Conditions: Smoking Cessation
Keywords: Smoking cessation Counseling Genetics and Genomics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 822
Healthy volunteers: yes

Brief summary:
The investigators' goal is to identify the most appropriate smoking cessation treatments for smokers based on genetic information. Smokers try to quit smoking but relapses are common.

Detailed description:
The investigators' goal is to determine whether genetic markers can be used to optimize smoking cessation pharmacotherapy to enhance efficacy, medication adherence, and reduce side effects. Smoking is a leading cause of preventable death and disability, and smoking cessation reverses the risk of mortality. However, cessation failure is common despite available cessation medications, which are associated with different efficacy, side effects, adherence, use constraints, and costs. This challenge can be addressed by improving current treatments via personalized medicine based on individual genetic markers to maximize efficacy and minimize side effects.

The investigators propose a prospective, genotype-based stratified randomization trial to compare two smoking cessation medications (combination NRT \[patch and lozenge\], varenicline vs. placebo) for 3 months in 720 smokers with known genotypes.

Arms:
arm 1: Combination Nicotine replacement therapy (cNRT) (patch and lozenge) and smoking cessation counseling will be provided to participants. Lozenges will be given for 12 weeks with a 1 week pre-quit titration and patch for 12 weeks. Seven smoking counseling sessions will be given during treatment. arm 2: Varenicline (pill) and smoking cessation counseling will be provided to participants for 12 weeks with 1 week pre-quit titration. Seven smoking cessation counseling sessions will be given during treatment. arm 3: Placebo pill and smoking cessation counseling will be provided to participants for 12 weeks with 1 week pre-quit titration. Placebo lozenges will be given for 12 weeks with a 1 week pre-quit titration and patch for 12 weeks. Seven smoking counseling sessions will be given during treatment.

Interventions: intervention 1: Combination NRT (Nicotine patch, Nicotine lozenge) intervention 2: Varenicline intervention 3: Placebo intervention 4: Intensive smoking counseling
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
Genetically Informed Smoking Cessation Trial Study Protocol 
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1 
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  
 
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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.  
 
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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 
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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 
cessation counseling) will occur in a private setting in the patient’s hospital room. We will collect 


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25
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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27
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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28
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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29
 
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. 


Genetically Informed Smoking Cessation Trial Study Protocol 
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30
 
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  


Genetically Informed Smoking Cessation Trial Study Protocol 
Version 10: February 12, 2019 
 
 
 
_____________________________________________________________________________________________ 
 
31
            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.  
 
 
 

ICF_001.pdf: 
 
FOR IRB USE ONLY 
IRB ID #: 201305128 
APPROVAL DATE: 02/26/19 
RELEASED DATE: 02/26/19 
EXPIRATION DATE: 02/25/20 
 
Version 6: 12/05/2017 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
Genetically Informed Smoking Cessation Trial 
 
Principal Investigator: 
Li-Shiun Chen 
 
Research Team Contact: 
Nina Smock 
(314) 362-1854 
 
 
This consent form describes the research study and helps you decide if you want to participate. It 
provides important information about what you will be asked to do during the study, about the risks 
and benefits of the study, and about your rights as a research participant. By signing this form you are 
agreeing to participate in this study. 
• If you have any questions about anything in this form, you should ask the research team 
for more information. 
• If you have questions about anything in this form, you should ask the research team for more 
information before you agree to participate.   
• You may also wish to talk to your family or friends about your participation in this study. 
• Do not agree to participate in this study unless the research team has answered 
your questions and you decide that you want to be part of this study. 
 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
This is a research study. We invite you to participate because you are a smoker who would like to quit 
smoking. The purpose of this research study is to find out more about how genetic information can be 
used to help people receive the most effective treatment to quit smoking successfully. The results of this 
study could lead to more effective ways to help people stop smoking. 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 
Initial Visit:  
If you agree to participate, you will be asked to take a breath test that will measure the level of carbon 
monoxide in your lungs. The test takes one minute to complete and involves exhaling into a carbon 
monoxide monitor. You will also provide a blood sample of approximately four tablespoons, which 
will be used to look at genes related to nicotine metabolism and other genetic markers.  Additionally, 
you will be interviewed by a trained staff member who will ask questions about your medical history, 
smoking history, use of alcohol and drugs, mood and personality traits, and information about the 
smoking history of your relatives and friends. This visit will last approximately two hours. 
 
Visit 1: Baseline Visit 
During your next visit (approximately 2-4 weeks from now) information about smoking and health 
will be collected from you. You will then be randomly (like flipping a coin) assigned to one of three 
smoking treatments: either 1) smoking cessation counseling and nicotine patch plus nicotine lozenge, 
2) smoking cessation counseling and varenicline (also known as Chantix), or 3) smoking cessation 
counseling and placebo (looks like a patch or lozenge or pill but without any active drug).  You will 
be treated for 3 months, but participation in the study will last for 1 year from the time you start 


 
FOR IRB USE ONLY 
IRB ID #: 201305128 
APPROVAL DATE: 02/26/19 
RELEASED DATE: 02/26/19 
EXPIRATION DATE: 02/25/20 
 
Version 6: 12/05/2017 
Page 2 of 12 
treatment. 
 
The visit takes about 90 minutes in the office and will include an interview about your smoking history, 
medical history, and mental health.  You are free to skip any questions that you would prefer not to 
answer. You will also take a carbon monoxide breath test that will measure the level of carbon 
monoxide in your lungs. The test will take one minute to complete and involves exhaling into a carbon 
monoxide monitor. We will record the result of the test and use it for research purposes. You will be 
asked to set a date on which you will quit smoking. We will give you the medications you are to use for 
3 months. We will instruct you on how to use the medications and side effects to be aware of.  These 
smoking cessation treatments will be provided at no cost to you. Finally, we will provide you with 
counseling to help you quit smoking. 
 
Visits 2-9 
You will receive phone calls from a member of our study team on the day before your quit date, the 
day you quit smoking, and 1, 2, and 4 weeks after you quit. These calls will take approximately 30 
minutes each, and we will ask you questions about your smoking status, use of the medications you 
were given to help you quit smoking and physical and mental health. We will also provide smoking 
cessation counseling.  
 
You will have two additional visits at 12 weeks and 6 months after you quit smoking. These visits will 
be in person or over the phone. During these visits, we will ask you questions about your smoking 
status, use of the medications to help you quit smoking and physical and mental health. You may take 
another carbon monoxide breath test that will measure the level of carbon monoxide in your lungs.  We 
will also provide smoking cessation counseling at week 12. This session will be the final counseling 
session. 
 
You will receive a final phone call from a member of our study team 12 months after your quit date. 
This call will last approximately 20 minutes and we will ask you about your smoking status and 
physical and mental health. 
 
 
Will you save my samples or research data to use in future research studies? 
As part of this study, we are obtaining blood, and coded data from you. By agreeing to be part of this 
study you give up any property rights you may have in the blood, and data. Cells from your blood will 
be used to develop cell lines, a living tissue.  A cell line is a family of cells that is grown in a laboratory 
and can be reproduced indefinitely.  DNA and plasma will then be extracted from these cell lines and 
used for research purposes. We would like to use your blood (DNA, plasma, cell lines from your blood), 
and data for other research projects in the future. These future studies may provide additional 
information that will be helpful in understanding smoking cessation, or other diseases or conditions, 
including research to develop investigational tests, treatments, drugs or devices that are not yet approved 
by the U.S. Food and Drug Administration.  It is unlikely that what we learn from these studies will have 
a direct benefit to you. There are no plans to provide financial compensation to you should this occur. 
By allowing us to use your blood and data, you give up any property rights you may have in the blood 
and data.  
 


 
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IRB ID #: 201305128 
APPROVAL DATE: 02/26/19 
RELEASED DATE: 02/26/19 
EXPIRATION DATE: 02/25/20 
 
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Page 3 of 12 
We will share your blood, genetic data from your blood and research data with other researchers.  They 
may be doing research in areas similar to this research or in other unrelated areas.  These investigators 
may be at Washington University or at other research centers.  We may also share your research data 
with large data repositories (a repository is a database of information) for broad sharing with the 
research community.  If your individual research data is placed in one of these repositories only 
qualified researchers, who have received prior approval from individuals that monitor the use of the 
data, will be able to look at your information.   
 
To ensure other investigators receiving the blood and data will not have your name or any other kind of 
link that would identify you, we maintain and securely store your blood and data and the link to your 
identity through a random identification number which is different from your study identification 
number.    
 
If you change your mind and do not want us to store and use your blood and data for future research you 
should contact the research team member identified at the top of this document.  The blood and data will 
no longer be used for research purposes. However, if some research with your blood and data has 
already been completed, the information from that research may still be used. Also, if the blood and data 
has been shared with other researchers it might not be possible to withdraw the blood and data to the 
extent it has been shared. 
 
Audio Recording 
One aspect of this study involves making audio recordings of interviews for accuracy in editing by the 
interview staff and quality control of the study. Your name will not be recorded and the recordings will 
not be shared with anyone outside of the research staff. They will be stored on password-protected 
computers in locked offices, and kept separate from identifiable data (consent form, payment form). The 
audio files will be destroyed 1 year after the completion of the study.  
  
 
This audio recording is optional, and you can still be in the study without being recorded. 
I give you permission to make audio recordings of me for internal research quality control during this 
study.  
 
_____ Yes  
            _____ No 
Initials 
 
Initials 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 822 people will take part in this study conducted by investigators at Washington 
University. 
 
HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study, your involvement will last for one year. Participation will include 
the initial in person visit that will last approximately one hour.  At Visit 1, you will be asked to 
participate in one to three in-person visits (each lasting approximately one hour) and 6-8 phone calls 
from a study team member (each lasting approximately 30 minutes) and reminder calls and text/emails if 
you consent below. For the results of this study to be useful, it is important that you are committed to 
participating in all of the in-person visits and phone calls.  If you do not think you can commit to this, 
you should not participate in this study. 


 
FOR IRB USE ONLY 
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APPROVAL DATE: 02/26/19 
RELEASED DATE: 02/26/19 
EXPIRATION DATE: 02/25/20 
 
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WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study. 
 
Some risks described in this consent document, if severe, may cause death.  
 
Risks from smoking cessation: You will be asked to quit smoking as part of this study. When people 
quit, they often experience smoking withdrawal, which is associated with a number of unpleasant 
experiences such as sleep disturbance, hunger, a strong desire to smoke again, and negative mood. Most 
smokers have tried to quit in the past and are familiar with these experiences. 
 
Likely /Common Withdrawal Experiences 
Mild 
• sleep disturbance 
• hunger 
• craving—a strong desire to smoke again 
• negative mood 
 
Less Likely /Less Common Withdrawal Experiences 
Mild 
• headache 
• inability to sleep 
 
Risks from the nicotine patch: The nicotine patch has very few side effects, but you may have a local 
skin reaction where the patch is attached, and rarely, 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 strange 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 (meaning the body has grown accustomed 
to it, so you no longer respond the way you did when you first started using it), symptoms of acute 
nicotine poisoning (nausea and vomiting) are possible. 
 
Likely /Common Nicotine Patch Side Effects 
Mild 
• local skin reaction 
• diarrhea 
• indigestion 
• nausea and vomiting 
• dry mouth 
• muscle and joint pain 
• sleeplessness 
• strange dreams 
 


 
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APPROVAL DATE: 02/26/19 
RELEASED DATE: 02/26/19 
EXPIRATION DATE: 02/25/20 
 
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Less Likely /Less Common Nicotine Patch Side Effects 
Mild 
• skin rash, redness, and itching or irritation of the skin 
 
Rare Nicotine Patch Side Effects 
Serious 
• systematic allergic reaction 
• increased heart rate 
• increased blood pressure 
• Central nervous system effects including: Impaired concentration, Depression, Anxiety, 
Insomnia, Nervousness 
 
Risks from the nicotine lozenge: The nicotine lozenge is available over the counter and has very few 
side effects. The most common side effects associated with the nicotine lozenge are heart burn, hiccup, 
nausea, upper respiratory tract infection, coughing, and sore throat. In most cases, these side effects 
have been mild to moderate in intensity and go away once the lozenge is removed. Although most 
smokers have tolerance to nicotine (meaning the body has grown accustomed to it, so you no longer 
respond the way you did when you first started using it), symptoms of acute nicotine poisoning (nausea 
and vomiting) are possible. 
 
Likely /Common Nicotine Lozenge Side Effects 
Mild 
• heart burn 
• hiccup 
• nausea 
• upper respiratory tract infection 
• coughing 
• sore throat 
 
Less Likely /Less Common Nicotine Lozenge Side Effects 
Mild 
•  redness, and itching or irritation of the throat 
 
Rare Nicotine Lozenge Side Effects 
Serious 
• systemic allergic reaction (an allergic reaction involving multiple parts of the body or the entire 
body) 
• increased heart rate 
• increased blood pressure 
• Central nervous system effects including: Impaired concentration, Depression, Anxiety, 
Insomnia, Nervousness 
 
Risks from varenicline: Varenicline is a medication approved by the Food and Drug Administration 
(FDA) for smoking cessation and is medically safe for most smokers except for individuals with severe 


 
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(end stage) kidney failure or hypersensitivity to varenicline. The most commons side effects associated 
with varenicline are nausea, vomiting, and headache. Rare side effects are  depression, suicidal ideation, 
and emotional lability. The FDA continues to monitor the medication risk, and we will closely monitor 
any side effects you may experience in this study.  
 
Likely /Common Varenicline Side Effects 
Mild 
• nausea 
• vomiting 
• indigestion 
• headache 
• fatigue 
• drowsiness 
• sleep problems (trouble sleeping of vivid, unusual or strange dreams) 
• constipation 
• gas 
 
Less Likely /Less Common Varenicline Side Effects 
Mild 
• mild joint pain 
• increased urination 
• changes in appetite 
 
Rare Varenicline Side Effects 
Serious 
• allergic reaction 
• depression or suicidal ideation 
• chest pain 
• difficulty in urination 
 
Risks from the interview:  You might find some of the questions personal or uncomfortable to answer. 
You can refuse to answer any specific questions or stop the interview at any time. 
 
Less Likely /Less Common Risks of Completing the Interviews 
Mild 
• emotional discomfort 
 
Risks from the breath test: There are no foreseeable risks associated with the breath test. 
 
Risks from the Blood Draw: You may experience some discomfort, bruising, and/or minor bleeding at 
the site of the needle insertion. Occasionally, some people experience dizziness or feel faint. The 
research staff is prepared to handle such situations. 
 
Likely / Common Risks of blood draw 


 
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Mild 
• bruising 
• discomfort 
• bleeding at site of needle insertion 
 
Rare Risks of blood draw 
Serious 
• infection at the site of needle stick 
• fainting or dizziness 
 
Risks from DNA tests: DNA, the material in cells that is passed from parents to children, will be 
obtained and tested from your blood sample.  Participation in this genetic study may ultimately reveal 
that you are at risk for smoking-related disorders and other diseases.  You will not receive any results 
from any of these analyses. 
 
There is a federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this 
law makes it illegal for health insurance companies, group health plans and employers with greater than 
15 employees to discriminate against you based on your genetic information. However, it does not 
protect you against discrimination by companies that sell life insurance, disability insurance or long 
term-care insurance.  
 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section 
in this consent form titled “How will you keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
You may or may not benefit from being in this study. 
 
However, we hope that, in the future, other people might benefit from this study because this research 
has the potential to provide improved treatment strategies for doctors trying to help patients quit 
smoking. This could result in more effective treatments for smokers in the future. 
 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
Before you decide whether or not to be in this study, you have other options that are available to you. 
Instead of being in this study, you could seek medications to help you quit smoking and smoking 
cessation counseling without being in a research study. 
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
There is no cost to you for being in this research study. The smoking cessation treatments will be 
provided to you at no cost.  
 
Message and Data rates may apply to the text messages. You will receive a maximum of 4 messages a 
month. You can text STOP or contact Nina Smock at 314-362-1854 to opt-out of receiving these 
messages.  You may also decline to receive text messages from the study. 
 


 
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WILL I BE PAID FOR PARTICIPATING? 
You will be paid $25 for the initial visit to obtain your genetic data. You will be paid $25 for Visit 
1. You will be paid $20 for completing phone calls at 12 weeks and 6 months and $10 for completing 
a brief phone call at one year. If you are asked to come in for an in person visit at 12 weeks or 6 
months, we will pay you an additional $20 for your time. The total compensation is up to $140. You 
will be paid by cash for in person visits and by check for telephone assessments.  You will need to 
provide your address so that the checks can be mailed to you. You may also need to provide your 
social security number (SSN) in order for us to pay you. You may choose to participate without 
being paid if you do not wish to provide your social security number (SSN) for this purpose. Your 
social security number is obtained for payment purposes only. 
 
WHO IS FUNDING THIS STUDY? 
The National Institutes of Health (NIH) is funding this research study.  This means that Washington 
University is receiving payments from the NIH to support the activities that are required to conduct 
the study.  No one on the research team will receive a direct payment or increase in salary from the 
NIH for conducting this study. Pfizer will provide active and placebo varenicline. 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact the investigator 
Dr. Li-Shiun Chen, MD at (314) 362-3932 and/or the Human Research Protection Office at 1-(800)-
438-0445. 
 
Decisions about payment for medical treatment for injuries relating to your participation in research 
will be made by Washington University. If you need to seek medical care for a research-related injury, 
please notify the investigator as soon as possible. 
 
WILL YOU KEEP MY NAME ON FILE TO GIVE TO OTHERS? 
We will keep information about you in our research database.  The database will contain information 
such as your name, address, age, and selected medical information such as diagnosis and treatment.  We 
will keep the information in this database secure in password-protected computers in a locked office. 
You may request that your personal information be removed from this file at any time by contacting the 
research coordinator Nina Smock at 314-362-1854 or the principal investigator Dr. Li-Shiun Chen, 
Department of Psychiatry, Washington University, 314-362-3932.  
 
I give you permission to put my name and personal information in a research database so that other 
researchers can contact me in the future about different research studies.  
 
_____ Yes  
_____ No 
Initials  
  Initials 
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
We will keep your participation in this research study confidential to the extent permitted by law. 
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research.  Some of these 


 
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records could contain information that personally identifies you. 
• Government representatives, (including the Office for Human Research Protections) to 
complete federal or state responsibilities 
• The U.S. Food and Drug Administration 
• The sponsor, National Institute of Health 
•     GlaxoSmithKline (GSK), as required by law, to report adverse events associated with GSK   
 products to the FDA. 
• Pfizer, to report any severe adverse events associated with Pfizer products.  
• Hospital or University representatives, to complete Hospital or University responsibilities 
• Washington University’s Institutional Review Board (a committee that oversees the conduct 
of research involving human participants.) The Institutional Review Board has reviewed and 
approved this study. 
 
To help protect your confidentiality, all research information is coded, using an individualized I.D. 
number. Paper forms are kept locked in file cabinets in our locked office. Electronic files are password 
protected and stored on a secured Washington University, Department of Psychiatry Server. Blood 
samples will be stored at Rutgers University. Only members of the research team have access to your 
study information. We encourage you to password protect your phone during the course of this study 
so that others cannot go through your phone and see text messages that have been sent from the study.   
 
If we write a report or article about this study or share the study dataset with others, we will do so 
in such a way that you cannot be directly identified. 
 
We will disclose, to the proper authority, information you share with us concerning child abuse, 
child sexual abuse, or harming yourself or others. 
 
Are there additional protections for my health information? 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by 
federal law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in 
this research, you must give the research team permission to use and disclose (share) your PHI for the 
study as explained in this consent form.  The research team will follow state and federal laws and 
may share your health information with the agencies and people listed under the previous section 
titled, “How will you keep my information confidential?” 
 
Once your health information is shared with someone outside of the research team, it may no longer 
be protected by HIPAA. 
 
The research team will only use and share your information as talked about in this form or as 
permitted or required by law.  When possible, the research team will make sure information cannot be 
linked to you (de-identified).  Once information is de-identified, it may be used and shared for other 
purposes not discussed in this consent form.  If you have questions or concerns about your privacy and 
the use of your PHI, please contact the University’s Privacy Officer at 866-747-4975. 
 
Although you will not be allowed to see the study information, you may be given access to your 
health care records by contacting your health care provider. 


 
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If you decide not to sign this form, it will not affect 
• your treatment or the care given by your health provider. 
• your insurance payment or enrollment in any health plans. 
• any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
• You authorize the use of your PHI for this research 
• This authorization does not expire. 
• You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization). 
 
• To revoke your authorization, complete the withdrawal letter, found in the Participant 
section of the Human Research Protection Office website at 
http://hrpo.wustl.edu/participants/withdrawing-from-a-study/ or you may request that the 
Investigator send you a copy of the letter. 
o If you revoke your authorization: 
▪ The research team may only use and share information already collected for 
the study. 
▪ Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s withdrawal 
from the research study or for safety reasons. 
▪ You will not be allowed to continue to participate in the study. 
 
Can we contact you by text? 
We would like to contact you by text message for the purposes listed below.   
• Appointment and phone call reminders 
 
Only the research team will have access to your texting communications.  We will only communicate by 
text to send you the information listed above.  If you have any questions or need to contact us for an 
urgent or emergent situation, please contact the research team member identified at the top of this 
document.  
 
You should be aware that there are risks associated with allowing us to text you for the purposes of this 
study.   
• There is always a risk that the text message could be intercepted or sent to the wrong 
telephone number. To avoid sending messages to the wrong number, the first text we send 
you will be a test message to ensure we have the correct telephone number. 
 
Do you agree to allow us to send your appointment and phone call reminders via text?   
 
Yes_____        No______ 
       Initials                Initials 
 
 


 
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IS BEING IN THIS STUDY VOLUNTARY? 
Taking part in this research study is completely voluntary. You may choose not to take part at all. If 
you decide to be in this study, you may stop participating at any time. Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed.  
If you decide not to be in this study, or if you stop participating at any time, you won’t be penalized or 
lose any benefits for which you otherwise qualify. 
 
What if I decide to withdraw from the study? 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter.  A sample withdrawal letter can be found at 
http://hrpo.wustl.edu/participants/ under Withdrawing from a Research Study. 
 
Will I receive new information about the study while participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can someone else end my participation in this study? 
Under certain circumstances, the researchers might decide to end your participation in this research 
study earlier than planned. This might happen because you have severe adverse effects from the 
medication and the study does not seem to be helping you. For safety, it may be in your best interest to 
allow follow-up outside the study. This decision would be made in consultation with the study physician. 
 
WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions. If you have any questions about the research study itself, 
please contact the research coordinator, Nina Smock, at (314) 362-1854. If you experience a 
research- related injury, please contact Dr. Li-Shiun Chen, at (314) 362-3932. 
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office, 660 South Euclid Avenue, Campus Box 8089, St. Louis, MO  
63110, or 1-(800)-438-0445 or email hrpo@wustl.edu.   General information about being a research 
participant can be found on the Human Research Protection Office web site, http://hrpo.wustl.edu.  To 
offer input about your experiences as a research subject or to speak to someone other than the research 
staff, call the Human Research Protection Office at the number above. 
 
 
This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study. 
As a participant you have rights and responsibilities as described in this document and including: 
• To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
• To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
• To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 
• To give the research team accurate and complete information. 
• To tell the research team promptly about any problems you have related to your participation, or 


 
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if you are unable to continue and wish to stop participating in the research study. 
 
Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: EXPIRATION DATE: 02/25/20. 
 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that he or she understands 
the risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed)