects in the future. 
 
2.a 
Inclusion Criteria  
            Inclusion:  
1) Adult (>=21 years of age), seeking treatment for smoking cessation. 
2) Able to speak English,  
3) Active smoking (Cigarettes Per Day (CPD) >=5) and exhaled CO >=8 ppm 
4) Agree to participate in this randomized smoking cessation trial with follow up 
assessments up to 12 months, and  

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2.a 
Exclusion Criteria  
            Exclusion:  
             
The subject will be excluded for having a condition that prevents him/her from effectively 
participating in the protocol.  
1) Pregnancy or breast feeding,  
2) Active use or recent use (<= to 1 month) of medication or e-cigarettes for nicotine 
dependence/smoking cessation, or use of e-cigarettes for more than 9 days in the prior 
month 
3) Allergy to Nicotine patch, Nicotine lozenge, or varenicline  
4) Unwillingness to prevent pregnancy during the medication phase and 1 month 
afterwards (women only),  
5) Significant cardiac conditions (myocardial infarction (heart attack), unstable angina, 
coronary angioplasty, cardiac bypass) or serious arrhythmia within 6 months 
6) Current heavy alcohol consumption (greater than or equal to 6 drinks/day, 6 
days/week) 
7) Active psychosis or poorly controlled depression in the past 6 months 
8) Any suicide attempt or poorly controlled depression in the past 6 months,  
9) End stage renal disease with hemodialysis 
2.b 
Ethical Considerations  
This study will recruit from all eligible subjects regardless of their age, gender, and ethnicity. No 
children or pregnant women will be included in this study. 
2.c 
Subject Recruitment Plans and Consent Process 
We propose to enroll previous participants of the COGEND study, VFH, and the local 
community. We expect we can successfully recruit 822 patients in 3 years.  
 
Step 1. Screening of Potentially Eligible Subjects 
 
The PI or research assistant will need to access the following data element. 
   
1) Subject agreed to be contacted to participate in a smoking cessation trial.  
 
Step 2. Ask the potential participant the following screening questions to determine eligibility. 
 
1) How many cigarettes do you smoke a day?  
2) Are you committed to participating in this study on treatment for smoking 
cessation for a full year?  
3) Are you willing to use birth control for 3 months while you are receiving medication 
treatment for smoking cessation and one month after? (ONLY for pre-menopausal 
women)  
4) Are you pregnant or breast feeding? (ONLY for pre-menopausal women)  
5) Do you currently take the medication Bupropion, Wellbutrin, Zyban, Varenicline, or 
Chantix, or nicotine patch or lozenge?  
6) Are you allergic to the Nicotine Patch, lozenge, or varenicline?  
7) Did you have significant cardiac conditions (an acute heart attack, unstable 
angina, coronary angioplasty, cardiac bypass) in the past 6 months? 
8) Do you currently drink alcohol at the level of at least 6 drinks per day, 6 days per 
week? 

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9) Have you had active depression or psychosis in the past 6 months? 
10) Do you currently have thoughts of suicide or have a suicide attempt in the past 6 
months? 
11) Do you have end stage kidney disease requiring hemodialysis? 
 
Step 3. Smoking Verification 
 
Patients will complete a carbon monoxide (CO) breath test. A cut-off level of >=8 ppm will be 
used to verify self-reported smoking.  
 
Step 4. Obtain Informed Consent 
 
Patients who express interest in participating will be informed in greater detail about the study 
and receive screening for eligibility criteria by the PI psychiatrist or the research assistant. The 
patients will learn about general requirements for participation (e.g., need for follow-up, 
participation in assessments, etc.) as well as risks associated with nicotine toxicity, nicotine 
withdrawal, blood sample and pharmacotherapy. If still interested and eligible, the patients will 
then be asked to provide written informed consent to participate, on a form approved by the 
Washington University School of Medicine Institutional Review Board. Study candidates will 
read the informed consent document and be given an opportunity to ask any questions 
regarding study participation. They will also complete the consent form. A follow up contact can 
be scheduled if potential participants would like to have more time to consider participation. 
Participants will receive a signed copy of the consent document. 
 
2.d 
Randomization Method and Blinding 
The participants will be randomized with the ratio 1:1:1 to the treatment arm of combination  
NRT (nicotine patch and lozenge) plus smoking cessation counseling, or the treatment arm of 
varenicline plus smoking cessation counseling, or the treatment arm of placebo (patch and 
lozenge or pill) plus smoking cessation counseling. 
 
Participants will be randomly assigned to 1) combination NRT plus counseling, 2) varenicline 
plus counseling, or 3) placebo plus counseling. SAS Version 9 statistical software will be used 
to generate the random assignment table stratified by CHRNA5 genotype rs16969968. The 
group assignment and genotype will be coded to ensure that the double blind is maintained, and 
the interface will prevent staff from having access to the participant’s assignment and genotype 
until after the baseline and post treatment assessments have been completed.  
2.e 
Risks and Benefits 
 
Risks associated with this research are judged to be minimal.  
 
Smoking withdrawal is associated with a number of unpleasant symptoms such as sleep 
disturbance, hunger, craving, and negative mood. Most smokers have tried to quit in the past 
and are familiar with these phenomena.  
 
With respect to the pharmacotherapy, participants will be made aware of the common side 
effects before they consent to participate in the study. It should be noted that the nicotine patch 
and lozenge are available over the counter. The nicotine patch has very few side effects, but             
participants may have a local skin reaction, and rarely, individuals may have a more systematic 

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allergic reaction. The most common side-effects associated with the nicotine patch are diarrhea,             
indigestion, nausea and vomiting, dry mouth, muscle and joint pain, sleeplessness, and 
abnormal dreams. Side effects associated with wearing an adhesive patch include skin rash, 
redness, and itching or irritation of the skin. The most likely side effects associated with the 
nicotine lozenge are heart burn, hiccup, nausea, upper respiratory track infection, coughing, and 
sore throat. In most cases, these side effects have been mild to moderate in intensity and go 
away once the patch is removed. Although most smokers have tolerance to nicotine, symptoms 
of acute nicotine toxicity (nausea and vomiting) are possible.  
 
Varenicline is approved by the FDA for smoking cessation and is medically safe for most 
smokers except for individuals with severe (end stage) kidney failure or hypersensitivity to 
varenicline. In addition, although no causal relationship has been established, current labeling 
for varenicline (FDA, 2011) recommends monitoring for serious neuropsychiatric symptoms 
including changes in behavior, agitation, depressed mood, suicidal ideation, and suicidal 
behavior. Varenicline labeling also notes that some individuals with pre-existing psychiatric 
conditions may experience worsening of their conditions. Preliminary data from the University of 
Wisconsin Center for Tobacco Research and Intervention (UW-CTRI) smoking cessation trials 
showed comparable rates of discontinuation and adverse events due to NRT and varenicline. 
The low rate of serious adverse events is consistent with recent data on the safety of 
varenicline. 
 
Blood draw may result in bruising, and very rarely, infection at the site of needle stick. 
 
Some patients may experience emotional distress during evaluations for depression and 
anxiety.  
 
Finally patient confidentiality would be compromised if unauthorized individuals were to 
establish the identity of any participant.  
 
What is done to minimize the risks? 
 
The principal investigator psychiatrist will be responsible for routine monitoring of  
unanticipated health events. This monitoring includes scheduled monthly meetings and review 
of written documentation. Unanticipated health event assessment, recording, reporting, and 
investigation will be accomplished through structured/standardized assessments of untoward 
occurrences/events, and regular monitoring by study physicians and other study investigators. 
The principal investigator has ultimate responsibility for ensuring that unanticipated health  
events are detected and reported in a timely manner. Health events that raise concerns (e.g., 
allergic reaction, symptoms suggestive of nicotine toxicity, significant change in mood, suicidal 
ideation) will be immediately reported to the study physician who will determine an appropriate 
course of action.  
 
Potential side effects of combination  NRT (patch and lozenge) will be closely monitored.  
The transdermal NRT is chosen for testing in participants for these safety reasons:  
1) Transdermal NRT has slower absorption, lower peak serum level, and fewer 
cardiovascular effects, vs. varencline, which has an FDA warning on use with cardiac 
patients 
2) NRT is the most commonly used cessation medication in post-MI patients 
3)Fewer drug interactions (vs. bupropion, which has an unsafe interaction with an MAO 
inhibitor if the patient is depressed).  
             

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Study participants will be closely monitored in accordance with current FDA recommendations 
as well as the consensus recommendations of the 2008 Guideline Panel which provides 
additional detailed instructions for clinicians regarding all FDA approved smoking cessation 
medications. We will follow the patient instruction and adverse events monitoring procedures 
used in the University of Wisconsin Center for Tobacco Research and Intervention (UW-CTRI). 
Patient education about possible side effects, access to a medication hotline, and ongoing 
monitoring will be consistent with FDA recommendations, clinical practice guidelines, and 
procedures successfully used in prior and ongoing UW-CTRI research using varenicline and 
combination NRT. This protocol is consistent with the 2010 FDA warning and recommendations 
for monitoring requirements regarding the black box warning of psychiatric risk for varenicline. In 
addition, we will make appropriate changes in study procedures if the FDA issues updates on 
varenicline. 
             
 
All medical information and data from the interviews will be kept in a locked file cabinet in a 
locked office and identified by a code number. The master list of subject names will be kept in a 
separate locked file cabinet in a separate locked office by the Principal Investigator. 
Computerized research data are identified only by subject identification numbers and codes, 
and confidential data files are password protected. Written records of counseling sessions and 
audio recordings of sessions will be kept in a locked cabinet and will be destroyed within one 
year of the termination of the project. Audio recordings will be obtained if authorized by the 
participant. Only authorized individuals will be permitted to review these records. We have 
followed these procedures in the past without any breeches of confidentiality, and we feel 
certain that we will be able to maintain the same level of security for this project.  
 
 
BENEFITS 
 
The potential benefits for smokers participating in this study include the chance to receive free 
smoking cessation counseling and pharmacotherapy, both of which double a smoker’s odds of 
quitting.  
 
In addition, this research has the potential to provide improved treatment strategies for clinicians 
trying to help patients quit smoking. This could result in more efficient provision of a maximally 
effective intervention for smokers.  
 
The proposed research will test combination NRT and varenicilne in patients with different 
genetic markers and identify effective pharmacotherapy according to the genetic markers. The 
results from this study will allow researchers to determine which smoker subgroups will benefit 
from pharmacotherapy and which smoker subgroups will not. This should contribute to the 
improvement of standard clinical care of such patients, and may result in improved medical 
outcomes. Given the limited risks of NRT and varenicilne, and the limited adverse effects, we 
believe that the potential risks involved in participating in the study are outweighed by the 
benefits to both society and the individual. 
 
2.f 
Early Withdrawal of Subjects  
 
Once enrolled, follow-up protocols will assess the presence of medication side effects and  

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unanticipated health events at all study visits and follow-up contacts. We will recommend 
dosage/use alternations as per good clinical practice if the patient experiences symptoms of 
nicotine toxicity or other troublesome side effects once they begin medication treatment.  
 
Should either excessive risk to study participants and/or lack of measurable benefit to study 
participants be determined, the study will be stopped and all participants notified in a manner  
appropriate to the nature of the risk and/or lack of benefit.  
             
2.g 
When and How to Withdraw Subjects  
 
We are conducting this research with strong safety measures in place (close monitoring and 
screening) to gather the needed data without imposing unacceptable risks. The participants will 
remain under the care of their own physician(s) throughout the study. To facilitate safety, 
participants who are not medically appropriate to take combination NRT or varenicline will not 
be included in the study (see exclusion criteria). Once enrolled, follow-up protocols will assess 
the presence of medication side effects and unanticipated health events at all study visits and 
follow-up contacts. We will recommend dosage/use alternations as per good clinical practice if 
the patient experiences symptoms of nicotine toxicity or other troublesome side effects once 
they begin medication treatment. We will refer patients to the study physician as needed.  
 
Participants’ medications will be continued if they have relapsed to smoking regularly. 
Subjects with symptoms of nicotine toxicity (including diarrhea, abdominal pain, vomiting, 
dizziness, and headache) reported at any research contact will be told to discontinue their  
medication immediately until they have a chance to discuss their symptoms with the study 
physician (Dr. Chen) or their primary care doctor, who will decide upon a course of action based 
upon the patient’s status and risk (e.g., a dose reduction or medication discontinuation). 
Emergency care will be administered as needed. If the only severe symptom is sleep 
disturbance, subjects will be instructed to remove the patch at night, but otherwise keep 
receiving treatment according to the protocol. Should either excessive risk to study participants 
and/or lack of measurable benefit to study participants be determined, the study will be stopped 
and all participants notified in a manner appropriate to the nature of the risk and/or lack of 
benefit.  
 
Any patient who reports discomfort as a result of completing the assessment of depression and 
anxiety will be reminded that the evaluation is discretionary, that it will be discontinued if the  
patient wishes, and that doing so will not affect the patient’s medical care. The experienced 
psychiatrist investigator will be on call in case a patient has an adverse reaction to a screening 
or outcome evaluation. We have administered these tests to over 2,500 patients without a single 
subject reporting more than mild, transient emotional distress.  
 
2.h 
Data Collection and Follow-up for Withdrawn Subjects  
 
For subjects who have withdrawn from the study treatment, and given consent for us to follow 
up, we will collect data on their basic smoking status, and adverse effects.   

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D3 Study Drug  
3.a 
Description  
The participants will be randomized with the ratio 1:1:1 to the treatment arm of combination NRT 
(nicotine patch and lozenge) plus smoking cessation counseling, the treatment arm of 
varenicline plus counseling,  or to the treatment arm of placebo (patch and lozenge or pill) plus 
smoking cessation counseling. 
 
3.b 
Treatment Regimen  
 
During the baseline visit (visit 1), all participants will be randomized at 1:1:1 to 1) one arm of 
combination nicotine and smoking cessation counseling, or 2) varenicline and smoking 
cessation counseling,  and 3) another arm of placebo and smoking cessation counseling at no 
cost to participants. Participants will receive enough patches to last 12 weeks. The duration of 
medication treatment is 12 weeks (standard for participants who smoke >9 cigs/day=8 weeks of 
21mg, 2 weeks of 14mg, and 2 weeks of 7mg nicotine patches; standard for participants who 
smoke 5-9 cigs/day=8 weeks of 14mg and 4 weeks of 7mg;).  
 
Nicotine Lozenge: The 4 mg dosage is recommended for patients who take their first cigarette 
within 30 minutes of waking and the 2mg dosage is recommended for patients who take their 
first cigarette more than 30 minutes after waking. Participants will begin taking lozenges a week 
before abstinence to replace some cigarettes. Participants will then take 1 lozenge every 1-2 
hours for 6 weeks, then 1 lozenge every 2-4 hours for 3 weeks, and 1 lozenge for every 4-8 
hours for 3 weeks. Participants will be encouraged to take a minimum of 4 pieces/day unless 
this amount produces adverse effects.  
 
Varenicline: Varenicline will be initiated with a titration for 7 days before the quit date. Before the 
quit date, participants will take one 0.5mg tablet daily for 3 days, then two 0.5mg tablets for 4 
days (one in the morning and one in the evening). After the quit date (day 8), participants will 
take 1mg tablet in the morning and in the evening.  
 
Placebo: 50% of participants assigned to the placebo group will receive placebo patch/lozenge, 
and 50% will receive the placebo pill as a control for the two active medication arms. 
 
All participants will be given complete instructions on proper medication use, and will be urged 
to contact his/her physician and a study hotline number immediately in case of listed symptoms 
of nicotine toxicity or side effects. Dose changes or discontinuation of NRT may be 
recommended; all changes will be addressed in analyses of adherence outcomes.  
 
3.c 
Method for Assigning Subjects to Treatment Groups  
The participants will be randomized with the ratio 1:1:1 to one treatment arm of combination 
NRT plus smoking cessation counseling, one treatment arm of varenicline plus counseling, or to 
placebo plus smoking cessation counseling. 
 
Participants will be randomly assigned to each of the 3 arms.  SAS Version 9 statistical software 
will be used to generate the random assignment table. The group assignment will be coded to 
ensure that the double blind is maintained, and the interface will prevent staff from having 

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access to the participant’s assignment until after the baseline and post treatment assessments 
have been completed. Adequacy of blinding will be tested and different raters will assess 
efficacy vs. safety to ensure blinding. 
3.d 
Preparation and Administration of Study Drug  
During the baseline visit (visit 1), all participants will be randomized at 1:1:1 to each of the 3 
arms described above and receive treatments at no cost to participants. 
3.e 
Subject Compliance Monitoring  
Subjects will be asked to report their use of medication in each follow up visit during the 3 month 
medication treatment period. 
3.f 
Prior and Concomitant Therapy  
Subjects currently taking the medication Bupropion, Wellbutrin, Zyban, will be excluded. 
 
Non-Study Treatment: Patients will be asked to refrain from non-study smoking cessation 
interventions such as intensive smoking cessation counseling and smoking cessation 
medication during treatment. Non-Study Treatment data will be assessed at each follow up visit 
to document whether the patient is receiving any non-study treatment for smoking cessation or 
other medical conditions, including medications, counseling, quit line, support groups, self-help 
books, and complementary/ alternative medicine remedies. 
3.g 
Packaging  
The study medication (Nicotine patch and place patch, varenciline, and placebo (patch and 
lozenge or pill) will have identical packaging when they are provided to the participants. 
3.h 
Blinding of Study Drug  
The group assignment will be coded to ensure that the double blind is maintained, and the 
interface will prevent staff from having access to the participant’s assignment until after the 
baseline and post treatment assessments have been completed.  
3.i 
Receiving, Storage, Dispensing and Return  
Participants will receive their study medication when they attend the in office visit 1 (baseline). 

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E Study Procedures  
 
E1 Screening for Eligibility 
We propose to enroll previous participants of the COGEND study and the GERS study and to 
expand enrollment opportunities to the community, by recruiting from the volunteers for health 
program in our University Hospital System, and smokers interested in smoking cessation in the 
local community. We expect we can successfully recruit 822 patients in 3 years.  
 
 
Step 1. Screening of Potentially Eligible Subjects 
 
The PI or research assistant will need to access the following data element. 
   
1) Subject agreed to be contacted to participate in a smoking cessation trial.  
 
Step 2. Ask the potential participant the following screening questions to determine eligibility. 
 
1) How many cigarettes do you smoke a day?  
2) Are you committed to participating in this study on treatment for smoking cessation for 
a full  year?  
3) Are you willing to use birth control for 2 months while you are receiving medication 
treatment for smoking cessation? (ONLY for pre-menopausal women)  
4) Are you pregnant or breast feeding? (ONLY for pre-menopausal women)  
5) Do you currently take the medication Bupropion, Wellbutrin, Zyban, Varenicline, or 
Chantix?  
6) Are you allergic to the Nicotine Patch, lozenge, or varenicline?  
7) Have you had significant cardiac conditions (heart attack, unstable angina, coronary 
angioplasty, cardiac bypass) in the past 6 months?  
8) Do you currently drink alcohol at the level of at least 6 drinks/day, 6 days/week?  
9) Have you had active depression or psychosis in the past 12 months?  
10) Do you currently have thoughts of suicide or have a prior suicide attempt in the past 
12 months?  
11) Do you have end stage kidney disease requiring hemodialysis?  
 
Step 3. Obtain Informed Consent 
 
Patients who express interest in participating will be informed in greater detail about the study 
and receive screening for eligibility criteria by the PI psychiatrist or the research assistant. The 
patients will learn about general requirements for participation (e.g., need for follow-up, 
participation in assessments, etc.) as well as risks associated with nicotine toxicity, nicotine 
withdrawal, blood draw, and pharmacotherapy. If still interested and eligible, the patients will 
then be asked to provide written informed consent to participate, on a form approved by the 
Washington University School of Medicine Institutional Review Board. Study candidates will 
read the informed consent document and be given an opportunity to ask any questions 
regarding study participation. They will also complete the HIPAA form and the consent form. A 

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follow up contact can be scheduled if potential participants would like to have more time to 
consider participation. Participants will receive a signed copy of the consent document. 
 
E2 Schedule of Measurements 
Participants will receive a baseline assessment of smoking history and withdrawal symptoms, 
provide a breath sample for alveolar CO level, provide blood sample for assessments of nicotine 
metabolism and genetic markers, receive smoking cessation counseling, and be randomized to 
one of two groups (transdermal nicotine replacement therapy and counseling vs placebo and 
counseling). These evaluations will be conducted by the Principal Investigator Dr. Chen or a 
research assistant. The baseline assessment will take approximately 90 minutes. Participants 
will be asked to also participate in 8 follow up visits, two in person at 3 months (if biochemical 
verification is needed) and 6 months (if biochemical verification is needed) and the rest by 
phone at the last pre-quit, quit date, 1 week, 2 weeks, 4 weeks, 3 months (if biochemical 
verification is not needed), 6  months (if biochemical verification is not needed)  and 1 year after 
the quit date.  
 
                 
 
E3 Initial Visit and Visit 1  
Initial Visit (if needed) 
Participants recruited from the community or volunteer for health will have a two hour initial visit 
to provide a blood sample for genetic analysis, and ask questions about health, use of alcohol 
and drugs, personality and family smoking history, and a carbon monoxide breath test.  
 
The initial visit if needed for the genetic data will take approximately two hours and includes the 
following:  
Blood sample 
Realm-R 

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Semi Structured Assessment of Nicotine Dependence – Short Version (SSAND) 
Alveolar CO level 
 
Visit 1: 
At the next visit (visit 1), participants will receive a baseline assessment of smoking history and 
withdrawal symptoms. This visit will take approximately 90 minutes.  
 
The baseline assessment includes the following:  
Demographics  
Smoking history  
Medical history 
Environmental factors  
Beck Depression Inventory (BDI)  
Beck Anxiety Inventory (BAI)  
Alveolar CO level 
Contact Information Sheet 
Adverse Events Screener 
Brief WISDM 37 
WSWS 
 
They will receive baseline cessation counseling, being randomized to nicotine or placebo 
patches or varenicline or placebo along an instruction sheet, and set a quit date.  
 
E4 Visit 2-9  
At Follow up visits at the last day pre-quit, quit date, 1 week, 2 weeks, 4 weeks, 3 months, 6 
months, and 1 year after the quit date, administer follow up assessments. 
 
At follow up visits, all participants will receive the follow up visit assessment.  
 
The follow up assessment by phone includes the following:  
Smoking Status 
Non-study treatment data 
Patch/Lozenge/Pill use and potential side effects 
Adherence 
Medical History 
Environmental factors 
Adverse Events Screener 
WSWS 
 
At the in-office follow up visits at 12 weeks and 6 months post-quit, the subject will provide a 
breath sample for alveolar CO level. 
 
In follow visits up to 12 weeks after quit date, subjects receive smoking cessation counseling. 
This session will be the final counseling session. 
 
4.a 
Safety and Compliance Monitoring 
This study has a Data Safety and Monitoring Plan (DSMP), and a Data and Safety Monitoring 
Board (DSMB).   

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The Individual Patient Safety Committee (IPSC) will include the study’s key personnel: Li-Shiun 
Chen, M.D., M.P.H., Sc.D., a psychiatrist; Robert Carney, Ph.D., a psychologist; Laura Bierut, 
M.D., a psychiatrist; The IPSC will review monthly reports on all participants. The IPSC will be 
blinded to the patient’s group assignment.  
 
In addition, we have a Data Safety and Monitoring Board (DSMB). The DSMB specifies overall 
monitoring that will be conducted by the principal investigator, including timely reporting of AEs 
and SAEs. Every 6 months, the DSMB will convene to review the overall safety data, and data 
on safety summarized by treatment condition. As per NIH guidelines, the objective of these 
reviews will be to determine whether continued conduct of the trial poses any undue risk for 
participants.  
 
The DSMB will include 1) a board-certified psychiatrist, Eric Lenze, MD, 2) a cardiologist, 
Sharon Cresci, MD, 3) an internist specialize in critical care and pulmonary health, Mario 
Castro, MD, 4) an internist with expertise in stroke prevention and personalized antithrombotic 
therapy, Brian Gage, MD, and 5) a statistician with expertise in research methodology, 
especially multicenter clinical trials and analysis of administrative data sets, J. Philip Miller. All 
five have extensive experience with clinical trials. The DSMB will be blinded through the trial 
and convene every 6 months to compare the groups with respect to adverse events, dropouts, 
withdrawals, suicidality, and other problems as well as efficacy. They will make a 
recommendation at each meeting regarding whether to continue or discontinue the trial, the 
decision will be adjudicated by the Washington University Human Studies Committee. 
 
4.b 
Medical Monitoring  
 
The principal investigator will be responsible for routine monitoring of the trial’s progress. This 
monitoring includes scheduled biweekly meetings with study staff and review of written 
documentation. Data that are reviewed at these meetings include the number and type of 
participants enrolled, the number and reasons for exclusions from enrollment, the number of 
participants treated and the stage of intervention, a summary and an individual review of any  
unanticipated health events, and outcome data. In addition, any unanticipated health events that 
raise concerns (e.g., allergic reaction, symptoms suggestive of nicotine toxicity) will be 
immediately reported to the study physicians (PI psychiatrist).  
 
To facilitate participant safety, study participants must meet study inclusion and exclusion 
criteria. Once enrolled, follow-up protocols will assess the presence of medication side effects 
and unanticipated health events at all study visits and follow-up contacts. We will recommend 
dosage/use alternations as per good clinical practice if the patient experiences symptoms of 
nicotine toxicity or other troublesome side effects. We will refer patients to the study physician 
as needed.  
 
If participants are smoking regularly, we will tell them to continue taking the study medication 
and set another quit date as soon as possible. Should either excessive risk to study participants 
and/or lack of measurable benefit to study participants be determined, the study will be stopped 
and all participants notified in a manner appropriate to the nature of the risk and/or lack of 
benefit.  
 

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This DSMP requires that investigators notify the Washington University IRB in a timely manner 
of the occurrence of any unanticipated health events which are severe, unanticipated, and 
possibly related to study medication or protocol. If the unanticipated health event might be 
related to the medication use, both the Food and Drug Administration (FDA) and the 
manufacturer (Glaxo, Inc. or Pfizer, Inc.) will be notified within 5 days of investigators  
becoming aware of the event. Examples of a serious unanticipated health event would be 
untoward occurrences that result in death, are life-threatening, require hospitalization or 
prolonging of existing hospitalization, create persistent or significant disability/incapacity, or 
involve congenital anomaly/birth defects. Unanticipated health events would include less serious 
problems that merit reporting because they are severe, unanticipated, and possibly related to 
study participation. Any serous unanticipated health event will be queried and reported even if it 
appears that the serious unanticipated health event is unrelated to study participation. The 
principal investigator will also be responsible for the accurate documentation, investigation, and 
follow-up of all study-related unanticipated health events.  
 
Unanticipated health event assessment, recording, reporting and investigation will be 
accomplished through staff training, structure/standardized assessments of untoward 
occurrences/events, and regular monitoring by study physicians and other study investigators. 
The principal investigator has ultimate responsibility for ensuring that unanticipated health 
events are detected and reported.  
 
4.c 
Definitions of Adverse Events 
 
Adverse events are assessed in each follow up visit up to the end of treatment.  
 
With respect to the pharmacotherapy, participants will be made aware of the common side 
effects before they consent to participate in the study. It should be noted that the nicotine patch 
is available over the counter. The nicotine patch has very few side effects, but participants may 
have a local skin reaction, and rarely, individuals may have a more systematic allergic reaction. 
The most common side-effects associated with the nicotine patch are diarrhea, indigestion, 
nausea and vomiting, dry mouth, muscle and joint pain, sleeplessness, and abnormal dreams. 
Side effects associated with wearing an adhesive patch include skin rash, redness, and itching 
or irritation of the skin. In most cases, these side effects have been mild to moderate in intensity 
and go away once the patch is removed. Although most smokers have tolerance to nicotine, 
symptoms of acute nicotine toxicity (nausea and vomiting) are possible.  
 
4.d 
Classification of Events 
With respect to the pharmacotherapy, participants will be made aware of the common side 
effects before they consent to participate in the study. It should be noted that the nicotine patch 
is available over the counter. The nicotine patch has very few side effects, but participants may 
have a local skin reaction, and rarely, individuals may have a more systematic allergic reaction. 
The most common side-effects associated with the nicotine patch are diarrhea, indigestion, 
nausea and vomiting, dry mouth, muscle and joint pain, sleeplessness, and abnormal dreams. 
Side effects associated with wearing an adhesive patch include skin rash, redness, and itching 
or irritation of the skin. In most cases, these side effects have been mild to moderate in intensity 
and go away once the patch is removed. Although most smokers have tolerance to nicotine, 
symptoms of acute nicotine toxicity (nausea and vomiting) are possible.  
 

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4.e 
Data Collection Procedures for Adverse Events 
Adverse events are assessed in each follow up visit up to 1 year. 
 
4.f 
Reporting Procedures 
This DSMP requires that investigators notify the Washington University IRB in a timely manner 
of the occurrence of any unanticipated health events which are severe, unanticipated, and  
possibly related to study medication or protocol. If the unanticipated health event might be 
related to the medication use, both the Food and Drug Administration (FDA) and the 
manufacturer (Glaxo, Inc. or Pfizer, Inc.) will be notified within 5 days of investigators  
becoming aware of the event. Examples of a serious unanticipated health event would be 
untoward occurrences that result in death, are life-threatening, require hospitalization or 
prolonging of existing hospitalization, create persistent or significant disability/incapacity, or 
involve congenital anomaly/birth defects. Unanticipated health events would include less serious 
problems that merit reporting because they are severe, unanticipated, and possibly related to 
study participation. Any serous unanticipated health event will be queried and reported even if it 
appears that the serious unanticipated health even is unrelated to study participation. The 
principal investigator will also be responsible for the accurate documentation, investigation, and 
follow-up of all study-related unanticipated health events.  
 
Unanticipated health event assessment, recording, reporting and investigation will be 
accomplished through staff training, structure/standardized assessments of untoward 
occurrences/events, and regular monitoring by study physicians and other study  
investigators. The principal investigator has ultimate responsibility for ensuring that 
unanticipated health events are detected and reported.  
 
4.g 
Adverse Event Reporting Period 
Adverse events will be recorded and reported throughout the entire duration of this study follow 
up period of 1 year for each participant. 
4.h 
Post-study Adverse Event 
Post-study adverse events will be recorded when the subject volunteers to report such events to 
the investigator team. 
E5 Study Outcome Measurements and Ascertainment 
 
Smoking Status and Withdrawal: All subjects will be contacted via phone for assessments of 
smoking status. We will assess long term outcomes following the SRNT Workgroup 
recommendations (Hughes et al, 2003). 
 
Primary Outcome Measure:  
 
7-day point prevalence abstinence [Time Frame: Week 12]  
The definition of this measure requires: (a) no self-reported smoking (not even a puff of a 
cigarette) for at least the 7 days prior to the assessment, and (b) CO biochemical verification of 
abstinence. 
 
 

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Secondary Outcome Measures: 
 
Continuous Abstinence (11 weeks) [Time Frame: 12 weeks with the first 1 week initial grace 
period] 
The definition of this measure requires: Not taking even 1 cigarette puff from target quit date to 
end of treatment with the first 1 week initial grace period. 
 
7-day point prevalence quit rate [Time Frame: Week 24] 
The definition of this measure requires: (a) no self-reported smoking (not even a puff of a 
cigarette) for at least the 7 days prior to the assessment, and (b) biochemical verification of 
abstinence. 
 
Number of days to lapse and relapse [Time Frame: Assessed from the target quit day through 
52 weeks.]  
The number of days to lapse is defined as the number of days from the target quit date until the 
participant reports smoking (even a single puff). The number of days to relapse is defined as the 
number of days from the target quit day until the first of seven consecutive days of smoking. 
 
Initial Cessation [Time Frame: Assessed for the first seven days after the target quit date.]  
Defined as at least 1 day of abstinence during the first 7 days after the target quit day. 
 
 
A research assistant will be ascertaining smoking status. Finally, we will gather carbon 
monoxide (CO) data at 12-wk in-person visits to biochemically validate self-reports: CO>8ppm 
will indicate smoking.  
 
Other Assessments: WSWS, Environmental factors will be assessed in each follow up visits. 

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F Statistical Plan  
 
F1  Sample Size Determination and Power 
 
 We will recruit 822 subjects for this study to examine whether genotypes predict the efficacy 
and side effects of cessation medications. The sample size is based on the statistical power 
calculation based on current research findings. Based on published finding of effect size 
(OR=3.1), we will have power of 0.84 to detect a hypothesized interaction effect size of 2.0 with 
the study design (2 sided α=0.05, abstinence rate 20% in the placebo group).  
 
F2  Interim Monitoring and Early Stopping 
The principal investigator will be responsible for routine monitoring of the trial’s progress. This 
monitoring includes scheduled biweekly meetings with study staff and review of written 
documentation. Data that are reviewed at these meetings include the number and type of 
participants enrolled, the number and reasons for exclusions from enrollment, the number of 
participants treated and the stage of intervention, a summary and an individual review of any  
unanticipated health events, and outcome data. In addition, any unanticipated health events that 
raise concerns (e.g., allergic reaction, symptoms suggestive of nicotine toxicity) will be 
immediately reported to the study physicians (PI psychiatrist and Safety Consultants cardiologist 
and internist).  
 
To facilitate participant safety, study participants must meet study inclusion and exclusion 
criteria. Once enrolled, follow-up protocols will assess the presence of medication side effects 
and unanticipated health events at all study visits and follow-up contacts. We will recommend 
dosage/use alternations as per good clinical practice if the patient experiences symptoms of 
nicotine toxicity or other troublesome side effects. We will refer patients to the study physician 
as needed. If participants are smoking regularly and heavily (>=5 cigs daily), we will tell them to  
discontinue taking the study medication.  
 
Should either excessive risk to study participants and/or lack of measurable benefit to study 
participants be determined, the study will be stopped and all participants notified in a manner 
appropriate to the nature of the risk and/or lack of benefit.  
 
There is no plan of interim analyses of the primary hypothesis.  
F3  Analysis Plan 
 
 
All analyses will first be conducted separately for European Ancestry (EA) and African American 
(AA) due to distinctly different allele frequencies and linkage disequilibrium across ancestry. If 
consistent genetic effects are seen across ancestry, samples of EA and AA ancestry will be 
combined in analyses with the covariate of race.  
 

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We will compare the abstinence outcome in the two placebo groups (placebo nicotine patch 
plus placebo nicotine lozenge vs. placebo varenicline pill).  If they are comparable which is 
consistent with prior experience of other placebo-controlled smoking cessation trials, they will be 
pooled for further analyses.   
 
The primary outcome is CO-confirmed point prevalent abstinence at end of treatment (12 
weeks), defined if subjects deny smoking during 7 days prior of the end of treatment and 
provide a breath sample with CO <8 ppm.  
 
Hypothesis #1 is to examine whether medication effect (cNRT vs. placebo) varies with CHRNA5 
(i.e. a genotype X medication interaction). A series of generalized linear models will be used to 
examine main effects of genotype (rs16969968) and medication before testing genotype x 
medication interactions, with sex, age, and study cohort as covariates using logistic regression 
models.  
 
Hypothesis #2 is to examine whether medication effect (varenicline vs. placebo) varies with 
CHRNA5 (i.e. a genotype X medication interaction). A series of generalized regression models 
will be used to examine main effects of genotype (rs16969968) and medication before testing 
genotype x medication interactions, with sex, age, and study cohort as covariates using logistic 
regression models.  
 
Analysis Plan.  
We will use generalized linear models with logit as the link function to model the primary 
outcome (7-day point prevalence abstinence at 12 weeks/end of treatment).  We will construct 
contrast models for each specific hypothesis testing and compare the goodness of fit for each 
contract. The primary method of analysis will be estimating a standard series of regression 
equations to test main effects, and gene – environment interaction (effect moderation). 
 
Our primary analyses will focus on SNPs, rs16969968, tagging nicotinic receptor genes 
CHRNA5-A3-B4 and medication in our hypotheses testing for gene-medication interactions.   
Additional covariates include age, gender, measures of nicotine dependence severity (such as 
pre-quit cigarettes smoked per day), adherence, and non-genetic factors. 
 
Secondary cessation outcomes include CO-confirmed 3-month continuous abstinence with a 1-
week grace period, 7-day abstinence at 6 months, and 1 year, time to relapse (using Cox 
regression models), and withdrawal severity. Generalized Estimation Equation (GEE)108 will be 
used in longitudinal models comprising abstinence outcomes across 3 months, 6 months, and 1 
year in secondary analyses.  
 
 
Detailed analysis plan is included in the Statistical Analysis Plan (SAP) in Appendix K10.  
 
F4  Statistical Methods  
This is a randomized smoking cessation trial. Simple X2 tests, logistic regression models and 
cox proportional hazard models will be used to study the association between genetic markers 
and cessation outcomes.  
 
We will use generalized linear models with logit as the link function to model the primary 
outcome (7-day point prevalence abstinence at 12 weeks/end of treatment).  We will construct 

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contrast models for each specific hypothesis testing and compare the goodness of fit for each 
contract. The primary method of analysis will be estimating a standard series of regression 
equations to test main effects, and gene – environment interaction (effect moderation). 
 
Detailed analysis plan is included in the Statistical Analysis Plan (SAP) in Appendix K10. 
F5  Missing Outcome Data 
If a participant prematurely discontinues the study medication, the reason for discontinuation will 
be determined and classified as primarily due to an adverse event, or lack of efficacy, not 
wanting to take another medication, or others. We will examine missing data for causes and 
compare the groups with respect to side effects and efficacy.  We will adhere to the intent-to-
treat principle for smoking outcome analyses, so that dropouts will be treated as smoking. In 
addition, we will analyze the missing data under conditions of both missing completely at 
random (MCAR) and missing at random (MAR), and use appropriate strategies such as 
imputation when appropriate.  
Participants who drop of the trial before they get a dose of the study medication/placebo will be 
included in the analyses of efficacy if they receive the medication packet. They will be included 
in the safety analyses if medication was dispensed to them.  We will ensure an appropriate 
informed consent process to minimize the probability of drop out. We will also assess level of 
adherence to the study protocol and these information will be available for use in secondary 
analyses. 
 
F6  Unblinding Procedures  
The study medication will only be unblinded when there is a moderate to severe adverse event 
and this information is required for a medical evaluation of the subject. The principal investigator 
will be notified and make a determination to coordinate study medication unblinding with the 
participant and the treating physician. 
 
G Data Handling and Record Keeping  
 
G1 Confidentiality and Security 
All medical information and data from the interviews will be kept in a locked file cabinet in a 
locked office and identified by a code number. The master list of subject names will be kept in a 
separate locked file cabinet in a separate locked office by the Principal Investigator. 
Computerized research data are identified only by subject identification numbers and codes, 
and confidential data files are password protected. Written records of counseling sessions  
will be kept in a locked cabinet and will be destroyed within one year of the termination of the 
project. Only authorized individuals will be permitted to review these records. We have followed 
these procedures in the past without any breeches of confidentiality, and we feel certain that we 
will be able to maintain the same level of security for this project. 
 
 
We will provide a private setting during the recruitment process in the hospital by the patient’s 
bed and the patient can ask questions privately. The intervention (medication and smoking 
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minimally necessary information from the participant to meet the aims of this study. The follow 
up phone visits will be made in a private research office. 
 
Paper/hard copy records (hard copy surveys, questionnaires, case report forms, pictures, etc.) - 
All medical information and data from the interviews will be kept in a locked file cabinet in a  
locked office and identified by a code number. The master list of subject names will be kept in a 
separate locked file cabinet in a separate locked office by the Principal Investigator. Written  
records of counseling sessions will be kept in a locked cabinet and will be destroyed within one 
year of the termination of the project. Only authorized individuals will be permitted to review  
these records. We have followed these procedures in the past without any breeches of 
confidentiality, and we feel certain that we will be able to maintain the same level of security for 
this project.  
              
Electronic records (computer files, electronic databases, etc.) - Computerized research data are 
identified only by subject  identification numbers and codes, and confidential data files are  
password protected.  
              
               
Questionnaire data and other data that the participants provide will also have a number code 
(but not the same as the DNA sample) that by itself cannot be linked to the participant. The keys 
to the codes that link the DNA samples and the other data will be kept at Washington University 
in a locked cabinet. No analyses or reports will be linked to the participant’s name or other 
information that would allow the participant to be identified. 
 
With respect to genetic data, laboratory staff have no direct contact with GISC participants. Data 
are stored by ID number. Subject identifiers and personal identifiers are always withheld from 
the laboratories and, thus, could not be linked to any repository identifiers. Under no 
circumstances would the laboratories accept any biomaterials or data with any subject 
identifiers. All identifiers remain with the principal investigator or the designated agents who 
actually collected blood and data. 
G2 Training  
All research staff will receive appropriate level of training on HIPPA and patient confidentiality 
before the study. They will also receive continued education and annual refreshment training on 
these topics. 
 
Training for smoking cessation counseling is outlined in the smoking cessation counseling guide 
(Appendix K11). This manual will standardize the counseling and allow the health counselors to 
follow the guidelines written in this smoking cessation counseling guide.  
G3 Case Report Forms and Source Documents 
Data that the participants provide will also have a number code (but not the same as the DNA 
sample) that by itself cannot be linked to the participant. The keys to the codes that link the DNA 
samples and the other data will be kept at Washington University in a locked cabinet. No 
analyses or reports will be linked to the participant’s name or other information that would allow 
the participant to be identified. 
 

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G4 Records Retention 
All medical information and data from the interviews will be kept in a locked file cabinet in a  
locked office and identified by a code number. The master list of subject names will be kept in a 
separate locked file cabinet in a separate locked office by the Principal Investigator. Written  
records of counseling sessions will be kept in a locked cabinet and will be destroyed within one 
year of the termination of the project. Only authorized individuals will be permitted to review  
these records. 
G5 Performance Monitoring  
The principal investigator will be responsible for routine monitoring of the trial’s progress. This 
monitoring includes scheduled biweekly meetings with study staff and review of written 
documentation. Data that are reviewed at these meetings include the number and type of 
participants enrolled, the number and reasons for exclusions from enrollment, the number of 
participants treated and the stage of intervention, a summary and an individual review of any  
unanticipated health events, and outcome data. In addition, any unanticipated health events that 
raise concerns (e.g., allergic reaction, symptoms suggestive of nicotine toxicity) will be 
immediately reported to the study physicians (PI psychiatrist and Safety Consultants cardiologist 
and internist).  
 
 
H Study Monitoring, Auditing, and Inspecting  
H1 Study Data Safety and Monitoring Plan 
This study has a Data Safety and Monitoring Plan (DSMP), and a Data and Safety Monitoring 
Board (DSMB). The Individual Patient Safety Committee (IPSC) will include three of the study’s 
key personnel: Li-Shiun Chen, M.D., M.P.H., Sc.D., a psychiatrist; Robert Carney, Ph.D., a 
psychologist, Laura Bierut, M.D., a psychiatrist; The IPSC will review monthly reports on all  
participants. The IPSC will be blinded to the patient’s group assignment.  
 
The principal investigator will be responsible for routine monitoring of the trial’s progress. This 
monitoring includes scheduled biweekly meetings with study staff and review of written 
documentation. Data that are reviewed at these meetings include the number and type of 
participants enrolled, the number and reasons for exclusions from enrollment, the number of 
participants treated and the stage of intervention, a summary and an individual review of any  
unanticipated health events, and outcome data. In addition, any unanticipated health events that 
raise concerns (e.g., allergic reaction, symptoms suggestive of nicotine toxicity) will be 
immediately reported to the study physicians (PI psychiatrist and Safety Consultants cardiologist 
and internist).  
 
To facilitate participant safety, study participants must meet study inclusion and exclusion 
criteria. Once enrolled, follow-up protocols will assess the presence of medication side effects 
and unanticipated health events at all study visits and follow-up contacts. We will recommend 
dosage/use alternations as per good clinical practice if the patient experiences symptoms of 
nicotine toxicity or other troublesome side effects. We will refer patients to the study physician 
as needed. If participants are smoking regularly, we will tell them to continue taking the study 
medication and set another quit date as soon as possible.  Should either excessive risk to study 
participants and/or lack of measurable benefit to study participants be determined, the study will 

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be stopped and all participants notified in a manner appropriate to the nature of the risk and/or 
lack of benefit.  
 
This DSMP requires that investigators notify the Washington University IRB in a timely manner 
of the occurrence of any unanticipated health events which are severe, unanticipated, and 
possibly related to study medication or protocol. If the unanticipated health event might be 
related to the medication use, both the Food and Drug Administration (FDA) and the 
manufacturer (Glaxo, Inc. or Pfizer. Inc.) will be notified within 5 days of investigators  
becoming aware of the event. Examples of a serious unanticipated health event would be 
untoward occurrences that result in death, are life-threatening, require hospitalization or 
prolonging of existing hospitalization, create persistent or significant disability/incapacity, or 
involve congenital anomaly/birth defects. Unanticipated health events would include less serious 
problems that merit reporting because they are severe, unanticipated, and possibly related to 
study participation. Any serous unanticipated health event will be queried and reported even if it 
appears that the serious unanticipated health even is unrelated to study participation. The 
principal investigator will also be responsible for the accurate documentation, investigation, and 
follow-up of all study-related unanticipated health events.  
 
Unanticipated health event assessment, recording, reporting and investigation will be 
accomplished through staff training, structure/standardized assessments of untoward 
occurrences/events, and regular monitoring by study physicians and other study investigators. 
The principal investigator has ultimate responsibility for ensuring that unanticipated health 
events are detected and reported. 
 
In addition, we have a Data Safety and Monitoring Board (DSMB). The DSMB specifies overall 
monitoring that will be conducted by the principal investigator, including timely reporting of AEs 
and SAEs. Every 6 months, the DSMB will convene to review the overall safety data, and data 
on safety summarized by treatment condition. As per NIH guidelines, the objective of these 
reviews will be to determine whether continued conduct of the trial poses any undue risk for 
participants.  
  
The DSMB will include 1) a board-certified psychiatrist, Eric Lenze, MD, 2) a cardiologist, 
Sharon Cresci, MD, 3) an internist specialize in critical care and pulmonary health, Mario 
Castro, MD, and 4) an internist with expertise in stroke prevention and personalized 
antithrombotic therapy, Brian Gage, MD, and 5) a statistician with expertise in research 
methodology, especially multicenter clinical trials and analysis of administrative data sets, J. 
Philip Miller. All five have extensive experience with clinical trials. The DSMB will be blinded 
through the trial and convene every 6 months to compare the groups with respect to adverse 
events, dropouts, withdrawals, suicidality, and other problems as well as efficacy. They will 
make a recommendation at each meeting regarding whether to continue or discontinue the trial, 
the decision will be adjudicated by the Washington University Human Studies Committee. 
H2 Counseling Monitoring Plan 
Patients will be seen by the health counselor at the baseline visit and the health counselor will 
provide smoking cessation counseling as outlined in the smoking cessation counseling guide. 
Following visit 1, follow-up phone calls will be made at the last day of pre-quit, quit date, 1, 2, 4, 
and 12 weeks post quit date to provide counseling sessions. The last counseling session at 12 
weeks post quit date may be in person or over the phone. The monitoring plan is outlined in the 
smoking cessation counseling guide.    

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H3 Auditing and Inspecting  
The Individual Patient Safety Committee (IPSC) will include two of the study’s key personnel: Li-
Shiun Chen, M.D., M.P.H., Sc.D., a psychiatrist; Robert Carney, Ph.D., a psychologist; Laura 
Bierut, M.D., a psychiatrist; . The IPSC will review monthly reports on all participants. The IPSC 
will be blinded to the patient’s group assignment.  

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I Study Administration 
 
I1 
Organization and Participating Centers 
Barnes Jewish Hospital at Washington University is the only site for this study. 
I2 
Funding Source and Conflicts of Interest 
The NIH career development award of Dr. Li-Shiun Chen will fund this study.  
The NIH R01 of Dr. Li-Shiun Chen which received a just in time request in 6/2014 will fund this 
study.  
I3 
Committees 
The Individual Patient Safety Committee (IPSC) will include two of the study’s key personnel: Li-
Shiun Chen, M.D., M.P.H., Sc.D., Robert Carney, Ph.D., a psychologist; a psychiatrist; Laura 
Bierut, M.D., a psychiatrist; . The IPSC will review monthly reports on all participants. The IPSC 
will be blinded to the patient’s group assignment.  
 
We have a Data Safety and Monitoring Board (DSMB) which will convene to review the overall 
safety data, and data on safety summarized by treatment condition every 6 months. The DSMB 
will include 1) a board-certified psychiatrist, Eric Lenze, MD, 2) a cardiologist, Sharon Cresci, 
MD, 3) an internist specialize in critical care and pulmonary health, Mario Castro, MD, and 4) an 
internist with expertise in stroke prevention and personalized antithrombotic therapy, Brian 
Gage, MD, and 5) a statistician with expertise in research methodology, especially multicenter 
clinical trials and analysis of administrative data sets, J. Philip Miller. All five have extensive 
experience with clinical trials. The DSMB will be blinded through the trial. They will make a 
recommendation at each meeting regarding whether to continue or discontinue the trial, the 
decision will be adjudicated by the Washington University Human Studies Committee. 
 
I4 
Subject Stipends or Payments  
We will compensate subjects with a cash of $25 for the initial visit (if blood sample is needed), 
$25 for Visit one if initial visit was needed, $40 for Visit 1 if initial visit was not needed, $20 for 
completing phone calls at  Visit 7 (12 weeks post-quit) and $20 for Visit 8 (6 months post-quit), 
and $10 when they complete phone Visit 9 (1 year post-quit). If participants are asked to come 
in to verify abstinence, we will compensate subjects with an additional $20 per in person visit. 
The total compensation is up to $140 if they complete the study. 
I5 
 Study Timetable 
 
The recruitment of 822 participants will take place in the first 3 years of this study and the 1 year 
follow up of the last participant will be completed in the end of the fourth year. 

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J Publication Plan  
 
We plan to publish the results in international conference and addiction related journals. 
K  Attachments  
K1  Informed consent  
K2  Baseline Interview 
K3  Follow up Interview 
K4 Beck Depression Inventory 
K5 Beck Anxiety Inventory 
K6 Initial Contact Letter 
K7 Screening Log 
K8 Contact Form 
K9 Patch Use Instruction/Pill Use Instruction 
K10  Detailed statistical analysis plan (SAP) 
K11 Smoking Cessation Counseling Guide 
 
L References 
 
 
 
            1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke  
            statistics--2011 update: a report from the American Heart  
            Association. Circulation. Feb 1 2010;123(4):e18-e209.  
            2. Rea TD, Heckbert SR, Kaplan RC, Smith NL, Lemaitre RN, Psaty BM.  
            Smoking status and risk for recurrent coronary events after  
            myocardial infarction. Ann Intern Med. Sep 17 2002;137(6):494-500.  
            3. Daly LE, Mulcahy R, Graham IM, Hickey N. Long term effect on  
            mortality of stopping smoking after unstable angina and myocardial  
            infarction. Br Med J (Clin Res Ed). Jul 30 1983;287(6388):324-326.  
            4. Fiore MC, Jaen CR. A clinical blueprint to accelerate the  

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            elimination of tobacco use. JAMA. May 7 2008;299(17):2083-2085.  
            5. Katz DA, Tang F, Faseru B, Horwitz PA, Jones P, Spertus J.  
            Prevalence and correlates of smoking cessation pharmacotherapy in  
            hospitalized smokers with acute myocardial infarction. Am Heart J.  
            Jul;162(1):74-80.  
            6. Smith PM, Burgess E. Smoking cessation initiated during hospital  
            stay for patients with coronary artery disease: a randomized  
            controlled trial. CMAJ. Jun 23 2009;180(13):1297-1303.  
            7. Mohiuddin SM, Mooss AN, Hunter CB, Grollmes TL, Cloutier DA,  
            Hilleman DE. Intensive smoking cessation intervention reduces  
            mortality in high-risk smokers with cardiovascular disease. Chest.  
            Feb 2007;131(2):446-452.  
            8. Joseph AM, Norman SM, Ferry LH, et al. The safety of transdermal  
            nicotine as an aid to smoking cessation in patients with cardiac  
            disease. N Engl J Med. Dec 12 1996;335(24):1792-1798.  
            9. Dawood N, Vaccarino V, Reid KJ, Spertus JA, Hamid N, Parashar S.  
            Predictors of smoking cessation after a myocardial infarction: the  
            role of institutional smoking cessation programs in improving  
            success. Arch Intern Med. Oct 13 2008;168(18):1961-1967.  
            10. Chen LS, Baker TB, Piper M, et al. Interplay of Genetic Risk  
            Factors (CHRNA5-CHRNA3-CHRNB4) and Cessation Treatments in Smoking  
            Cessation Success. . American Journal of Psychiatry. May 30, 2012 on  
            line 2011.  
            11. Pipe AL, Eisenberg MJ, Gupta A, Reid RD, Suskin NG, Stone JA.  
            Smoking cessation and the cardiovascular specialist: Canadian  
            Cardiovascular Society position paper. Can J Cardiol. Mar-Apr  
            2011;27(2):132-137.  
            12. Bierut LJ, Stitzel JA, Wang JC, et al. Nicotine Dependence and  
            the a5-a3-b4 Nicotinic Receptor gene cluster: Variants in the  
            Nicotinic Receptors Alter the Risk for Nicotine Dependence. American  
            Journal of Psychiatry. 2008;9(165):1163-1171.  
            13. Wang JC, Cruchaga C, Saccone NL, et al. Risk for nicotine  
            dependence and lung cancer is conferred by mRNA expression levels  
            and amino acid change in CHRNA5. Hum Mol Genet. May 14  
            2009;18(6):3125-3135.  
            14. Bergen A, Javitz H, Krasnow R, et al. CHRNB2, CHRNA5, and CHRNA3  
            SNPs and abstinence in treatment-seeking smokers. Society for  
            Research on Nicotine and Tobacco. Houston, TX; 2012.