Conditions: Smoking Cessation Smoking Behaviors Smoking
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
The goal of this study is to assess varenicline vs. placebo for its effect on decreasing cue reactivity in light and intermittent smokers.

Detailed description:
The study will consist of randomization to receive either varenicline or placebo over 6 weeks and include 5 study visits. Participants are offered an optional additional 6 weeks of active varenicline. Cue reactivity will be assessed in both a lab-based setting (viewing series of images and rating cravings) and in a real-world setting (text-based daily interaction).

Arms:
arm 1: Varenicline BID arm 2: None

Interventions: intervention 1: Varenicline intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Chantix intervention 2: Placebo

Protocol document:
Prot_SAP_000.pdf: 
Version: 12/03/2019                                                       pg. 1 
Q-Pilot-Varenicline 
  
Pilot Study on  
Varenicline in Light and Intermittent Smokers  
 
A Supportive Care-Drug Intervention Study  
 
 
 
 
 
Sponsor-Investigator: 
 
Dr. James Davis – Duke Cancer 
Institute  
 
 
 
Funding Source: 
Duke Cancer Institute  
 
 
 
Protocol Source: 
Dr. James Davis - Duke Cancer 
Institute  
 
 
 
Duke IRB#: 
NCT ID: 
Pro00103506 
NCT04089982 
  
 
 
 
Principal Investigator 
James Davis, MD 
2424 Erwin Road, Suite 201, Durham, NC 
Phone: 919-668-5055 
Fax: 919-668-5088 
james.m.davis@duke.edu  
 
 
Statistician 
Carl Pieper PhD  
Carl.pieper@duke.edu 
 
 
Study Coordinator 
Leah Thomas 
leah.thomas@duke.edu 
  
 
 
 


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1. TABLE OF CONTENTS 
 
1. 
TABLE OF CONTENTS ....................................................................................................2 
2. 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY .....................................................5 
2.1. 
Purpose ....................................................................................................................5 
2.2. 
Background and Significance ..................................................................................7 
2.3. 
Design and Procedure .............................................................................................9 
2.4. 
Duration of study ..................................................................................................11 
2.5. 
Data Analysis and Statistical Considerations .......................................................12 
3. 
STUDY SCHEMA ..........................................................................................................13 
4. 
BACKGROUND AND SIGNIFICANCE ...........................................................................14 
4.1. 
Study Purpose/Rationale ......................................................................................14 
5. 
OBJECTIVES AND ENDPOINTS ....................................................................................14 
6. 
INVESTIGATIONAL PLAN ............................................................................................15 
6.1. 
Recruitment and Enrollment Procedures: ............................................................15 
6.2. 
Study/Treatment duration....................................................................................16 
6.3. 
Treatment- Medication .........................................................................................16 
6.4. 
Behavioral counseling ...........................................................................................17 
6.5. 
Cue Reactivity ........................................................................................................17 
6.6. 
Text-Based Assessment .........................................................................................17 
7. 
STUDY DRUG- DOSAGES ............................................................................................18 
7.2. 
Packaging and Labeling .........................................................................................19 
7.3. 
Supply, Receipt, and Storage ................................................................................20 
7.4. 
Dispensing and Preparation ..................................................................................20 
7.5. 
Disposal and Destruction ......................................................................................20 
7.6. 
Dose modification .................................................................................................20 
7.7. 
Safety considerations ............................................................................................20 
7.8. 
Missed doses .........................................................................................................20 
7.9. 
Concomitant medications/therapies....................................................................20 
7.10. Study drug blinding ...............................................................................................20 
7.11. Randomization ......................................................................................................21 
7.12. Rationale for Correlative Studies ..........................................................................21 
7.13. Definition of Evaluable Subjects, On Study, and End of Study ............................21 
7.14. Early Study Termination ........................................................................................21 
8. 
SELECTION OF SUBJECTS: ELGIBILITY .........................................................................21 
9. 
ASSESSMENTS AND PROCEDURES .................................................................22 
9.1. 
Overview of assessments......................................................................................22 
9.2. 
Screening Examination ..........................................................................................24 
9.3. 
Treatment Period ..................................................................................................26 
9.4. 
COMPENSATION ....................................................................................................27 
9.5. 
Study Assessments ................................................................................................28 
10. END OF TREATMENT ..................................................................................................31 
10.1. Follow-up Period ...................................................................................................31 
10.2. End of Study ...........................................................................................................31 
10.3. Early Withdrawal of Subject(s) .............................................................................32 
11. SAFETY MONITORING AND REPORTING ...................................................................32 


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11.1. Adverse Events ......................................................................................................32 
11.2. Serious Adverse Events .........................................................................................33 
11.3. Emergency Un-blinding of Investigational Treatment .........................................34 
11.4. Other Reportable Information ..............................................................................34 
11.5. Special Warnings and Precautions .......................................................................35 
11.6. Stopping Rules .......................................................................................................35 
11.7. Safety Oversight Committee (SOC) .......................................................................35 
11.8. External Data and Safety Monitoring Board (DSMB) ..........................................35 
12. QUALITY CONTROL AND QUALITY ASSURANCE ........................................................35 
12.1. Monitoring .............................................................................................................35 
12.2. Audits .....................................................................................................................36 
12.3. Data Management and Processing .......................................................................37 
13. STATISTICAL METHODS AND DATA ANALYSIS ..........................................................38 
13.1. Analysis Sets ..........................................................................................................38 
13.2. Patient Demographics and Other Baseline Characteristics .................................38 
13.3. Treatments ............................................................................................................38 
13.4. Primary Objective ..................................................................................................38 
13.5. Secondary Objectives ............................................................................................39 
13.6. Sample size estimation .........................................................................................39 
13.7. Exploratory Objectives ..........................................................................................40 
13.8. Interim AnalysEs ....................................................................................................40 
14. ADMINISTRATIVE AND ETHICAL CONSIDERATIONS .................................................40 
14.1. Regulatory and Ethical Compliance ......................................................................40 
14.2. DUHS Institutional Review Board and DCI Cancer Protocol Committee ............40 
14.3. Informed Consent ..................................................................................................41 
14.4. Study Documentation ...........................................................................................41 
14.5. Privacy, Confidentiality, and Data Storage ..........................................................42 
14.6. Data and Safety Monitoring..................................................................................43 
14.7. Protocol Amendments ..........................................................................................43 
14.8. Records Retention .................................................................................................43 
REFERENCES .......................................................................................................................44 
15. APPENDICES ...........................................................................................................51 
APPENDIX 1: EXCLUSIONARY MEDICATION .....................................................................51 
APPENDIX 2: DEMOGRAPHICS/CONTACT INFORMATION FORM ...................................52 
APPENDIX 3: SMOKING HISTORY QUESTIONNAIRE .........................................................54 
APPENDIX 4: SELF-EFFICACY/MOTIVATION .....................................................................57 
APPENDIX 5: PATIENT HEALTH QUESTIONNAIRE-952,53 ...................................................58 
APPENDIX 6: COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) .............................60 
APPENDIX 7: GENERALIZED ANXIETY DISORDER .............................................................61 
APPENDIX 8: ALCOHOL USE DISORDERS IDENTIFICATION TEST (AUDIT)54 .....................62 
APPENDIX 9: MEDICAL HISTORY .......................................................................................63 
APPENDIX 10: PHYSICAL EXAM/REVIEW OF SYSTEMS (ROS) .................................... 69-59 
APPENDIX 11: MINNESOTA NICOTINE WITHDRAWAL SCALE ..........................................71 
APPENDIX 12: FAGERSTRÖM TEST OF NICOTINE DEPENDENCE ......................................72 
APPENDIX 13: POSITIVE AND NEGATIVE AFFECT SCHEDULE (PANAS)67 .........................74 
APPENDIX 14: CENTER FOR EPIDEMIOLOGIC STUDIES DEPRESSION SCALE (CESD)68 .....75 
APPENDIX 15: PERCEIVED STRESS SCALE (PSS-4)69,70 .......................................................76 
APPENDIX 16: RECENT SMOKING QUESTIONNAIRE ........................................................77 
APPENDIX 17: MOOD AND PHYSICAL SYMPTOMS SCALE-2 (MPSS-2) ............................78 


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APPENDIX 18: MODIFIED CIGARETTE EVALUATION QUESTIONNAIRE (MCEQ)72 ...........79 
APPENDIX 19: QUESTIONNAIRE OF SMOKING URGES (QSU-BRIEF)73,74 .........................80 
APPENDIX 20: SMOKING AND MEDICATION USE75,76 ......................................................81 
APPENDIX 21: MEDICATION SIDE EFFECTS QUESTIONNAIRE ..........................................82 
APPENDIX 22: TEXT BASED MESSAGING ..........................................................................84 
APPENDIX 23: PHONE CALL FOLLOW-UP QUESTIONS .....................................................87 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
2.1. 
PURPOSE 
 
Product Name: Varenicline  
 
Development Phase: Phase 1  
 
Protocol Title:  Pilot Study on Varenicline in Light and Intermittent Smokers  
 
The overarching goal of this proposal is to assess varenicline with and without cue-extinction therapy for their effect on 
decreasing cue reactivity in light and intermittent smokers.  
 
Aim 1 - Cue Reactivity  
1. Lab-Based Cue Reactivity: To determine whether varenicline vs. placebo shows greater reduction in 
laboratory-based smoking cue reactivity assessed over multiple time points (baseline (4-weeks pre- target 
quit day(TQD)), 2-weeks pre-TQD, 1-week pre-TQD, and 2-weeks post-TQD).  Lab-based cue reactivity will be 
assessed at each visit through a laboratory based cue-reactivity assessment paradigm in which the 
participant is presented with blocks of visual images and after each block is asked to provide a self-report of 
cigarette craving.  
 
2. Real-World Cue Reactivity: To determine whether varenicline vs. placebo shows greater reduction of cue 
reactivity during “real-world” testing through daily text-based responses over the 6-week study period: 4 
weeks prior to the TQD and 2 weeks after the TQD.  Real world cue reactivity will be assessed each day 
through participant texting the study application. Participants will be asked to send a text after each 
cigarette they smoke, when they experience a craving, and at the end of each day.   
 
Aim 2 - Smoking Abstinence and Reduction  
3. Smoking Abstinence: To determine whether varenicline is more effective than placebo for achieving 7-day 
point prevalence smoking abstinence at the 2-weeks post-TQD day visit.  Abstinence will be defined as self-
report of no smoking for the last 7 days, CO breath test < 7 ppm, and salivary cotinine under 14 ng/ml.  
 
4. Smoking Reduction: To determine whether varenicline is more effective than placebo for smoking reduction 
over the 4-week pre-TQD smoking period and over the 2 week post-TQD period.  Smoking reduction will be 
assessed in three ways: 1. Daily end-of-the-day text messages in which participants provide a self-report of 
how many cigarettes they smoked that day (in addition to paper self-report diaries), 2. CO breath testing at 
each study visit, and 3. Salivary cotinine testing at each study visit.  
 
Aim 3 – Medication Adherence and Tolerability  
5. Adherence: To determine whether varenicline has acceptable adherence when compared to placebo in this 
population. Medication adherence will be measured using daily text-based assessment of medication use 
and paper self-report diaries.  
 


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6. Tolerability: To determine tolerability through participant self-report on an open-ended question on 
potential self-effects asked at baseline and at each study visit.  
 
Aim 4 - Moderators and Mediators (exploratory) 
 
7. Baseline Variables (Treatment Moderators):  To determine whether a variety of baseline variables (age, 
gender, sex, race, nicotine dependence, anxiety, depression, stress, baseline smoking enjoyment) are 
associated with differential treatment response between varenicline and placebo described within 
objectives 1-4.  For example, does age predict the capacity for varenicline to reduce cue reactivity as 
measured in a laboratory setting or real-world setting, or the capacity for varenicline to induce smoking 
abstinence or reduction.   
 
8. Cue Variables (Treatment Moderators): To determine whether a variety of experiential or environmental 
variables (stress level, frustration, anger, sadness, boredom, positive affect, social interaction, time of day, 
familiar smoking place, smells, visual stimuli, alcohol use) are associated with our primary the intensity of 
cue reactivity for a particular cue and with smoking on a particular day. The frequency and intensity 
reported on these variables will also be assessed as treatment moderators – i.e. for their association with 
objectives 1-4 (laboratory-based and real-world cue reactivity, smoking abstinence and reduction). 
 
9. Adherence (Moderator): To determine whether adherence to varenicline is associated with outcomes 
across multiple time points (2-weeks pre-TQD, 1-week pre-TQD, and 2-weeks post-TQD). Medication 
adherence will be measured using daily text-based questions and self-report diaries, and will be assessed for 
an association with objectives 1-4 (laboratory-based and real-world cue reactivity, smoking abstinence and 
reduction).   
 
10. Change in Reward (Mediators): To determine whether changes (baseline to each time point) in physical 
smoking satisfaction, pleasure from smoking or other forms of “smoking reward” are associated with 
differential treatment response in objectives 1-4 (laboratory-based and real-world cue reactivity, smoking 
abstinence and reduction).   
 
Hypotheses 
This protocol is hypothesis-supporting and hypothesis-testing.  
 
Aim 1 - Cue Reactivity  
1. Lab-Based Cue Reactivity: Varenicline vs. placebo will show a greater reduction in laboratory-based smoking 
cue reactivity assessed over multiple time points (baseline (4-weeks pre-TQD), 2-weeks pre-TQD, 1-week 
pre-TQD, and 2-weeks post-TQD).  Lab-based cue reactivity will be assessed at each visit through a 
laboratory based cue-reactivity assessment paradigm in which the participant is presented with blocks of 
visual images and after each block is asked to provide a self-report of cigarette craving.  
 
2. Real-World Cue Reactivity: Varenicline vs. placebo will show a greater reduction of cue reactivity during 
“real-world” testing through daily text-based responses over the 6-week study period: 4 weeks prior to the 
TQD and 2 weeks after the TQD.  Real world cue reactivity will be assessed each day through participant 
texting the study application. Participants will be asked to send a text after each cigarette they smoke, 
whenever they experience a craving, and at the end of each day.   
 
Aim 2 - Smoking Abstinence and Reduction  


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3. Smoking Abstinence: Varenicline vs. placebo will show higher 7-day point prevalence smoking abstinence at 
the 2-weeks post-TQD day visit.  Abstinence will be defined as self-report of not smoking for the last 7 days, 
CO breath test < 7 ppm, and salivary cotinine under 14 ppm.  
 
4. Smoking Reduction: Varenicline vs. placebo will show greater smoking reduction over the 4-week pre-TQD 
smoking period and over the 2-weeks post-TQD period.  Smoking reduction will be assessed in three ways: 1. 
Daily end-of-the-day text messages in which participants provide a self-report of how many cigarettes they 
smoked that day (in addition to paper self-report diaries), 2. CO breath testing at each study visit, and 3. 
Salivary cotinine testing at each study visit.  
 
Aim 3 – Medication Adherence and Tolerability  
5. Adherence: Varenicline will show acceptable adherence when compared to placebo in this population 
(adherence to varenicline will not be significantly lower than placebo). Medication adherence will be 
measured using daily text-based assessment of medication use and paper self-report diaries.  
 
6. Tolerability: Varenicline will show good tolerability (the total incidence of study related side effects will not 
be higher than placebo). Side effects will be measured by self-report in an open-ended question at baseline 
and at each study visit.  
 
Aim 4 - Moderators and Mediators (exploratory) 
 
7. Baseline Variables (Treatment Moderators):  A variety of baseline variables (age, gender, sex, race, nicotine 
dependence, anxiety, depression, stress, baseline smoking enjoyment) are associated with differential 
treatment response between varenicline and placebo described within objectives 1-4.  For example, does 
age predict the capacity for varenicline to reduce cue reactivity as measured in a laboratory setting or real-
world setting, or the capacity for varenicline to induce smoking abstinence or reduction.   
 
8. Cue Variables (Treatment Moderators): A variety of experiential or environmental variables (stress level, 
frustration, anger, sadness, boredom, positive affect, social interaction, time of day, familiar smoking place, 
smells, visual stimuli, alcohol use) are associated with our primary the intensity of cue reactivity for a 
particular cue and with smoking on a particular day. The frequency and intensity reported on these variables 
will also be assessed as treatment moderators – i.e. for their association with objectives 1-4 (laboratory-
based and real-world cue reactivity, smoking abstinence and reduction). 
 
9. Adherence (Moderator): We will explore whether adherence to varenicline is associated with outcomes 
across multiple time points (2-weeks pre-TQD, 1-week pre-TQD, and 2-weeks post-TQD). Medication 
adherence will be measured using daily text-based questions (in addition to paper self-report diaries) and 
will be assessed for an association with objectives 1-4 (laboratory-based and real-world cue reactivity, 
smoking abstinence and reduction).   
 
10. Change in Reward (Mediators): We will explore a whether changes (baseline to each time point) in physical 
smoking satisfaction, pleasure from smoking or other forms of “smoking reward” are associated with 
differential treatment response in objectives 1-4 (laboratory-based and real-world cue reactivity, smoking 
abstinence and reduction).   
 
 
 
2.2. 
BACKGROUND AND SIGNIFICANCE 
 
1. Overarching Aim: The overarching aim of this study is to improve our understanding of the neurobehavioral 
mechanisms among smokers who are driven to smoke primarily by conditioned cues rather than nicotine withdrawal. 


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Heavy smokers appear to smoke due to nicotine withdrawal and also cues, whereas light and intermittent smokers (LITS) 
appear to smoke primarily due to cues.1 Heavy smokers commonly experience nicotine withdrawal symptoms an hour or 
two after smoking each cigarette, and smoke regularly throughout the day to avoid withdrawal symptoms.2 On the other 
hand, LITS (≤10 cigarettes per day or on some days) typically do not experience nicotine withdrawal, and thus, primarily 
smoke in response to smoking cues (cue-based smoking).3 The neurobiological basis of cue-based smoking is “cue 
reactivity,” a desire to smoke in response to smoking cues.4 This is initially learned by pairing smoking cues with smoking 
(nicotinic reward), and is maintained through repeated pairing of smoking cues and smoking.4 A number of medications 
have been used to help LITS quit smoking but mostly none have not been successful.5 One promising mechanistic 
pathways through which we may be able to decrease cue reactivity in LITS is nicotinic receptor antagonism - blocking 
nicotinic reward during smoking should decrease cue reactivity. Varenicline blocks nicotinic receptors and is known to 
decrease nicotinic reward.6 Thus, in this study we will assess the effects of varenicline on changes in cue reactivity in 
LITS.  
 
2. There is a need for effective treatment for light smoking. As we work toward eliminating tobacco use, we need to 
assess and develop strategies that meet the needs of our current population of smokers. In the past, the smoking 
population was dominated by heavy smokers, but many heavy smokers have now quit or reduced their smoking such 
that the majority of smokers today can be classified as either light daily smokers (smoking ≤ 10 cigarettes per day) or 
non-daily/intermittent smokers (smoking ≤ 10 cigarettes non-daily/intermittently).7,8  Compared to non-smokers, 
smoking even one cigarette per day, whether daily or less, increases the risk of morbidity and mortality by nearly 
50%.1,9–13 The motivations for smoking are different for light or intermittent smokers (LITS) than for those that are 
smoking more heavily. Heavy smokers typically experience nicotine withdrawal throughout the day and smoke regularly 
to avoid withdrawal symptoms.1 The half-life of nicotine is roughly 2 hours,2 and those who experience nicotine 
withdrawal, such as heavy smokers, tend to smoke every 1-2 hours while awake to maintain sufficiently high serum 
nicotine in an attempt to avoid withdrawal symptoms. Heavy smokers also respond to smoking cues (cue reactivity), 
such that when a smoking cue arises they will often smoke an additional cigarette to overcome the cue-associated 
craving.14,15 On the other hand, LITS typically do not experience significant nicotine withdrawal symptoms during periods 
of smoking abstinence.7,16,17 As a result, LITS do not smoke throughout the day to avoid withdrawal symptoms but 
instead smoke primarily in response to smoking cues.16,18 Dr. Saul Shiffman posited a “two-factor model” in which two 
factors primarily motivate smoking: 1) avoidance of nicotine withdrawal, and 2) in response to smoking cues.18 In this 
model, cues might be sensory (sight or smell of tobacco), social (interaction with a friend who smokes), affective (both 
negative and positive emotions), associative (always smoke with coffee), or contextual (situations in which multiple cues 
are present).18 Interestingly, cue-induced craving for nicotine in LITS is just as intense as it is in heavy smokers.18 
Accordingly, when LITS smoke due to cues, nicotine levels achieved are just as high as in heavy smokers,19 and have 
almost as much difficulty quitting smoking as do heavy smokers.18,19  
 
3.  The disease population:  Smoking is the leading  cause of preventable morbidity and mortality in the US.8,9  Smoking 
causes 480,000 deaths per year10 and is the cause of 28.6% of all cancer-related deaths.20 Perhaps more striking is that 
for every death caused by smoking, 30 smokers will live with a severe smoking related illness, including lung disease, 
heart disease, peripheral vascular disease, stroke, thromboembolic disease, diabetes, bone fractures, cataracts, 
dementia, and developmental disorders.8 Additionally, the financial costs of smoking to society are calculated to be over 
$300 billion per year.8,21,22 As evidence grows in support of the magnitude of health impacts of smoking, we in the health 
profession are faced with a growing urgency to provide effective treatments for nicotine dependence. Historically, 
population-based smoking cessation treatment has involved major drives to inform the public of the harms of smoking. 
Today, allied health professions are uniformly trained to ask about smoking, advise smokers to quit, and refer to 
effective treatment.23 Efforts such as these have resulted in a decrease in US smoking rates from 42.7% in 1964, at the 
time of the Surgeon General’s first report, to 15.5% as of 2016.8,11,24,25 However, with a decrease in smoking rates over 
the last 50 years, there has been a major shift in the characteristics of smokers who comprise the US smoking population 


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today. Today, smoking occurs primarily among people with low education, low income, and high rates of psychiatric and 
substance abuse disorders (approximately 40% of smokers have a mental illness).8,26–28 In fact, those who do not 
complete high school are now 9 times more likely to smoke than those who complete high school.26 Education, income, 
and mental illness are all significant barriers to successful smoking cessation treatment.29–31 Today’s smoker has a 
success rate for unassisted quit attempts of only 3-5%32 and may require as many as 30 unassisted quit attempts before 
successfully quitting.33 Together, the high morbidity and mortality of smoking, new barriers, and the low success rate of 
unassisted quit attempts, have created an ethical mandate within the healthcare field for more effective, evidence-
based smoking cessation treatment.  
 
4.  Why the stated objectives of the research are important:  Smoking cessation medications that are effective for 
reducing withdrawal in heavy smokers34,35 have been relatively ineffective for treatment of light smokers.7,36 The nicotine 
patch, a full agonist at the nicotinic acetylcholine receptor, reliably decreases nicotine withdrawal symptoms and 
reduces the frequency of smoking urges associated with smoking abstinence.37 A study on light daily smokers (5-10 
cigarettes per day) showed 6-month post-quit abstinence rates of 40% when taking varenicline vs. placebo (21%).38  This 
study sample (those who smoke 5-10 cigarettes/day) represents the heaviest of the light and intermittent smoking 
category. At the higher end (e.g. 5-10 cigarettes per day) of the light smoking continuum, individuals are more likely to 
experience and respond to a medication that reduces withdrawal symptoms.39 In summary, studies on pharmacologic 
treatment of LITS have shown very little success except for varenicline which has only been tested in LITS who use 5-10 
cigarettes per day. 
 
5.  The rationale for performing this research: A novel approach to pharmacotherapy in LITS is targeting cue-based 
smoking through the use of varenicline. Varenicline has been found to decrease reward during cue exposure in 
humans40 and studies have demonstrated that administration of varenicline decreases cue-based nicotine self-
administration in low self-administering nicotine-dependent rats.41,42  This suggests that a similar strategy might be 
successful in human light smokers.  
 
2.3. 
DESIGN AND PROCEDURE  
Treatment study: This study is designed to assess laboratory based and real world cue reactivity as well as smoking 
reduction and abstinence in LITS using varenicline vs. placebo over a 6-week period.  The study design will be a 2-arm 
randomized, placebo-controlled trial on a sample of 12 light and intermittent smokers (LITS). Randomization groups will 
be to treatment with varenicline vs. placebo. This study will consist of a screening visit and the following 4 study visits:  
Visit 1: Baseline - 4 weeks pre-TQD 
Visit 2: 2 weeks pre-TQD  
Visit 3: 1 pre-TQD 
Visit 4: 2 post-TQD 
The primary outcome will be cue reactivity measured in a laboratory setting, and in a real world setting through text-
based response. Secondary outcomes will include smoking abstinence at 2-weeks post-TQD, smoking reduction across 
the 6-week study, and medication adherence and tolerance. The study will also provide exploratory assessments of 
moderators (individual variables, cue-based moderators, and smoking reward as a potential mediator. The study sample 
will consist of LITS (≤10 cigs/day) who smoke a minimum of 4 cigarettes per month and a maximum of 10 cigarettes per 
day. Participants will be randomized with 1:1 allocation to two arms (varenicline vs placebo), with 6 participants in each 
arm. Participants who pass screening will be randomized and receive study medication at their baseline visit (4 weeks 


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prior to the TQD). The following outline procedures for cue reactivity testing in a laboratory and real-world setting and 
testing of smoking abstinence and reduction:  
 
Laboratory-Based Cue Reactivity: At each study visit, participants will be tested for cue reactivity in a lab-based 
paradigm. This will be assessed through a cue exposure test in which participants provide a report of their craving level 
after exposure to each block of images/pictures. They will also be exposed to smoking paraphernalia (lighters, 
cigarettes) prior to image blocks. More information can be found in section 6.5.  
 
Real-word Cue Reactivity: Every day throughout the 6-week study period information will be collected through the 
following text-based situations: 1. Text “S” when they smoke a cigarette and answer several text-based questions, 2. 
Text “C” when they experience a craving and answer several text-based questions, and 3. At the end of the day 
(9:00PM), they will receive a text asking how many cigarettes they smoked that day and whether they took their 
morning and evening medications. See section 6.6 for more information and Appendix 22 for text message 
questions/prompts.  
 
Behavioral treatment: At the baseline visit, all participants will receive 20 minutes of smoking cessation counseling 
including standard smoking cessation materials from the Quit at Duke Smoking Cessation Program.  
 
Smoking Abstinence: 7-day point prevalence abstinence will be measured at the 2-weeks post-TQD study visit by self-
report of not smoking for the last 7 days, a CO under 7 ppm, and salivary cotinine < 14 ng/ml.   
 
Smoking reduction: Change in smoking from baseline to 2-weeks post-TQD will be assessed in 3 ways: 1. By self-report 
through daily text-based assessments of cigarettes per day and paper diaries, 2. By CO assessed at each study visit, and 
3. Salivary cotinine assessed at each study visit.  
 
Varenicline Extension: All participants who attend the final study visit (2-weeks post-TQD) will be offered an additional 6 
weeks of varenicline. This will be provided to all participants regardless of their study allocation status. There are 
multiple reasons for this: 1. To provide evidence-based treatment to all participants, 2. To encourage those who might 
suspect they are on placebo to continue on until the final study visit, and 3. To provide a full 12 weeks of treatment for 
those who are on varenicline (standard of care). This will be up to the participants discretion and is not required.  
 
Phone-based follow-up: Phone-based follow-up will occur at the below intervals: 
 
Call 1- After Baseline Visit: A phone follow-up will occur 2-5 days after the participant starts taking their 
medication to ensure that they are taking the medication correctly and to see if there are any initial side effects. 
A self-report of smoking (cigarettes/day) will also be collected. If there are side effects, a study medical provider 
will call them to follow-up and make any necessary dosage changes.  
 
 


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Call 2- 1-Week Post-TQD: A phone follow-up will occur 1 week after their TQD to ensure that they are taking the 
medications correctly, see if there are any side effects, and to assess self-report of smoking (cigarettes/day). If 
there are side effects, a study medical provider will call them to follow-up and make any necessary dosage 
changes. 
 
Call 3- After Final Study Visit (No Varenicline Extension): A phone follow-up will occur 2-5 days after the 
participant stops taking their medication to asses for any residual side effects. If there are side effects, a study 
medical provider will call them to follow-up and make any necessary recommendations. They will be asked to 
provide a self-report of smoking (cigarettes/day).  
 
OR 
 
Call 3- After Final Study Visit (Varenicline Extension): A phone follow-up will occur 2-5 day after the participant 
starts taking the medication to ensure that they are taking the medication correctly, to assess for any side 
effects, and to obtain a self-report of smoking (cigarettes/day). If side effects are reported, the study medical 
provider will call the participant and make necessary recommendations or dosage adjustments.  
 
Call 4- 9-Week Follow-up Call (Varenicline Extension): A phone follow-up will occur at 5-weeks post-TQD (3 
weeks after starting varenicline extension). This call will be to ensure that they are taking the medication 
correctly, assess for side effects, and obtain self-reported smoking (cigarettes/day). If there are side effects, a 
study medical provider will call them to follow-up and make any necessary dosage changes. 
 
 
Call 5- After Varenicline Extension (Varenicline Extension): A phone follow-up will occur 2-5 days after the end 
of the 6-week varenicline extension period (8-weeks post- TQD) to see if they are any residual side effects from 
taking the medication. A self-report of smoking (cigarettes/day) will also be collected. If there are side effects, a 
study medical provider will call them to follow-up and make any necessary dosage changes.   
 
 
2.4. 
DURATION OF STUDY  
Timeline (Table 1): The proposed study will be conducted over a 7-month period, with 2 months of preparation and 4 
months for recruitment/study implementation, and 1 month to assess outcomes.  
 
Table 1. Study Calendar 
6 months 
Stage 1  
(2 months) 
Aug 15- October 15 
Stage 2  
(3 months)  
Oct 15, 19 - January 1, 20  
Stage 3  
(2 weeks)  
January 1-15 20 
Staff Training  
 
 
 
IRB Approval/Database Build  
 
 
 
Recruitment + Enrollment  
 
 
 
Treatment  
 
 
 


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Analyze Study Outcomes 
 
 
 
 
2.5. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS   
Statistical approach: general considerations. All analyses will follow an intent-to-treat approach with two-tailed tests 
and alpha = 0.05. Given repeated observations across multiple individuals and time points, many of the analyses in this 
study will be estimated by multilevel modeling (MLM) as implemented under mixed models.43 MLM hierarchically 
organizes data as a function of person-specific variables and time-point specific variables. Unlike repeated-measures 
ANOVA, MLM is able to derive estimates with non-normal, including binary, distributions and unequal variances across 
time points and individuals, and, importantly, in the presence of missing values.44,45 In addition to modeling between-
person differences, MLM is also able to model within-person variables that change over time. Results will be described 
as means and standard deviations (or, medians and interquartile ranges if there are outliers or skewed data). Initially, for 
hypothesis testing, we will assess the distribution of the outcomes, and, if necessary, attempt to transform the response 
variable to bring about approximate normality of the distribution.  In our initial analysis, we will test for a Group x Time 
interaction in the outcome.  
 
Missing data. Because MLM procedures are based on maximum likelihood estimation and use all available data, 
MLM can accommodate missing data when the missing values are assumed to be missing at random.44,45 Missing 
data will be examined to determine whether they can be defined as missing at random (MAR), which will give 
unbiased estimates of effect size. Often in smoking studies, missing values will be due to drop-out or other 
forms of treatment ‘failure’ which cannot be analyzed as MAR. To account for this, we will assume MAR to 
estimate group effects, to provide a conservative bound on effect size, but include missing values for drop-outs 
or other forms of treatment failure set to the worst response in the effect determination. 
 
Power analysis.  At a simple level, the primary comparison is the between group difference in change in the outcome. 
Assuming a level alpha (two-tailed) of 0.05, equal variances between the groups, then, at power of 80% and 90%, our 
design can detect a standardized difference (difference in mean/SD) in the change between the groups of 0.74 and 0.85 
respectively. Effect sizes of this magnitude have been labeled as ‘large’ in the power analysis literature.46 Because we are 
using techniques similar to Dr. Shiffman, we will refer to his study,16 whose supplemental materials show in increase in 
craving after exposure to lab-based smoking cues in non-daily smokers from 16.49 (SD=15.13) to 19.19 (SD=16.10). If 
these estimates hold (SD=15.5), the between group difference detectable is 11.56 (=0.74*15.5). Use of the mixed model 
with interim data points, and control for baseline, should provide an estimated effect with smaller variance, and, hence, 
reduced effect size detectable, and greater power. 
 
Secondary outcomes. Smoking behavior will be assessed via recent smoking CO breath testing, and saliva cotinine 
testing by comparing baseline measurements to later time points. This will allow us to determine whether there is 
a greater decrease in smoking in groups from each study group vs. control. These outcomes will be analyzed by 
mixed models to allow for change over time by person in the individual outcome. We have pre- specified these 
and other secondary outcomes to be analyzed, and at the project’s end we will have a rich database to conduct 
other exploratory analyses. These outcomes are exploratory and correlative, and as such will not adjust for Type-I 
error in these analyses. Rather, any resulting publication will contain a statement of the exploratory nature of the 
findings, warn of the multiple testing issue, and note a requirement for replication. 
 


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3. STUDY SCHEMA  
 
 


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4. BACKGROUND AND SIGNIFICANCE 
4.1. 
STUDY PURPOSE/RATIONALE 
The overarching aim of this study is to improve our understanding response to varenicline among smokers who are 
driven to smoke primarily by conditioned cues rather than nicotine withdrawal. Heavy smokers appear to smoke due to 
nicotine withdrawal and also cues, whereas light and intermittent smokers (LITS) appear to smoke primarily due to 
cues.1 Heavy smokers commonly experience nicotine withdrawal symptoms an hour or two after smoking each 
cigarette, smoke regularly throughout the day to avoid withdrawal symptoms.2 On the other hand, light and intermittent 
smokers (<10 cigarettes per day or on some days) typically do not experience nicotine withdrawal, and thus, primarily 
smoke in response to smoking cues (cue-based smoking).3 The neurobiological basis of cue-based smoking is “cue 
reactivity”- a desire to smoke in response to smoking cues is initially learned by pairing smoking cues with smoking 
(nicotinic reward), and is maintained through repeated pairing of smoking cues and smoking.4 A number of medications 
have been used to help LITS quit smoking but mostly none have not been successful.5 One promising mechanistic 
pathways through which we may be able to decrease cue reactivity in LITS is nicotinic receptor antagonism - blocking 
nicotinic reward during smoking should decrease cue reactivity. Varenicline blocks nicotinic receptors and is known to 
decrease nicotinic reward.6 Thus, in this study we will assess the effects of varenicline on changes in cue reactivity in 
LITS.  
 
5. OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoint 
Analysis 
Primary (1)  
 
Lab-Based Cue Reactivity: To determine 
whether varenicline vs. placebo shows 
greater reduction in laboratory-based 
smoking cue reactivity.   
This will be assessed over all study visits: (Baseline (4-weeks pre-
quit), 2-weeks pre-quit, 1-week pre-quit and 2-weeks post-quit).  
Lab-based cue reactivity will be assessed at each visit through a 
paradigm in which the participant is presented with blocks of 
visual images and after each block is asked to provide a self-
report of cigarette craving. 
See 
Section 
13.4 
Secondary (2) 
Real-World Cue Reactivity: To determine 
whether varenicline vs. placebo shows 
greater reduction of cue reactivity during 
“real-world” testing.  
This will be assessed through daily text-based responses over the 
6-week study period. Real world cue reactivity will be assessed 
each day through participant texting the study application.  
Participants will be asked to send a text after each cigarette they 
smoke, when they experience a craving, and at the end of each 
day.   
See 
Section 
13.5 
Secondary (3)  
Smoking Abstinence: To determine whether 
varenicline is more effective than placebo 
for achieving 7-day point prevalence 
smoking abstinence at the 2-weeks post-
TQD day visit.  
Abstinence will be defined as self-report of not smoking for the 
last 7 days, CO breath test < 7 ppm, and salivary cotinine under 
14 ng/ml.  
See 
Section 
13.5 
Secondary (4)  
Smoking Reduction: To determine whether 
varenicline more effective than placebo for 
smoking reduction over the 4-week pre-TQD 
smoking period and over the 2 week post-
TQD period.   
Smoking reduction will be assessed in three ways: 1. Daily end-
of-the-day text messages in which participants provide a self-
report of how many cigarettes they smoked that day (in addition 
to paper self-report diaries), 2. CO breath testing at each study 
visit, and 3. Salivary cotinine testing at each study visit. 
See 
Section 
13.5 
Secondary (5) 
Adherence: To determine whether 
varenicline has acceptable adherence when 
compared to placebo in this population.  
Medication adherence will be measured using daily text-based 
assessment of medication use and paper self-report diaries. 
See 
Section 
13.5 


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6. INVESTIGATIONAL PLAN 
6.1. 
RECRUITMENT AND ENROLLMENT PROCEDURES:  
 
Recruitment Sites: We plan to consent up to 30 participants and enroll/randomize 12 participants over a 3-month 
period. The study will take place at the Duke Center for Smoking Cessation.  
 
General Recruitment Strategies: We will conduct general recruitment through social media advertising and paper 
flyering.  
 
Recruitment through the Duke Smoking Cessation Program: The study will recruit through the Duke Smoking Cessation 
Program – a network of 12 specialized smoking cessation clinics each run by a Medical Provider and all overseen by Dr. 
Davis (Principal Investigator). All Duke Smoking Cessation Program providers are trained in on-going studies and assist in 
Secondary (6)  
Tolerability: To determine tolerability 
through participant self-report.  
Tolerability will be assessed through an open-ended question on 
potential self-effects asked at baseline and each study visit.  
See 
Section 
13.5 
Exploratory (7)  
Baseline Variables (Moderator):  To 
determine whether a variety of baseline 
variables (age, gender, sex, race, nicotine 
dependence, anxiety, depression, stress, 
baseline smoking enjoyment) are associated 
with differential treatment response 
between varenicline and placebo described 
within objectives 1-4.  
Baseline variables will be assessed through surveys conducted at 
baseline.  
See 
Section 
13.5 
Exploratory (8) 
Cue Variables (Moderator): To determine 
whether a variety of experiential or 
environmental variables (stress level, 
frustration, anger, sadness, boredom, 
positive affect, social interaction, time of 
day, familiar smoking place, smells, visual 
stimuli, alcohol use) are associated with our 
primary the intensity of cue reactivity for a 
particular cue and with smoking on a 
particular day.  
Cue variables will be assessed through text based questions sent 
to participants. The frequency and intensity reported on these 
variables will also be assessed as treatment moderators – i.e. for 
their association with objectives 1-4 (laboratory-based and real-
world cue reactivity, smoking abstinence and reduction). 
See 
Section 
13.5 
Exploratory (9) 
Adherence (Moderator): To determine 
whether adherence to varenicline is 
associated with outcomes across multiple 
time points (2-weeks pre-TQD, 1-week pre-
TQD, and 2-weeks post-TQD).  
Medication adherence will be measured using a text-based 
questions and will be assessed for an association with objectives 
1-4 (laboratory-based and real-world cue reactivity, smoking 
abstinence and reduction).   
See 
Section 
13.5 
Exploratory(10)  Change in Reward (Mediators): To 
determine whether changes (baseline to 
each time point) in physical smoking 
satisfaction, pleasure from smoking or other 
forms of “smoking reward” are associated 
with differential treatment response in 
objectives 1-4 (laboratory-based and real-
world cue reactivity, smoking abstinence 
and reduction).   
Smoking reward will be assessed at study visits through surveys 
designed to capture satisfaction, enjoyment, resolution of urge 
etc. related to smoking.  
See 
Section 
13.5 


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the recruitment of patients into studies (if patients are interested in research studies). All patients who do not 
successfully quit smoking after participating in a study are rescheduled with a Duke Smoking Cessation Program 
provider. This study would employ the use of nine Duke Smoking Cessation Program clinics (Duke Primary Care [DPC] 
Oxford, DPC Croasdaile, Duke Family Medicine, Duke Outpatient Clinic, Duke Private Diagnostic Clinic [PDC] - South 
Durham, PDC Brier Creek, PDC Raleigh, Asthma, Allergy, and Airway Center, and Duke Employee and Occupational 
Health and Wellness). Anyone who is referred for a clinic visit will have his or her medical record reviewed for research 
study eligibility. If they meet the eligibility criteria, then a research staff member will contact them via phone or MyChart 
message to see if they are interested. If interested, they are phone screened or asked to complete a REDCap screening 
survey, and then potentially scheduled for a screening visit. Individuals that have opted out of research via the medical 
record will not be contacted.  
 
Recruitment through the Duke Primary Care Research Consortium: Prior research conducted through our center has 
relied in part on the Duke Primary Care Research Consortium. This consortium oversees all research within Duke Primary 
Care: a network of over 30 clinics primarily around the Research Triangle Area. The consortium is primarily interested in 
whether studies offered to patients would provide safe and effective means for supporting or improving health 
outcomes. Duke Primary Care clinics serve a broad cross section of the community. Patients from the Duke Primary Care 
Research Consortium will be recruited from one of the 30 clinics. A study team member will conduct a query into the 
electronic health record through MaestroCare reports.  After identifying individuals who fall within our recruitment 
categories, we will directly contact these patients by MyChart message and/or telephone to offer them additional 
information about the research study (Duke’s Cold Call Policy).  
 
6.2. 
STUDY/TREATMENT DURATION 
The Target Quit Day (TQD) is defined as “Time Zero.” There are 4 visits after the screening visit: Baseline (4-weeks pre-
TQD), 2-weeks pre-TQD, 1-week pre-TQD, and 2-weeks post-TQD. Varenicline/placebo will begin 4 weeks prior to the 
TQD (at the baseline visit). Varenicline/placebo will continue for 2 weeks after the quit day. In total, participants will use 
study medication (placebo vs. varenicline) for 6 weeks. Participants who attend the final study visit (2-week post-TQD) 
will be offered an additional 6 weeks of varenicline (the varenicline extension).  Phone-based follow up will occur at 3 
time points:  2-5 days after baseline visit, 1 week after the TQD, and 2-5 days after the 2-week post-TQD visit. For those 
opting for the varenicline extension period, they will receive additional calls at 5-weeks post-TQD (3 weeks into the 
extension) and 2-5 days after the end of the varenicline extension period.  
 
6.3. 
TREATMENT- MEDICATION 
Double Blind Design: The study is double-blinded such that participants, research assistants, and study medical 
providers (each of whom have contact with participants) are unaware of group allocations. Pill bottles provided to 
participants will feature generic research labels (Medication X vs. Medication Z) through the pharmacy at Duke’s 
Investigational Chemotherapy Services (ICS). The Clinical Research Coordinator (CRC), who oversees operations and has 
no contact with participants, will be aware of participant group allocation. Varenicline Extension: Participants who 
attend the 2-week post-TQD visit and opt to receive 6 additional weeks of varenicline will be provided with additional 
medications marked “varenicline” regardless of randomization status. Randomization status will not be broken prior to 
the varenicline extension.   
 
Medication Distribution and Initiation: After randomization at the baseline visit, participants will be given one of the 
following medications based on allocation status: varenicline vs. placebo. Both medications will look the same. 
Medications and placebo will be given twice daily for a total of 6 weeks, with a ramp up period for the first week (see 


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Section 7). The first dose of medication will be given 4-weeks prior to the TQD.  Participants will be provided with 
medication instructions (verbal and written), including the day on which they should start taking their medications. 
Participants will be asked to keep medication dispensing journals and smoking diaries. This will be confirmed/reviewed 
at subsequent study visits. Total length of medication use will be 6 weeks within the randomized protocol.  Varenicline 
Extension: Participants who attend the 2-week post-TQD visit and opt to receive the additional 6 weeks of varenicline 
will receive medication marked “varenicline” regardless of randomization status.  Randomization status will not be 
broken prior to the varenicline extension. Varenicline will be given twice daily for a total of 6 weeks, with a ramp up 
period during the first week of the varenicline extension period.  
 
Packaging of Medications:  See section 7.2.  
 
 
6.4. 
BEHAVIORAL COUNSELING 
Counseling: At the screening visit, participants will receive 20 minutes of smoking cessation counseling using evidence-
based quit smoking methods and materials used in the Duke Smoking Cessation Program.47 A review of instructions for 
the quit day, including having their last cigarette up to midnight the night prior to the quit day will be provided. Quit day 
preparation will include information on how to remove cigarettes from their house, and that abstaining from heavy 
alcohol or drug use is recommended. The counseling session will also include an exploration of individual motivations for 
quitting, reasons for relapse in the past, smoking triggers, and simple strategies for managing urges. A one-page handout 
will be provided, highlighting key points from the counseling session, and participants will be offered the Quit at Duke 
Smoking Cessation Program.   
 
Reason for Brief Counseling:  It is considered standard-of-care to receive evidence-based counseling together with 
pharmacotherapy.47 For this study, counseling is administered at the Baseline visit to provide guidance for quitting 
smoking. 
 
6.5. 
CUE REACTIVITY 
Participants will sit in a comfortable chair in front of a computer screen and will be presented with series of images 
(“blocks”) adapted from the International Affective Picture System (IAPS), a database of standardized images known to 
elicit attention, emotion, and smoking urges.48,49  Image blocks will fall into four categories: A) Neutral; B) Proximal 
Smoking (e.g., cigarettes, ashtrays); C) Social Smoking (e.g., people smoking); and D) Unpleasant (e.g., crime scenes, 
disfiguring injuries).  Neutral image blocks will serve as attentional controls to assess differential response from control 
images to smoking or affective images. Following each block, participants will be asked to provide ratings (0-10) of 
craving intensity. Blood pressure and heart rate will also be taken. Additionally, participants will also be exposed to in 
vivo cues by following instructions to touch/hold/smell smoking paraphernalia, including cigarettes, ashtrays, and 
lighters. There will be 3 blocks of 4 image sets presented, taking a total of 17 minutes.  
 
6.6. 
TEXT-BASED ASSESSMENT 
We will ask participants to interact with a text-based program every day throughout the 6-week study period. There will 
be three triggers for text-based interaction:  1. When the participant smokes a cigarette, they will send a text “s” to the 
text-based program, which will trigger a serious of questions, 2. When the participant feels craving to smoke a cigarette, 
they will send a text “c” to the text-based program, which will trigger a serious of questions, and 3. At the end of the 


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day, the program will send a question on number of cigs smoked that day and medication adherence. Samples of the 
text prompts/questions can be found in Appendix 22.  Participants will be instructed not to text while driving and only to 
text when it is safe to do so. This is the same texting program approved for use in Pro00089760.  Specifically, this 
protocol uses the same text-based questions, the same database format, the same operational program, and data safety 
measures, and is run by the same group of people for the same type of subjects (light smokers).  If participants are noted 
to not be utilizing the text-based system, research study staff will call them via phone after 2 days of non-
responsiveness.  
 
 
7. STUDY DRUG- DOSAGES 
The standard dose of varenicline is 1 mg BID50  and is known to be well tolerated. 
Varenicline or Placebo will be taken twice daily taken for 6 weeks, starting 4 weeks prior to the quit day and for 2 weeks 
after the quit day (6 weeks total).  
 
Varenicline 
The dose will be increased during week 1. 
• 
Varenicline 0.5 mg, each morning x 3 days, then  
• 
Varenicline 0.5 mg BID x 4 days, then  
• 
Varenicline 1.0 mg BID x 5 weeks  
 
Placebo:   
Information on drug structure, formulation, and manufacturing will be provided by Central Compounding, and 
distributed by the Investigative Chemotherapy Services (ICS).  
 
Varenicline Extension (for participants who attend the 2-week post-quit visit): 
• 
Varenicline 0.5 mg, each morning x 3 days, then  
• 
Varenicline 0.5 mg BID x 4 days, then  
• 
Varenicline 1.0 mg BID x 5 weeks  
 
7.1.1. 
 DRUG MECHANISM OF ACTION 
From FDA: “Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The 
efficacy of CHANTIX in smoking cessation is believed to be the result of varenicline’s activity at a sub-type of the nicotinic 
receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to α4β2 
receptors. Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to 
α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower 
level than nicotine. Varenicline blocks the ability of nicotine to activate α4β2 receptors and thus to stimulate the central 
nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward 
experienced upon smoking. Varenicline is highly selective and binds more potently to α4β2 receptors than to other 
common nicotinic receptors (>500-fold α3β4, >3500-fold α7, >20,000-fold α1βγδ), or to non-nicotinic receptors and 
transporters (>2000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.”50 


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7.1.2. 
RATIONALE FOR USE OF STUDY DRUG IN THIS PARTICULAR SUPPORTIVE CARE CONTEXT 
Rational for Design: A randomized controlled comparative design is important for this study because it establishes a 
comparison between each component and its comparator - varenicline vs. placebo.   
 
7.2. 
PACKAGING AND LABELING 
Blinded study drug(s) will be provided in bottles to the Investigational Chemotherapy Services (ICS) Pharmacy.  All 
medications will be labeled according to Investigational Chemotherapy Service (ICS) Standard Operating Procedures to 
include at least: drug name/strength (with neutral language accounting for the blind/active-control), quantity, lot 
number, bottle number, expiration or retest date, IRB protocol number, and “for investigational use only.”  Placebo 
medications will be provided in non-descript packaging, similarly to non-placebo medications. 
   
Investigational Chemotherapy Service - Duke Cancer Institute 
(919) 668-0657 
Patient: ________________________________ 
Take 1 capsule, twice daily as directed (modified for ramp up period).  
Varenicline 1mg OR Placebo (see dispensing schedule below)  
Protocol number (Duke IRB PRO########) 
Bottle # (unique number for tracking) 
Dr. James Davis 
Return bottles to pharmacy 
Disp:                                                             Do not use after:___________ 
Caution: New Drug-Limited by Federal (United States) Law to Investigational Use Only 
 
Medication Dispensing Schedule 
 
Baseline Visit: Dispense 3 weeks of medication (varenicline vs. placebo): 1-week start up package (escalating dose) plus 
2 weeks of continuation treatment (1 mg BID). 
 
2-weeks pre-TQD Visit: Dispense 4 weeks of Medication (varenicline vs. placebo): 3 weeks of continuation treatment (1 
mg BID) plus on additional week (1 mg BID; in case of rescheduling).  
 
2-week post-TQD Visit: If requested, dispense 6 weeks of Varenicline: 1-week start up package (escalating dose) plus 5 
weeks of continuation treatment (1 mg BID). 
 


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7.3. 
SUPPLY, RECEIPT, AND STORAGE 
The Investigational Chemotherapy Services (ICS) Pharmacy will be responsible for receiving, storing, and inventorying 
the study drug(s) according to its Standard Operating Procedures.  
 
7.4. 
DISPENSING AND PREPARATION 
All study medications will be dispensed by the Investigational Chemotherapy Services (ICS) pharmacy. ICS will maintain 
detailed dispensation logs. Study staff will pick up medication orders prior to study visits. Once received, internal drug 
dispensation logs will be kept to ensure tracking of pill bottles.  
 
7.5. 
DISPOSAL AND DESTRUCTION 
Unused study drugs will be returned to the ICS for disposal/destruction.  
 
7.6. 
DOSE MODIFICATION 
If side effects from this drug are observed and determined to be minor, the medication dosing may be changed with the 
evening dose either moved earlier in the day or eliminated.   
 
7.7. 
SAFETY CONSIDERATIONS 
At each visit and follow-up phone call, we will also ask participants about the presence of side effects of any kind.  If 
participants are found to have side effects of any kind, they will be recorded and will be assessed by the study medical 
provider to determine severity, whether it may have been caused by the drug, and whether it requires dose adjustment 
or discontinuation of the drug.   
 
7.8. 
MISSED DOSES 
Missed doses of medications will not be replaced. There will be no “catch up” for missed doses. We will capture data on 
missed doses through the medication adherence diary.   
 
7.9. 
CONCOMITANT MEDICATIONS/THERAPIES 
A medication list is provided for medications, which are contraindicated in the study (see Appendix 1). Participants will 
be asked to report the use of any new medications during the study. If new medications are started, the study medical 
provider will assess whether or not the participant must be removed from the study.   
 
7.10. STUDY DRUG BLINDING 
The study is double-blinded such that the participants, principal investigator, research assistants, and the study medical 
provider are unaware of group allocations. Pill bottles provided to participants will feature generic research labels 
(Medication X vs. Medication Z). Medications are dispensed by the ICS Pharmacy. The Clinical Research Coordinator 


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(CRC), who oversees operations and has no contact with participants, will be aware of participant group allocation. 
Emergency un-blinding procedures are in 11.3. 
 
7.11. RANDOMIZATION 
Prior to the study start date, a randomization list will be generated through the REDCap Randomization Module51 for a 
sample of 12 with 1:1 allocation (6 in each arm) to varenicline vs. placebo via random permutation of integers without 
replacement.  
 
7.12. RATIONALE FOR CORRELATIVE STUDIES 
No correlative study will be performed.  
 
7.13. DEFINITION OF EVALUABLE SUBJECTS, ON STUDY, AND END OF STUDY 
This study defines a subject as evaluable if he or she competes the 2-week post-quit study visit.   
 
7.14. EARLY STUDY TERMINATION 
This study can be terminated at any time for any reason by the PI-sponsor. If this occurs, all subjects on study should be 
notified as soon as possible. Additional procedures and/or follow up should occur in accordance with Section 10.3, which 
describes the procedure for prematurely withdrawn patients.  
 
8. SELECTION OF SUBJECTS: ELGIBILITY 
Inclusion Criteria:  
1. 
Age 18 years or above  
2. 
Daily smoker using 10 or less cigarettes per day but a minimum of at least 1 cigarettes per week or 4 cigs/month.   
3. 
Willing to quit smoking in the next 30 days  
4. 
Is able to provide written informed consent (in English) to participate in the study and is able to 
read/understand the procedures and study requirements.  
5. 
Is willing to voluntarily sign and date an informed consent form that is approved by an institutional review board 
before the conduct of any study procedure. 
6. 
If female and of childbearing potential, is willing to use medically acceptable contraceptive measures for the 
duration of the study. Acceptable methods of contraception include (1) surgical sterilization (such as tubal 
ligation or hysterectomy, (2) approved hormonal contraceptives (such as birth control pills, patches, implants or 
injections), (3) barrier methods (such as condom or diaphragm) used with a spermicide, or (4) an intrauterine 
device (IUD). Contraceptive measures such as rhythm method or Plan B™, sold for emergency use after 
unprotected sex, are not acceptable methods for routine use. 
7. 
Have access to a cell phone that can send and receive SMS text messages.  
 
Exclusion Criteria:  
1. 
Use of a smoking cessation medication (e.g. nicotine replacement, varenicline, bupropion) in last 7 days.  
2. 
Current use of tobacco product other than cigarettes (e.g. e-cigarettes, smokeless tobacco) in the last 7 days 
3. 
Score of 10 or greater on Patient Health Questionnaire (PHQ-9) Depression Scale52,53 


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4. 
Answer > 0 on suicidality question (Questions 9) of Patient Health Questionnaire (PHQ-9) Depression Scale52,53  
5. 
Score of 15 or greater on the General Anxiety Disorder 7-item (GAD-7) Scale54,55 
6. 
Active alcohol use disorder or hazardous drinking. This will be initially screened on the phone with the AUDIT-
C56,57, and a score 5 or greater is exclusionary for both men and women. Positive scores of 3 or 4 will result in 
study clinician assessment and discretion. At the in person-screening visit, the AUDIT56,57 will be administered 
with scores of 8 or greater exclusionary.  
7. 
Use of illicit drugs in the last month (marijuana, cocaine, opiates, benzodiazepines, and/or methamphetamine)  
8. 
Severe symptomatic depression and or anxiety (study medical provider discretion) 
9. 
Diagnosis of bipolar disorder, schizophrenia, PTSD and or adult ADHD (study medical provider discretion)  
10. 
Chronic medical illness including diabetes with the use of insulin, Hemoglobin A1c > 7 (study medical provider 
discretion), heart disease diagnosed by angiogram, or COPD diagnosed by pulmonary function testing and 
requiring an oxygen supply  
11. 
Specific medications (Appendix 1)  
12. 
Abnormal finding on physical exam (study medical provider discretion)  
13. 
Positive Urine Pregnancy Test (women of child bearing potential only; QuickVue Urine Pregnancy)58   
14. 
Positive Urine Toxicology-5 Screen (methamphetamine, cocaine, opiates, benzodiazepines, THC)59  
15. 
Unstable hypertension (Blood pressure > 160/100)  
16. 
Renal failure with active or pending hemodialysis  
 
Use of Inclusion/Exclusion Criteria: The primary considerations for the use of inclusion/exclusion criteria include 
consent (English, age), patient safety (illness, medications, blood tests, pregnancy), and generalizability (willingness to 
quit, cigarette use, drug and alcohol use, psychiatric illness).   
 
Assessment and Follow-up of Specific Exclusion Criteria: If a participant is excluded based on criteria above, the study 
medical provider will further assess the exclusion through medical interview as needed. If this interview reveals a safety 
issue for the excluded individual, the medical provider will seek immediate medical assistance if necessary.  
 
9. ASSESSMENTS AND PROCEDURES 
9.1. 
OVERVIEW OF ASSESSMENTS 
Medications will be continued for 6 weeks in each group with laboratory testing at (baseline (4-weeks pre-quit), 2-weeks 
pre-quit, 1-week pre-quit, and 2-weeks post-quit).  The goal of study visits is to assess lab-based craving and to confirm 
the number of cigarettes smoked per day with objective confirmation via expired breath carbon monoxide (CO) and 
salivary cotinine. Follow-up phone calls will occur at 2-5 days after the baseline visit, 1-week post-TQD, and 2-5 days 
after the 2-week post-quit visit. For the varenicline extension period, additional phone follow-ups will occur at 5-weeks 
post-TQD (3 weeks into period) and 2-5 days after the varenicline extension period. The purpose of follow up phone calls 
is to assess side effects and self-reported cigarettes per day. Other assessments will be made through daily texts:  Real 
world cue response, cigarettes per day and adherence to medications.   
 
Assessment of smoking abstinence: Smoking abstinence will be tested at all study visits. A smoking diary will be used to 
assess self-reported cigarettes per day from the time of their last visit as well as real-time text data. At all visits, 
abstinence will be assessed by an expired air carbon monoxide (CO) breath test < 7ppm (96.0% sensitivity)60–62 and 
salivary cotinine.  
 
Efficacy assessments (smoking): Smoking abstinence will be tested at all assessment visits using self-report diaries and 
two forms of biochemical confirmation. Smoking diaries will be filled out every day with a request that the total number 


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of cigarettes smoked each day are entered and recorded by the participant in his or her diary. These will be reviewed at 
each study visit. Data from the real-time texting will also be used. At all visits, smoking status will be biochemically 
confirmed by a CO breath test and by salivary cotinine.  
 
Medication adherence tracking: Medication use will be tracked through self-report paper diaries and text based 
questions – with one question on medication use per day.  This will provide daily assessment of medication use 
adherence including number of pills taken and time of day pill was taken (morning vs evening).  
  
Tolerance: Medication side effects will be assessed through a questionnaire provided at each study visit and at follow-up 
phone calls. To avoid “cueing” the patients on side effects (leading to over-reporting) participants will not be given a list 
of potential side effects with this questionnaire. Instead, they will be asked about side effects using open-ended 
question.  
 
Management Findings Indicating Risk: Potential participants are screened for a number of factors/conditions including 
but not limited to suicidality, pregnancy (women of childbearing potential only), and other general health/mental health 
assessment measures that could indicate risk to the potential participant.  All study findings from the screening visit are 
discussed with a study medical provider, who will provide evaluation, and if necessary will alert the participant’s primary 
care provider or emergency services as needed.  
 
Phone calls:  Phone-based follow up will include questions on smoking, medication use, and side effects.   
 
 


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*Citations for assessments can be found in section 9.5. Full assessments can be found in the Appendices. 
 
9.2. 
SCREENING EXAMINATION 
 
Table 2. Assessments 
Screening 
Visit 
 
Baseline 
Visit- 4-
week pre-
TQD (V1) 
2-week 
Pre-TQD 
Visit 
(V2) 
1-Week 
Pre-TQD 
Visit 
(V3) 
TQD  
 
2-week 
Post- TQD 
Visit 
(V4) 
SCREENING TESTS 
1.  Demographics/Contact Information 
X 
 
 
2. Smoking History; Native/Converted, Daily/non-daily smoking 
X 
 
 
3. Self-efficacy/motivation to quit (2 items) 
X 
 
 
4. Patient Health Questionnaire (PHQ-9) 
X 
 
 
4a. If positive PHQ-9, #9, C-SSRS Screener 
X 
 
 
5. Generalized Anxiety Diagnosis (GAD-7) 
X 
 
 
6. Alcohol Use Disorders Test (AUDIT, if applicable) 
X 
 
 
7. Medical History + Medications 
X 
 
 
8. Physical Exam and Review of Systems 
X 
 
 
9. Urine Drug Screen 
X 
 
 
 
 
10. Urine Pregnancy Test 
X 
 
 
 
 
11. Minnesota Nicotine Withdrawal Symptoms Scale (MNWS) 
X 
 
 
 
 
12. Fagerström Test for Nicotine Dependence (FTND) 
X 
 
 
 
 
13. Positive and Negative Affect (PANAS) 
X 
 
 
 
 
REPEATED TESTS 
1. Lab-Based Cue Reactivity Test 
 
X 
X 
X 
 
X 
2. Center for Epidemiologic Studies Depression Scale (CES-D) 
 
X 
X 
X 
 
X 
3. Perceived Stress Scale (PSS-4) 
 
X 
X 
X 
 
X 
4. Recent Smoking Questionnaire 
 
X 
X 
X 
 
X 
5. Mood and Physical Symptoms Scale (MPSS-2) 
 
X 
X 
X 
 
X 
6. Cigarette Evaluation Questionnaire (MCEQ) 
 
X 
X 
X 
 
X 
7. Smoking Urges (QSU, Brief 10-item) 
 
X 
X 
X 
 
X 
8. Medication Side Effects Question 
 
X 
X 
X 
 
X 
9.  Salivary Cotinine 
 
X 
X 
X 
 
X 
10. Carbon Monoxide Breath Test 
X 
X 
X 
X 
 
X 
11. Self-report Medication/Smoking Diary 
 
X 
X 
X 
 
X 


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“Phone” Screening Procedures: The research study staff will conduct “phone screens” to verify that potential subjects 
fit the basic inclusion criteria for this particular study. These are traditionally done over the phone but may also be 
conducted in person or via the REDCap electronic survey. The research staff will be familiar with all IRB-approved study 
forms include the protocol, phone script, and phone screening questionnaire for the study. Each potential subject will be 
given a brief description of the study to assess eligibility and interest during the phone screen procedures. They will be 
asked to provide verbal consent for additional screening questions (to determine study eligibility). Every phone screen 
will be reviewed by a study medical provider to confirm eligibility prior to a participant coming for the screening visit. 
Preliminary contact information will be stored electronically in REDCap or in encrypted documents on secure servers, 
and any paper documentation is stored behind two locked doors. Research study staff will be responsible for scheduling 
screening visits, documenting pertinent information on the phone screen forms (for study medical provider review), and 
providing directions and appointment reminders for those potential participants meeting inclusion criteria. Each 
potential subject will be contacted via phone or email up to three times. If a subject is not reached after the maximum 
number of contact attempts, he/she will not be considered further for participation in the study unless the subject re-
establishes contact. Screening appointments will be entered onto a shared the Outlook calendar (accessible to only 
study staff and identified by a phone screen ID number). Any changes to appointments, such as cancellations or requests 
to reschedule visits will be documented on the calendar. Those who pass the “phone screening” will be scheduled for an 
in-person screening visit. 
 
Screening Visit Procedures: At the screening visit, participants are provided with the study Informed Consent Form by 
the Clinical Research Coordinator (CRC), and are given time to read over the document. They are provided the 
opportunity to ask the CRC any questions before signing the informed consent document. Once the Study Consent Form 
is signed, the potential participant will be provided with a copy of Duke’s HIPAA Notice of Privacy Practices. Subject data 
to be collected at the screening visit includes: information on general demographics, general medical history including 
smoking history, vitals (height, weight, blood pressure, heart rate, and CO breath test), various assessments (see Table 
2), a physical exam, a urine pregnancy test (for women of child-bearing potential), and urine drug screen.  The study 
medical provider will perform the physical examination. The study medical provider will also provide 20 minutes of 
smoking cessation behavioral counseling. The screening visit will last approximately 120 minutes (2 hours).  
 
If individuals score >0 on the PHQ-9, question 9, they will be administered the Columbia-Suicide Severity Rating Scale (C-
SSRS) by study medical provider to determine eligibility. In case of severe emergency, EMS will be called. If individuals 
score higher than the cutoff for the AUDIT-C (administered via phone screen), then they may be asked to complete the 
full Alcohol Use Disorders Test (AUDIT) to determine study eligibility as it pertains to alcohol use.  
 
If an individual is not interested in the study or screens out at any point, he or she will be referred to alternative 
treatment services. 
 
If the participant passes all the screening criteria, they can be either scheduled for their baseline visit or continue 
directly into their baseline visit on the same day.  
 
Participants will also be provided with daily self-report journals to document recent smoking, medication adherence, 
urges/withdrawal, and side effects. They will be asked to return these at the next study visit (completed).  
 
 


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9.3. 
TREATMENT PERIOD 
Treatment Visits:  
Visit 1: Baseline Visit (4-weeks pre-TQD; described above) 
Visit 2: 2-weeks pre-TQD 
Visit 3: 1-week pre-TQD  
Visit 4: 2-weeks post-TQD 
 
Visit 1: Baseline visit- 4-weeks pre-TQD:  For convenience, this visit may be provided on the same day as the screening 
visit or on a different day in order to accommodate the participant’s schedule. During the baseline visit, the participant 
will undergo randomization and initiate treatment with either varenicline vs. placebo. The participant and research 
study staff (including medical provider) will not know which group they are assigned as they will be labeled as Group 1 
or Group 2. Medication instructions will be provided, including how and when to take medications.  
 
Participants will be provided with 3 weeks worth of medications. There will be 1 weeks worth of the ramp up dose (0.5) 
mg and then 2 weeks worth of the full dose (1 mg BID).  
 
Participants will be asked to complete the lab-based cue reactivity test as well as complete additional self-report 
assessments of mood and smoking (see Table 2). They will also provide a saliva sample for salivary cotinine, complete a 
CO breath test, and have their vitals assessed.  
 
They will be signed up for the text-based program and provided with an instruction booklet on what to expect from the 
texting component of the program.  
 
Participants will also be provided with daily self-report journals to document recent smoking, medication adherence, 
urges/withdrawal, and side effects. They will be asked to return these at the next study visit (completed).  
 
Visit 2-4: At each visit, participants will complete tests/assessments (see Table 2). Participants will also complete an 
expired CO breath test, salivary cotinine testing, and have their blood pressure, heart rate, and weight measured. Self-
report diaries on medication adherence, smoking, urge/withdrawal and side effects will be reviewed and confirmed for 
accuracy. Participants will receive 4 weeks’ worth of new study medications at the 2-weeks pre-TQD visit (V2). This, in 
combination with their previous mediations) will allow them 7 weeks’ worth of medication (6 weeks on treatment and 1 
week buffer if they need to reschedule.  Participants who attend the 2-weeks post-TQD (V4) will be offered 6 additional 
weeks of varenicline.   
 
Phone follow-up: Phone follow-up will occur at the below intervals: 
 
 
Call 1- After Baseline Visit: A phone follow-up will occur 2-5 days after the participant starts taking their 
medication to ensure that they are taking the medication correctly and to see if there are any initial side effects. 


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A self-report of smoking (cigarettes/day) will also be collected. If there are side effects, a study medical provider 
will call them to follow-up and make any necessary dosage changes.  
 
 
Call 2- 1-Week Post-TQD: A phone follow-up will occur 1 week after their TQD to ensure that they are taking the 
medications correctly, see if there are any side effects, and to assess self-report of smoking (cigarettes/day). If 
there are side effects, a study medical provider will call them to follow-up and make any necessary dosage 
changes. 
 
Call 3- After Final Study Visit (No Varenicline Extension): A phone follow-up will occur 2-5 days after the 
participant stops taking their medication to asses for any residual side effects. If there are side effects, a study 
medical provider will call them to follow-up and make any necessary recommendations. They will be asked to 
provide a self-report of smoking (cigarettes/day).  
 
OR 
 
Call 3- After Final Study Visit (Varenicline Extension): A phone follow-up will occur 2-5 day after the participant 
starts taking the medication to ensure that they are taking the medication correctly, to assess for any side 
effects, and to obtain a self-report of smoking (cigarettes/day). If side effects are reported, the study medical 
provider will call the participant and make necessary recommendations or dosage adjustments.  
 
Call 4- 9-Week Follow-up Call (Varenicline Extension): A phone follow-up will occur at 5-weeks post-TQD (3 
weeks after starting varenicline extension). This call will be to ensure that they are taking the medication 
correctly, assess for side effects, and obtain self-reported smoking (cigarettes/day). If there are side effects, a 
study medical provider will call them to follow-up and make any necessary dosage changes. 
 
 
Call 5- After Varenicline Extension (Varenicline Extension): A phone follow-up will occur 2-5 days after the end 
of the 6-week varenicline extension period (8-weeks post- TQD) to see if they are any residual side effects from 
taking the medication. A self-report of smoking (cigarettes/day) will also be collected. If there are side effects, a 
study medical provider will call them to follow-up and make any necessary dosage changes.   
 
Questions to be asked at the above phone follow-ups can be found in Appendix 21.  
 
9.4. 
COMPENSATION 
Participant Compensation: Participants will receive the following compensation:  
Visit 1: Baseline Visit (4-weeks pre-TQD) = $50  
Visit 2: 2-weeks Pre-TQD Visit = $50  


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Visit 3: 1-week Pre-TQD Visit = $75  
Visit 4: 2-weeks Post-TQD Visit = $100  
Completion of 75% of all text messages for the week will provide $25/week Total = $150  
 
Total compensation = $425   
 
Use of ClinCards for compensation: Compensation will utilize Greenphire Inc. ClinCards,63 which allows for electronic 
upload of funds to a “cash withdrawal card” provided to each participant. The Study Coordinator or Clinical Research 
Specialist will provide each participant with a ClinCard at the screening visit and will add the compensation to the card. 
After approval, the participant will have the money loaded onto the card within 3-5 business days.  
 
9.5. 
STUDY ASSESSMENTS 
 
9.5.1. 
 DEMOGRAPHICS/CONTACT INFO 
Demographic/contact information will be collected at the screening visit. This can be found in Appendix 2.  
 
9.5.2. 
SMOKING HISTORY 
At the screening visit, the subject will complete the Smoking History questionnaire (Appendix 3). This non-standardized 
questionnaire that provides information on the number of pack years, social support, additional tobacco product use, 
and other drug use. 
 
9.5.3. 
SELF-EFFICACY/MOTIVATION  
At the screening visit, the participant will complete 2 questions asking about confidence and motivation to quit. These 
can be found in Appendix 4.  
 
9.5.4. 
PATIENT HEALTH QUESTIONNAIRE (PHQ-9)64,65 
The Patient Health Questionnaire PHQ-9 for Depression (Appendix 5) will be used to screen for current (within 2 weeks) 
depression at the screening visit. Participants who have scores of zero or higher on question 9 (suicidality) will be 
administered the C-SSRS and eligibility will be determined by the study medical provider. Patients with severe and 
symptomatic depression may also be excluded based on study medical provider discretion. 
 
9.5.5. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE-SCREENER (C-SSRS)64  
The Columbia Suicide Severity Rating Scale-Screener (C-SSRS) is a questionnaire used for suicide assessment. It assesses 
suicidal ideation, intensity of ideation, and suicidal behavior. If the participant scores positive on question 9 of the PHQ-
9, then the C-SSRS-Screener will be administered and reviewed by a study provider. The C-SSRS can be found in 
Appendix 6. 


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9.5.6. 
GENERALIZED ANXIETY DISORDER (GAD-7)54,55  
Anxiety will be assessed using the GAD-7 (Appendix 7) at the Screening visit. The measure will be used to exclude 
participants from the study who have severe symptomatic anxiety based on study medical provider discretion.  
 
9.5.7. 
ALCOHOL USE DISORDERS TEST (AUDIT)67,68  
The AUDIT (full) is a 10-item questionnaire used to screen people for alcohol use. This will only be administered at the 
Screening visit if the potential participant scored higher than the cutoff scores on the AUDIT-C (on phone screen) and 
meets all other eligibility criteria. This can be found in Appendix 8.  
 
9.5.8. 
MEDICAL HISTORY 
Medical history assessments will be completed by each subject. This assessment will include questions about any 
significant medical diagnoses, recent hospitalizations, surgeries, family history, social history, and medication use. 
Appendix 9 provides an overview of medical history information to be collected and is considered a baseline measure.   
 
9.5.9. 
PHYSICAL EXAM/REVIEW OF SYSTEMS 
At the Screening visit, a study medical provider will conduct a physical exam of the participant for general health. 
Abnormal findings during the exam can be used to exclude participants from the study. They study medical provider will 
also discuss the review of systems (ROS), which is a list of possible symptoms covering the organ systems. These can be 
found in Appendix 10. 
 
9.5.10. 
MINNESOTA NICOTINE WITHDRAWAL SCALE (MNWS)65 
The Minnesota Nicotine Withdrawal Symptoms Scale (MNWS) is a 15-item scale that is designed to measure nicotine 
withdrawal symptoms (i.e. craving, irritability, anxiety, difficulty concentrating, restlessness, increased appetite or 
weight gain, depression, and insomnia). The MNWS will be administered at the screening visit. The complete MNWS can 
be found in Appendix 11. 
 
9.5.11. 
FAGERSTROM TEST FOR NICOTINE DEPENDENCE (FTND)66 
The FTND (Appendix 12) is a validated measure consisting of 6 items that assess a participant’s level of physical nicotine 
dependence. The FTND will be administered the screening visit.    
 
9.5.12. 
POSITIVE AND NEGATIVE AFFECT SCHEDULE (PANAS)67 
The PANAS is a self-report questionnaire consisting of two 10-item scales measuring both positive and negative affect as 
personality traits. This can be found in Appendix 13.  
 


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9.5.13. 
CENTER FOR EPIDEMIOLOGIC STUDIES DEPRESSION SCALE (CES-D)68 
The Center for Epidemiologic Studies Depression Scale (CES-D) is a 20-item scale that asks participants to rate how often 
they have had symptoms of depression (following the DSM-V). The scale will be administered at all 4 study visits. The 
complete CES-D can be found in Appendix 14. 
 
9.5.14. 
PERCEIVED STRESS SCALE (PSS-4)69,70  
The Perceived Stress Scale (PSS-4) is a 4-item used to measure the perception of stress. Higher PSS scores have been 
associated with lower rates of smoking cessation. The scale will be administered at all 4 study visits and can be found in 
Appendix 15. 
 
9.5.15. 
 RECENT SMOKING QUESTIONNAIRE 
At all in-person study visits, a participant’s recent smoking habits will be assessed using the Recent Smoking 
Questionnaire (Appendix 16). This non-standardized, 4-item questionnaire provides information about the participants 
smoking behavior over the last 7 days.   
 
9.5.16. 
MOOD AND PHYSICAL SYMPTOMS SCALE (MPSS-2)71  
The Mood and Physical Symptoms Scale is a two-question scale to assess urges to smoke over a 24-hour period. It will be 
administered at all 4 study visits. The MPSS-2 can be found in Appendix 17.  
 
9.5.17. 
MODIFIED CIGARETTE EVALUATION QUESTIONNAIRE (MCEQ)72  
The Modified Cigarette Evaluation Questionnaire (mCEQ) is a 12-item survey that assesses the rewarding and aversive 
effects of smoking. It will be administered at all 4 study visits. The mCEQ can be found in Appendix 18. 
 
9.5.18. 
QUESTIONNAIRE OF SMOKING URGES (QSU-BRIEF)73,74 
The Questionnaire of Smoking Urges (QSU) is a 10-item survey to assess smoking cravings and urges. This will be 
administered at all 4 study visits and can be found in Appendix 19.  
 
9.5.19. 
SMOKING AND MEDICATION USE75,76 
Participants will be given a diary that will assess their cigarette use and medication adherence throughout the study. The 
diary will be given at screening visit and will be collected and reviewed at all study visits.  Any omissions will be reviewed 
with the participant by study staff and every effort will be made to obtain accurate and complete diary data. The 
combined smoking, medication use, and urge/mood withdrawal diary can be found in Appendix 20.   
 
9.5.20. 
MEDICATION SIDE EFFECTS QUESTIONNAIRE 
Participants will be asked about any medication side effects they have been experiencing at all 4 study visits. Of self-
reported side effects, they will be asked to rate the severity of the side effect (1- not at all severe to 7-extremely severe) 
as well as its frequency (From “Just once” to “More than once a day”). The research study staff as well as the study 


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medical provider will review this form. If a side effect has a severity of 3 or greater, they require follow-up from the PA. 
Severity scores of 1-2 are considered mild, 3-5 are considered moderate, and 6-7 are considered severe.  An example of 
the Medication Side Effects Questionnaire can be found in Appendix 21. 
 
9.5.21. 
TEXT-BASED MESSAGING 
During the text messaging period, participants will be asked to text when they smoke and when they have, which will 
trigger additional questions. They will also be asked about overall cigarettes smoked that day as well as medication 
adherence.  Examples of questions can be found in Appendix 22.  
 
9.5.22. 
EXHALED CARBON MONOXIDE BREATH TEST60–62 
The Exhaled Carbon Monoxide Breath Test will be used as objective confirmation of participant-reported number of 
cigarettes smoked per day. Exhaled Carbon Monoxide Breath testing will be evaluated at all in-person follow-up visits. 
Values less than 7 ppm are considered abstinent (96.0% sensitivity and 93.3% specificity).  
 
9.5.23. 
SALIVARY COTININE 
The salivary cotinine test is sensitive and specific for smoking cessation (95.0% sensitivity and 97.0% specificity). Cotinine 
has a 20-hour half-life and as such is useful for identification of tobacco use several days after smoking.77    
 
10. 
END OF TREATMENT 
The 2-week post-TQD visit, will be the end of randomized treatment.  Participants who choose to continue treatment 
may request the varenicline extension and receive 6 additional weeks of varenicline at this point.   
 
10.1. FOLLOW-UP PERIOD 
If participants do not complete the varenicline extension period, they will receive one final phone call 2-5 days after 
their 2-weeks post-TQD study visit. They will be asked about any lingering side effects and self-report smoking 
(cigarettes per day). Any reported side effects will be reported to the study medical provider, who will follow-up with 
the participant and make any necessary recommendations.   
 
If participants opt to complete the 6 additional weeks of varenicline, they will receive one final phone call 2-5 days after 
the varenicline extension period. They will be asked about any lingering side effects and self-report smoking (cigarettes 
per day). Any reported side effects will be reported to the study medical provider, who will follow-up with the 
participant and make any necessary recommendations.   
 
10.2. END OF STUDY 
Study participation will end with the 2-week post-TQD visit, unless a participant chooses to receive the varenicline 
extension. If the latter, then they will continue on for an additional 6 weeks of varenicline treatment. If participants 
express interest in continued smoking cessation services, a referral will be made to the Duke Smoking Cessation Program 


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or other resources for further support. After all participants have completed the study, the study data collection period 
will be considered over, and the team will begin analysis of results. 
 
10.3. EARLY WITHDRAWAL OF SUBJECT(S) 
Subjects may voluntarily withdraw from the study at any time. The PI may also withdraw a subject from the study at any 
time based on his/her discretion. Reasons for PI-initiated withdrawal may include, but is not limited to the following: 
• 
Adverse events 
• 
Abnormal laboratory values 
• 
Abnormal test procedure results 
• 
Patient Compliance 
• 
Protocol deviation 
• 
Administrative issues 
• 
Disease progression 
• 
Pregnancy 
 
10.3.1. 
FOLLOW-UP REQUIREMENTS FOR EARLY WITHDRAWAL 
If a participant has cause for premature withdrawal, or if the PI decides that the participant should withdraw, he or she 
will be asked to return all medications and no further medications will be dispensed.   
 
10.3.2. 
 REPLACEMENT OF EARLY WITHDRAWAL(S) 
We will not replace participants who drop out of the study.  
 
11. 
SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse events, as defined 
below.  At each study visit, the PI or study staff must assess, through non-suggestive inquiries of the subject or 
evaluation of study assessments, whether an AE or SAE has occurred. 
 
11.1. ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study therapy and which does not 
necessarily have a causal relationship with this treatment. For this protocol, the definition of AE also includes worsening 
of any pre-existing medical condition. An AE can therefore be any unfavorable and unintended or worsening sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study therapy 
that may or may not be related to use of the study therapy. From the time the subject is randomized through the End of 
Study visit (as defined in Section 10), all AEs must be recorded in the side effect case report form (located on REDCap). 
AEs will only be assessed according to the CTCAE version 4.0 if required for a monitoring visit/audit. If CTCAE grading 
does not exist for an AE, the severity of the AE will be graded as mild (1), moderate (2), or severe (3). Any AE’s that are 
considered life-threatening (4) or fatal (5) will be reported according to the Serious Adverse Event reporting (see section 
11.2). 
 


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Attribution of AEs will be indicated as follows: 
- 
Definite:  The AE is clearly related to the study therapy 
- 
Probably:  The AE is likely related to the study therapy 
- 
Possible:  The AE may be related to the study therapy 
- 
Unlikely:  The AE is doubtfully related to the study therapy 
- 
Unrelated:  The AE is clearly NOT related to the study therapy 
 
Any AE’s reported by participants as having a severity of 3 or greater (on a scale of 1-7) will require study medical 
provider review/follow-up. AE’s are considered mild if they have a severity of 1-2, moderate if they have a severity of 3-
5, and severe if they have a severity of 6-7.  
 
11.1.1. 
AES OF SPECIAL INTEREST 
Adverse Events related to Varenicline used in prior studies have been minimal and no SAEs have occurred. As such there 
are no adverse events that will require special attention.  
 
11.1.2. 
REPORTING OF AES 
During each annual IRB review of the protocol, a list of all AEs will be provided to the IRB for review. This report includes 
whether the AE was likely related to study procedures, whether it impacted subject participation, whether the AE was 
resolved, and any other action taken. 
 
11.2. SERIOUS ADVERSE EVENTS 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 
• 
Fatal 
• 
Life-threatening 
• 
Constitutes a congenital anomaly or birth defect 
• 
A medically significant condition (defined as an event that compromises subject safety or may require medical or 
surgical intervention to prevent one of the three outcomes above) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption to conduct normal life functions 
 
11.2.1. 
REPORTING OF SAES 
Life-threatening (grade 4 or 5) SAEs, deaths, and unknown reactions or unexpected events that occur in the course of 
any patient’s treatment of study (from the time of consent) or within 30 days following cessation of treatment are 
reportable. SAEs will be submitted to the IRB per standard protocol. The initial report for each SAE or death should 
include at minimum the following information: 
• 
Protocol # and title 
• 
Patient initials, study identification number, sex, age 
• 
Date the event occurred 


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• 
Description of SAE 
• 
Description of patient’s condition 
• 
Indication whether the patient remains of study 
• 
Causality or causal relationship 
 
De-identified source documentation (i.e. physician study notes) must be sent with the SAE Report Form. Follow-up 
information including severity, action taken, concomitant medications, and outcome should be communicated to Duke 
IRB as soon as possible using the same forms mentioned above. 
As soon as an investigator becomes aware of an AE that meets the definition of serious: 
• 
The Study Coordinator will submit to IRB or designee within 24 hours of Investigator’s awareness, even if it is not 
felt to be drug related. 
 
SAEs will be reported by the PI in an expedited manner to the Duke University Health System (DUHS) Institutional 
Review Board (IRB) office, NIDA, and FDA.  
 
SAEs will be reported to the DUHS IRB using the following timelines: 
• 
24 hours – for an unanticipated study-related death 
• 
1 week (5 business days) – for an unanticipated problem that is a serious adverse event 
• 
2 weeks (10 business days) – for an unanticipated problem that does not meet the criteria of a serious adverse event 
 
In accordance with applicable regulations, investigators will submit the SAE report to their local IRB according to local 
IRB institutional guidelines. Dr. Davis, the study PI is responsible for reporting the serious adverse event to the FDA in 
accordance with 21 CFR 312.32. Any SAE that is possibly related and unexpected will be reported to the FDA no later 
than 15 calendar days upon notification of the event.  The FDA will be notified of any unexpected fatal or life-
threatening suspected adverse reactions no later than 7 calendar days after notification. This will be done by the study 
coordinator. 
• 
These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form) completed by the study 
coordinator/DCI. 
 
11.3. EMERGENCY UN-BLINDING OF INVESTIGATIONAL TREATMENT 
The Clinical Research Coordinator, Sr. will not be blinded to the treatment. The Principle Investigator as well as the 
Clinical Research Specialist, other Clinical Research Coordinator, study medical provider, and statistician will be blinded. 
In the case that Emergency un-blinding is required, the Principle Investigator will contact the Clinical Research 
Coordinator, Sr. directly to obtain the necessary information. Emergency contact information for un-blinding will be the 
email and cell phone number of Jillian Dirkes, jillian.dirkes@duke.edu, 423-833-4376.   
 
11.4. OTHER REPORTABLE INFORMATION 
Other reportable information including pregnancy, development of disease, or hospitalization for non-study related 
causes will be reported as AEs or SAEs depending on the severity and assessed as to whether these are related to study 
procedures. 
 


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11.5. SPECIAL WARNINGS AND PRECAUTIONS 
There are no special warnings or precautions for this study. 
 
11.6. STOPPING RULES 
The study will be stopped prior to its completion if: 1. difficulty in study recruitment or retention will significantly impact 
the ability to evaluate the study endpoints; 2. any new information becomes available during the study that necessitates 
stopping the study; 3. there are significant treatment related toxicities that become evident through the course of the 
study (e.g. severe and repetitive unanticipated side effects or death); or 4. other situations occur that might warrant 
stopping the study. Emergency unblinding procedures can be found in section 11.3. Determination of breaking the blind 
will be up to the principal investigator.  
 
11.7. SAFETY OVERSIGHT COMMITTEE (SOC) 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-investigator phase 
I and II, therapeutic interventional studies that do not have an independent Data Safety Monitoring Board (DSMB). The 
primary focus of the SOC is review of safety data, toxicities, and new information that may affect subject safety or 
efficacy. Annual safety reviews include but may not be limited to review of safety data, enrollment status, stopping rules 
if applicable, accrual, toxicities, reference literature, and interim analysis as provided by the sponsor-investigator. The 
SOC in concert with the DCI Monitoring Team (see Section 12 for Monitoring Team description) oversees the conduct of 
DUHS cancer-related, sponsor-investigator greater-than-minimal-risk intervention studies that do not have an external 
monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and reported in accordance with 
the protocol, standing operating procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory 
requirements. The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings from the DCI 
Monitoring Team visit and additional safety and toxicity data submitted by the Principal Investigator. 
 
11.8. EXTERNAL DATA AND SAFETY MONITORING BOARD (DSMB) 
DSMBs are usually advised for Phase III multi-center clinical trials in which study participants are exposed to substantial 
risk or vulnerable populations are studied. This study, however, will be conducted at only one study site in Durham, 
North Carolina. Based on extensive clinical experience with varenicline, there is no reason to expect significant risks to 
subjects. Additionally, vulnerable populations will not be studied in this protocol. Hence, we have concluded that 
oversight by the scientific and medical team will be adequate for this study and that a formal DSMB will not be needed.   
 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
 
12.1. MONITORING  
This clinical research study will be monitored both internally by the PI and institutionally by the Duke Cancer Institute 
(DCI).  In terms of internal review, the PI will continuously monitor and tabulate adverse events.  Appropriate reporting 
to the Duke University Medical Center IRB will be made.  If an unexpected frequency of Grade III or IV events occur, 
depending on their nature, action appropriate to the nature and frequency of these adverse events will be taken.  This 


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may require a protocol amendment, dose de-escalation, or potentially closure of the study.  The PI of this study will also 
continuously monitor the conduct, data, and safety of this study to ensure that: 
• 
Interim analyses occur as scheduled; 
• 
Stopping rules for toxicity and/or response are met; 
• 
Risk/benefit ratio is not altered to the detriment of the subjects; 
• 
Appropriate internal monitoring of AEs and outcomes is done; 
• 
Over-accrual does not occur; 
• 
Under-accrual is addressed with appropriate amendments or actions; 
• 
Data are being appropriately collected in a reasonably timely manner. 
• 
DCI review and monitoring of this protocol occurs in accordance with the NCI-approved Data and Safety Monitoring 
Plan.   
 
Briefly, protocol review begins with an initial review by the Cancer Protocol Committee (CPC), which assesses the ethics 
and safety of the protocol.  Documentation of these assessments will be maintained.  Formal, independent monitoring 
will be conducted by the DCI Monitoring Team after the first 3 subjects are enrolled, followed by annual monitoring of 1-
3 subjects until the study is closed to enrollment and subjects are no longer receiving study interventions that are more 
than minimal risk.  DCI Monitoring Team reports and additional data/safety/toxicity reports submitted by the PI will be 
reviewed by the Safety Oversight Committee (SOC) on an annual basis.  Additional monitoring may be prompted by 
findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns.  
Monitoring visits may also be initiated upon request by DUHS and DCI Leadership, CPC, SOC, a sponsor, an investigator, 
or the IRB. 
 
A senior study staff member based at the Center for Smoking Cessation in Durham will be responsible for monitoring 
each site at least quarterly. This monitoring will include review of all consent forms completed since the previous 
monitoring visit, 3-5 case report forms (or more if deemed necessary), any on-site regulatory documentation, and 
training documentation for site study staff.  
 
12.2. AUDITS 
The Duke School of Medicine Clinical Trials Quality Assurance (CTQA) office may conduct confidential audits to evaluate 
compliance with the protocol and the principles of GCP. The PI agrees to allow the CTQA auditor(s) direct access to all 
relevant documents and to allocate his/her time and the time of the study team to the CTQA auditor(s) in order to 
discuss findings and any relevant issues. 
 
CTQA audits are designed to protect the rights and well-being of human research subjects. CTQA audits may be routine 
or directed (for cause). Routine audits are selected based upon risk metrics generally geared towards high subject 
enrollment, studies with limited oversight or monitoring, Investigator-initiated Investigational Drugs or Devices, 
federally-funded studies, high degree of risk (based upon adverse events, type of study, or vulnerable populations), 
Phase I studies, or studies that involve Medicare populations. Directed audits occur at the directive of the IRB or an 
authorized Institutional Official. 
 
CTQA audits examine research studies/clinical trials methodology, processes, and systems to assess whether the 
research is conducted according to the protocol approved by the DUHS IRB. The primary purpose of the audit/review is 
to verify that the standards for safety of human subjects in clinical trials and the quality of data produced by the clinical 
trial research are met. The audit/review will serve as a quality assurance measure, internal to the institution. Additional 


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goals of such audits are to detect both random and systemic errors occurring during the conduct of clinical research and 
to emphasize “best practices” in the research/clinical trials environment. 
 
 
 
12.3. DATA MANAGEMENT AND PROCESSING 
 
12.3.1. 
CASE REPORT FORMS (CRFS) 
The electronic and paper CRF will be the primary data collection document for the study. The CRFs will be updated in a 
timely manner following acquisition of new source data. Only approved study staff including the PI, PA, and CRS are 
permitted to make entries, changes, or corrections in the CRF. 
 
Errors will be crossed out with a single line, and this line will not obscure the original entry. Changes or corrections will 
be dated, initialed, and explained (if necessary). The PI or authorized key personnel will maintain a record of the changes 
and corrections. 
 
An audit trail will be maintained automatically by the electronic CRF management system REDCap.78 Designated 
personnel will complete user training, as required or appropriate per regulations. 
 
12.3.2. 
DATA MANAGEMENT PROCEDURES AND DATA VERIFICATION 
Designated personnel using the electronic CRF will have access based on their specific roles in the protocol. The PI, PA, 
and CRS will have access. 
 
Completeness of entered data will be checked automatically by the eCRF system, and users will be alerted to the 
presence of data inconsistencies. Additionally, the CRC will cross-reference the data to verify accuracy. Missing or 
implausible data will be highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of 
data, completion or confirmation that data is not available, etc.). 
The database will be reviewed and discussed prior to database closure, and will be closed only after resolution of all 
remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
 
12.3.3. 
STUDY CLOSURE 
Following completion of the studies, the PI will be responsible for ensuring the following activities: 
• 
Data clarification and/or resolution 
• 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
• 
Review of site study records for completeness 
• 
Shipment of all remaining laboratory samples to the designated laboratories 


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13. STATISTICAL METHODS AND DATA ANALYSIS  
All statistical analysis will be performed under the direction of the statistician designated in key personnel. Any data 
analysis carried out independently by the investigator must be approved by the statistician before publication or 
presentation. 
 
13.1. ANALYSIS SETS 
Dataset will be collected through the 12 week post quit follow-up visit. Data will include information from 
test/assessment, self-report diaries, and objective tests of urine, saliva, and expired CO. All data measures will be 
captured using REDCap,78 an encrypted, HIPAA compliant, data collection system. Data entry is time-stamped for use in 
calendar-based assessment visits with capacity for upload into statistical programs Excel, Statview, SAS, SPSS, MPlus, 
and R. Trained Duke staff will conduct data integrity processes for REDCap data.78  
 
13.2. PATIENT DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Participants will be adult smokers recruited through the Duke Center for Smoking Cessation. 
 
13.3. TREATMENTS 
Study Drug: Varenicline (1mg) vs. Placebo  
 
13.4. PRIMARY OBJECTIVE 
Varenicline vs. placebo will demonstrate greater reduction in cue reactivity.  
 
13.4.1. 
VARIABLES 
Cue reactivity, cigarettes smoked per day, expired CO, and salivary cotinine  
 
13.4.2. 
STATISTICAL HYPOTHESIS, MODEL, AND METHOD OF ANALYSIS 
Statistical approach: general considerations. All analyses will follow an intent-to-treat approach with two-tailed tests 
and alpha = 0.05. Given repeated observations across multiple individuals and time points, many of the analyses in this 
study will be estimated by multilevel modeling (MLM) as implemented under mixed models.43,45,79 MLM hierarchically 
organizes data as a function of person-specific variables and time-point specific variables. Unlike repeated-measures 
ANOVA, MLM is able to derive estimates with non-normal, including binary, distributions and unequal variances across 
time points and individuals, and, importantly, in the presence of missing values. In addition to modeling between-person 
differences, MLM is also able to model within-person variables that change over time. Results will be described as 
means and standard deviations (or, medians and interquartile ranges if there are outliers or skewed data). Initially, for 
hypothesis testing, we will assess the distribution of the outcomes, and, if necessary, attempt to transform the response 
variable to bring about approximate normality of the distribution.  In our initial analysis, we will test for a Group x Time 
interaction in the outcome. If non-significant, we will test a main effects model, including Group and Time. To allow for 


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correlations between observations, an unstructured correlation structure will be assumed. While the two groups should 
be equal at baseline due to randomization, in our analyses, the outcome will be estimated as changes from baseline. In 
compliance with recommendations from the Joint Commission, we will control for baseline. For each study, we have 
specified a primary outcome (cue reactivity), and thus will not need to adjust an overall Type-I error rate for multiple 
testing (e.g. Bonferroni Correction80,81) of primary outcomes. 
 
 
13.4.3. 
HANDLING OF MISSING VALUES, CENSORING, AND DISCONTINUATIONS 
Missing data. Because MLM procedures are based on maximum likelihood estimation and use all available data, 
MLM can accommodate missing data when the missing values are assumed to be missing at random.86,91 Missing 
data will be examined to determine whether they can be defined as missing at random (MAR), which will give 
unbiased estimates of effect size. Often in smoking studies, missing values will be due to drop-out or other 
forms of treatment ‘failure’ which cannot be analyzed as MAR. To account for this, we will assume MAR to 
estimate group effects, to provide a conservative bound on effect size, but include missing values for drop-outs 
or other forms of treatment failure set to the worst response in the effect determination. 
 
13.5. SECONDARY OBJECTIVES 
Secondary outcomes. Physiologic arousal will be assessed during cue reactivity testing via skin conductance, heart 
rate, and blood pressure measurements. Physiologic outcomes will be used as a correlate of self- reported craving 
in response to visual cues. Smoking behavior will be assessed via smoking diaries, CO testing, and cotinine testing 
comparing baseline measurements to later time points to determine whether there is a greater decrease in 
smoking in groups from each study group vs. control. These outcomes will be analyzed by mixed models to allow 
for change over time by person in the individual outcome. We have pre- specified these and other secondary 
outcomes to be analyzed, and at the project’s end we will have a rich data base to conduct other exploratory 
analyses. These outcomes are exploratory and correlative, and as such will not adjust for Type-I error in these 
analyses. Rather, any resulting publication will contain a statement of the exploratory nature of the findings, warn 
of the multiple testing issue, and note a requirement for replication. 
 
Treatment of covariates and potential moderators. We will assess baseline variables for association with 
cue response and smoking behavior outcomes. Baseline variables assessed will include age, gender, race, 
education, baseline nicotine dependence, stress, anxiety, depression, self-efficacy, and nicotine metabolic 
rate. If a baseline variable is found to be associated with change in cue reactivity or smoking behavior, it 
will be treated as a covariate in a secondary analysis and assessed as a potential moderator of treatment 
effect.  
 
13.6. SAMPLE SIZE ESTIMATION 
Sample size estimation based on margin of error 
 
Power analysis. As a pilot study, statistical power will be minimal due the small sample size.  
 


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13.7. EXPLORATORY OBJECTIVES 
Objectives 7-10 are all exploratory. These are analysis of moderation and mediation and are underpowered to 
show statistical significance. They are provided to help guide future study.  
 
13.7.1. 
KEY EXPLORATORY OBJECTIVE 
Not applicable.  
13.7.2. 
OTHER EXPLORATORY OBJECTIVES 
Not applicable. 
 
13.8. INTERIM ANALYSES 
This study is being conducted in order to provide preliminary evidence for a P01 grant proposal on light smokers 
that will be submitted on January 25, 2020. Regardless of our progress in this study, we will conduct an interim 
analysis in late December or early January in order to provide results for this grant proposal. The blind will be 
broken for this analysis. An additional interim analysis may be conducted near the time of the grant review if 
additional data is deemed helpful for grant review.  
 
14. ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
14.1. REGULATORY AND ETHICAL COMPLIANCE 
This protocol was designed and will be conducted and reported in accordance with the International Conference 
on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki, 
and applicable federal, state, and local regulations. 
 
14.2. DUHS INSTITUTIONAL REVIEW BOARD AND DCI CANCER PROTOCOL COMMITTEE 
The protocol, informed consent form, advertising material, and additional protocol-related documents must be 
submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for review. 
The study may be initiated only after the Principal Investigator has received written and dated approval from the 
CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form. The CPC should be informed about any protocol 
amendments that potentially affect research design or data analysis (i.e. amendments affecting subject 
population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.).  


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The Principal Investigator must obtain protocol re-approval from the IRB within one year of the most recent IRB 
approval.  The Principal Investigator must also obtain protocol re-approval from the CPC within one year of the 
most recent IRB approval, for as long as the protocol remains open to subject enrollment. 
 
14.3. INFORMED CONSENT 
The informed consent form must be written in a manner that is understandable to the subject population. Prior 
to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of the 
research, methods, potential risks and benefits, subject concerns, and other study-related matters. This 
discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility of 
coercion. Appropriate accommodations will be made available for potential subjects who cannot read English or 
are visually impaired. Potential subjects will have the opportunity to contact the Principal investigator or 
authorized key personnel with questions, and will be given as much time as needed to make an informed 
decision about participation in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator must obtain written informed 
consent from the subject or a legally acceptable representative. The original informed consent form will be 
stored with the subject’s study records, and a copy of the informed consent form will be provided to the subject. 
The Principal Investigator is responsible for asking the subject whether the subject wishes to notify his/her 
primary care physician about participation in the study. If the subject agrees to such notification, the Principal 
Investigator will inform the subject’s primary care physician about the subject’s participation in the clinical 
study. 
 
14.4. STUDY DOCUMENTATION 
Study documentation includes but is not limited to source documents, case report forms (CRFs), monitoring logs, 
appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, and 
regulatory documents that can be found in the DCI-mandated “Regulatory Binder”, which includes but is not 
limited to signed protocol and amendments, approved and signed informed consent forms, FDA Form 1572, CAP 
and CLIA laboratory certifications, and clinical supplies receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation 
of the trial. Source documents include but are not limited to hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 


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pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial. When possible, 
the original record should be retained as the source document.  However, a photocopy is acceptable provided 
that it is a clear, legible, and an exact duplication of the original document. 
 
An electronic case report form (CRF) will be the primary data collection document for the study. The CRFs will be 
updated within two weeks of acquisition of new source data. Only approved study staff, including the Principle 
Investigator, Study medical provider/PA, and Clinical Research Specialist are permitted to make entries, changes, 
or corrections in the CRF. For paper CRFs, errors will be crossed out with a single line, and this line will not 
obscure the original entry.  Changes or corrections will be dated, initialed, and explained (if necessary). The 
Principal Investigator or authorized key personnel will maintain a record of the changes and corrections. For 
electronic CRFs, an audit trail will be maintained by the electronic CRF management system (REDCap). 
 
 
14.5. PRIVACY, CONFIDENTIALITY, AND DATA STORAGE 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained.  Research Data Security Plans (RDSPs) will be approved by the appropriate institutional Site Based 
Research group.   
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course 
of the study.  Prospective participants will be consented in an exam room where it is just the research staff, the 
patient and family, if desired. For all future visits, interactions with research staff (study doctor and study 
coordinators) regarding research activities will take place in a private exam room. All research-related 
interactions with the participant will be conducted by qualified research staff who are directly involved in the 
conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key 
accessible only by the research staff. Subjects will be identified only by a unique study number and subject 
initials. Electronic records of subject data will be maintained using a dedicated database, REDCap78, which is 
approved for research use by Duke IRB.  Access to electronic databases will be limited to key personnel. 
Additionally, the study team will use the Data Access Group feature available in REDCap. This feature allows 
identified study team members to only see their relevant patients. Specifically, the different sites in this trial will 
only be able to access the data associated with the participants in their Data Access Group. 
Subject data may be stored temporarily on encrypted and password-protected portable memory devices such as 
flash drives and external hard drives, but only when absolutely necessary. Data stored on portable memory 
devices will be de-identified. Subject data will be deleted from the portable memory device at the earliest 
opportunity. The security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine.   
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.     


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Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications in 
scientific journals. 
 
14.6. DATA AND SAFETY MONITORING 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring Plan. For a 
more detailed description of the DSMP for this protocol, refer to Sections 11 and 12.  
 
14.7. PROTOCOL AMENDMENTS 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB and submitted 
to the IND prior to implementation.  IRB approval is not required for protocol changes that occur to protect the 
safety of a subject from an immediate hazard.  However, the Principal Investigator must inform the IRB, FDA, 
and all other applicable regulatory agencies of such action immediately. 
 
14.8. RECORDS RETENTION 
The Principal Investigator will maintain study-related records for at least six years after study completion.  


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24.  Cummings KM, Proctor RN. The Changing Public Image of Smoking in the United States: 1964–
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2014;23(1):32-36. doi:10.1158/1055-9965.EPI-13-0798 
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7802.173797 
26.  Centers for Disease Control and Prevention. Cigarette and Tobacco Use Among People of Low 
Socioeconomic Status. Centers for Disease Control and Prevention. 


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https://www.cdc.gov/tobacco/disparities/low-ses/index.htm. Published March 26, 2019. Accessed 
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29.  Christiansen B, Reeder K, Hill M, Baker TB, Fiore MC. Barriers to effective tobacco-dependence 
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31.  Trainor K, Leavey G. Barriers and Facilitators to Smoking Cessation Among People With Severe 
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33.  Chaiton M, Diemert L, Cohen JE, et al. Estimating the number of quit attempts it takes to quit 
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34.  Jiloha RC. Pharmacotherapy of smoking cessation. Indian J Psychiatry. 2014;56(1):87-95. 
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35.  Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an 
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36.  Medscape, Center for Tobacco Research and Intervention- University of Wisconsin. Tobacco Use 
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39.  Tindle HA, Shiffman S. Smoking Cessation Behavior Among Intermittent Smokers Versus Daily 
Smokers. Am J Public Health. 2011;101(7):e1-e3. doi:10.2105/AJPH.2011.300186 
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Craving Responses. Arch Gen Psychiatry. 2011;68(5):516-526. 
doi:10.1001/archgenpsychiatry.2010.190 
41.  Hall BJ, Slade S, Wells C, Rose JE, Levin ED. Bupropion-Varenicline Interactions and Nicotine Self-
Administration Behavior in Rats. Pharmacol Biochem Behav. 2015;0:84-89. 
doi:10.1016/j.pbb.2015.01.009 
42.  Le Foll B, Chakraborty-Chatterjee M, Lev-Ran S, et al. Varenicline decreases nicotine self 
administration and nicotine- and cue-induced reinstatement of nicotine-seeking behavior in rats 
when a long pretreatment time is used. Int J Neuropsychopharmacol Off Sci J Coll Int 
Neuropsychopharmacol CINP. 2012;15(9):1265-1274. doi:10.1017/S1461145711001398 
43.  Searle, SR, Casella, G, McCulloch, CE. Variance Components. New York, NY: John Wiley & Sons, Inc.; 
1992. 
44.  Allison, PD. Handling Missing Data by Maximum Likelihood. Orlando, FL: SAS Global Forum; 2012. 
http://www.statisticalhorizons.com/wp-content/uploads/MissingDataByML.pdf. 
45.  Schafer JL, Olsen MK. Multiple Imputation for Multivariate Missing-Data Problems: A Data 
Analyst’s Perspective. Multivar Behav Res. 1998;33(4):545-571. doi:10.1207/s15327906mbr3304_5 
46.  Coe R. It’s the effect size, stupid: what effect size is and why it is important. 
https://www.leeds.ac.uk/educol/documents/00002182.htm. Published September 25, 2002. 
Accessed July 2, 2019. 
47.  Patnode CD, Henderson JT, Thompson JH, Senger CA, Fortmann SP, Whitlock EP. Behavioral 
Counseling and Pharmacotherapy Interventions for Tobacco Cessation in Adults, Including Pregnant 
Women: A Review of Reviews for the U.S. Preventive Services Task Force. Rockville (MD): Agency 
for Healthcare Research and Quality (US); 2015. http://www.ncbi.nlm.nih.gov/books/NBK321744/. 
Accessed April 18, 2019. 
48.  Lang, PJ, Bradley, MM, Cuthbert, BN. International Affective Picture System (IAPS): Affective 
Ratings of Pictures and Instruction Manual. Gainesville, FL: University of Florida; 2008. 
49.  The Center for the Study of Emotion and Attention. International Affective Picture System (IAPS). 
https://csea.phhp.ufl.edu/media.html#topmedia. Accessed July 1, 2019. 
50.  Pfizer Labs, Food and Drug Administration. Chantix (Varenicline) Tablets. New York, NY; 2008. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021928s008lbl.pdf. 
51.  University of Chicago Center for Research Informatics. REDCap Randomization Module. 2015. 


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52.  Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J 
Gen Intern Med. 2001;16(9):606-613. 
53.  Martin A, Rief W, Klaiberg A, Braehler E. Validity of the Brief Patient Health Questionnaire Mood 
Scale (PHQ-9) in the general population. Gen Hosp Psychiatry. 2006;28(1):71-77. 
doi:10.1016/j.genhosppsych.2005.07.003 
54.  Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety 
disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-1097. doi:10.1001/archinte.166.10.1092 
55.  Löwe B, Decker O, Müller S, et al. Validation and standardization of the Generalized Anxiety 
Disorder Screener (GAD-7) in the general population. Med Care. 2008;46(3):266-274. 
doi:10.1097/MLR.0b013e318160d093 
56.  Babor, TF, Higins-Biddle, JC, Saunders, JB, Monteiro, MG. AUDIT. Second Edition. Switzerland: 
World Health Organization; 2001. 
57.  Frank D, DeBenedetti AF, Volk RJ, Williams EC, Kivlahan DR, Bradley KA. Effectiveness of the AUDIT-
C as a Screening Test for Alcohol Misuse in Three Race/Ethnic Groups. J Gen Intern Med. 
2008;23(6):781-787. doi:10.1007/s11606-008-0594-0 
58.  Quidel. QuickVue+ hCG Combo Test | Quidel. https://www.quidel.com/immunoassays/rapid-
pregnancy-tests/quickvue-plus-hcg-combo-test. Published 2019. Accessed May 29, 2019. 
59.  Nair H, Woo F, Hoofnagle AN, Baird GS. Clinical Validation of a Highly Sensitive GC-MS Platform for 
Routine Urine Drug Screening and Real-Time Reporting of up to 212 Drugs. Journal of Toxicology. 
doi:10.1155/2013/329407 
60.  Sandberg A, Sköld CM, Grunewald J, Eklund A, Wheelock ÅM. Assessing Recent Smoking Status by 
Measuring Exhaled Carbon Monoxide Levels. PLoS ONE. 2011;6(12). 
doi:10.1371/journal.pone.0028864 
61.  MacLaren DJ, Conigrave KM, Robertson JA, Ivers RG, Eades S, Clough AR. Using breath carbon 
monoxide to validate self-reported tobacco smoking in remote Australian Indigenous 
communities. Popul Health Metr. 2010;8:2. doi:10.1186/1478-7954-8-2 
62.  Deveci SE, Deveci F, Açik Y, Ozan AT. The measurement of exhaled carbon monoxide in healthy 
smokers and non-smokers. Respir Med. 2004;98(6):551-556. 
63.  Greenphire ClinCard System to Optimize Clinical Payment Tracking for Major University. 
Greenphire. https://greenphire.com/press-releases/greenphire-clincard-system-to-optimize-
clinical-payment-tracking-for-major-university/. Accessed April 17, 2019. 
64.  Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: Initial Validity 
and Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults. Am J 
Psychiatry. 2011;168(12):1266-1277. doi:10.1176/appi.ajp.2011.10111704 


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65.  Toll BA, O’Malley SS, McKee SA, Salovey P, Krishnan-Sarin S. Confirmatory factor analysis of the 
Minnesota Nicotine Withdrawal Scale. Psychol Addict Behav J Soc Psychol Addict Behav. 
2007;21(2):216-225. doi:10.1037/0893-164X.21.2.216 
66.  Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström Test for Nicotine 
Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict. 1991;86(9):1119-
1127. 
67.  Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and 
negative affect: the PANAS scales. J Pers Soc Psychol. 1988;54(6):1063-1070. 
68.  Radloff LS. The CES-D Scale: A Self-Report Depression Scale for Research in the General Population. 
Appl Psychol Meas. 1977;1(3):385-401. doi:10.1177/014662167700100306 
69.  Lee E-H. Review of the Psychometric Evidence of the Perceived Stress Scale. Asian Nurs Res. 
2012;6(4):121-127. doi:10.1016/j.anr.2012.08.004 
70.  Cohen S, Kamarck T, Mermelstein R. A Global Measure of Perceived Stress. J Health Soc Behav. 
1983;24(4):385-396. doi:10.2307/2136404 
71.  West R, Hajek P. Evaluation of the mood and physical symptoms scale (MPSS) to assess cigarette 
withdrawal. Psychopharmacology (Berl). 2004;177(1-2):195-199. doi:10.1007/s00213-004-1923-6 
72.  Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. Confirmatory factor 
analyses and reliability of the modified cigarette evaluation questionnaire. Addict Behav. 
2007;32(5):912-923. doi:10.1016/j.addbeh.2006.06.028 
73.  Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges (QSU-brief) 
in laboratory and clinical settings. Nicotine Tob Res Off J Soc Res Nicotine Tob. 2001;3(1):7-16. 
doi:10.1080/14622200020032051 
74.  Toll BA, Katulak NA, McKee SA. Investigating the factor structure of the Questionnaire on Smoking 
Urges-Brief (QSU-Brief). Addict Behav. 2006;31(7):1231-1239. doi:10.1016/j.addbeh.2005.09.008 
75.  Patrick DL, Cheadle A, Thompson DC, Diehr P, Koepsell T, Kinne S. The validity of self-reported 
smoking: a review and meta-analysis. Am J Public Health. 1994;84(7):1086-1093. 
76.  Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A. Validity assessment of self-reported 
medication use by comparing to pharmacy insurance claims. BMJ Open. 2015;5(11):e009490. 
doi:10.1136/bmjopen-2015-009490 
77.  Raja M, Garg A, Yadav P, Jha K, Handa S. Diagnostic Methods for Detection of Cotinine Level in 
Tobacco Users: A Review. J Clin Diagn Res JCDR. 2016;10(3):ZE04-ZE06. 
doi:10.7860/JCDR/2016/17360.7423 


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78.  Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture 
(REDCap)--a metadata-driven methodology and workflow process for providing translational 
research informatics support. J Biomed Inform. 2009;42(2):377-381. doi:10.1016/j.jbi.2008.08.010 
79.  Committee for Medicinal Products for Human Use (CHMP). Guideline on Adjustment for Baseline 
Covariates in Clinical Trials.; 2015. https://www.ema.europa.eu/en/documents/scientific-
guideline/guideline-adjustment-baseline-covariates-clinical-trials_en.pdf. 
80.  Glickman ME, Rao SR, Schultz MR. False discovery rate control is a recommended alternative 
to Bonferroni-type adjustments in health studies. J Clin Epidemiol. 2014;67(8):850-857. 
doi:10.1016/j.jclinepi.2014.03.012 
81.  Simes RJ. An improved Bonferroni procedure for multiple tests of significance. Biometrika. 
1986;73(3):751-754. doi:10.1093/biomet/73.3.751 
 
 
 


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15. APPENDICES 
APPENDIX 1: Exclusionary Medication 
Information regarding exclusionary medications can be found in Appendix 1, which is a separate 
document. This document will be provided to the Duke IRB as a separate document. This list will be 
updated yearly. Any changes made to the medication exclusion list will be at the discretion of the study 
medical provider.  
 
 


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APPENDIX 2: Demographics/Contact Information Form 
 
Age ___________    Date of Birth _______________________ 
 
Gender:  Male      Female       Transgender Female Transgender Male   Other (please specify)  
Prefer not to answer 
 
Marital Status 
 Single, never married 
 Married or domestic partnership 
 Widowed 
 Divorced 
 Separated
 
Race 
 White 
 Black or African American 
 Asian 
 Native Hawaiian or Other Pacific Islander 
 American Indian or Alaska Native 
 Other (please specify) 
 More than one race
 
Ethnicity  
 
 Hispanic or Latino      Not Hispanic or Latino
 
What is the highest level of schooling you have completed?  
 Elementary school or less 
 Some high school 
 High school graduate or equivalent 
 Some college or technical/vocational school 
 College graduate or higher
 
What is the highest level of schooling you have completed?  
 Employed for wages  
 
 
 Self-employed 
 Out of work and looking for work 
 Out of work but not currently looking for 
work 
 
 
 A homemaker 
 A student 


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 Military 
 Retired 
 Unable to work 
 
Contact Information Form 
First Name ___________________    M.I. _______    Last Name ________________________ 
Number and Street Address ____________________________________________________ 
City___________________________    State _________    Zip code _____________________ 
Email address ________________________________________________________________ 
Primary Telephone # ___________________    Other Telephone # ______________________ 
 
Do you give Center for Smoking Cessation permission to leave a message at the above numbers or contact you 
by email? 
 Yes  
 No   
 
If I cannot be reached or if there is an emergency, you can leave a message with: 
Name: _____________________________________ 
Relationship: _______________________________ 
Telephone #: _______________________________ 
 
□ I understand in the event that I do not return messages and fail to come to appointments my emergency 
contact person may be contacted. 
 
 


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APPENDIX 3: Smoking History Questionnaire 
Please answer the following questions are about your history of smoking, use of other products and medications.   
1. Do you smoke at least 1 cigarette each day? 
1 = Yes 
0 = No 
 
2. (If answered “Yes” do Q1) How many cigarettes do you smoke each day on average? ________ [1-99] 
3. (If answered “No” do Q1) How many cigarettes do you smoke each week on average? ________ [1-99] 
4. How many years have you smoked? ________ [1-99] 
 
 
 
 
 
 
 
 
5. Are you willing to attempt to quit smoking in the next 30 days? 
1 = Yes 
0 = No 
 
6. Do you usually smoke menthol or non-menthol cigarettes?  
1 = Non-Menthol 
2 = Menthol 
3 = Both 
99 = Don’t know  
 
7. Does your spouse/partner smoke?  
 
1 = Yes 
 
2 = No 
 
3 = Do not have a spouse/partner 
 
99 = Don’t know  
 
8. If you decided to quit, how likely would the people close to you support your decision to quit? 
1 = Not likely at all 
2 = Very unlikely 
Calculated Field in REDCap: Pack Years: Number of cigarettes per week (Q2)/20 x years smoked (Q4).   
 (Q2 is divided by 20 because there are 20 cigarettes in a pack). 
 
Calculated Field in REDCap: Pack Years: Number of cigarettes per week (Q3)/140 x years smoked (Q4).   


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3 = Somewhat unlikely 
4 = Neither likely nor unlikely 
5 = Somewhat likely 
6 = Very likely 
7 = Extremely likely 
99 = Don’t know 
 
9.  How many times in your life have you stopped smoking for one day or longer because you were trying to quit 
smoking?  _______ [0-99]  
 
10. Have you used the following tobacco products in the last week? (Select all that apply) 
 
1 = Cigarettes 
 
2 = Cigars 
 
3 = Pipes 
 
 
4 = Hookah 
 
5 = Cigarillos 
 
6 = E-cigarettes 
 
7 = Chewing tobacco 
 
8 = Orbs/sticks/sheets 
 
9 = Snuff 
 
10 = Other 
 
11. During the last week, did you use any of the following drugs? (Select all that apply)  
 
0 = None 
 
1 = Marijuana 
 
2 = Cocaine/Crack 
 
3 = Meth 
 
4 = PCP 
 
5 = Heroin 
 
6 = Other (please specify) 


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12. During the last week, did you use an opiate such as Codeine, Morphine, MS Contin, OxyContin, Oxycodone, Percocet, 
Hydrocodone, Vicodin, Hydromophone, Dilaudid, Duragesic or Fentanyl?   
1 = Yes 
0 = No 
99 = Don’t know  
 
10. During the last week, did you use a benzodiazepine such as Lorazapam, Ativan, Valium, Alprazolam, Xanax, 
Clonazepam or Klonopin?  
1 = Yes 
0 = No 
99 = Don’t know 
 
 
 


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APPENDIX 4: Self-efficacy/Motivation 
1) On a scale from 1-10, how confident are you that you can quit smoking? 
1 
      
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not at all 
 
A little  
Moderately 
 
Very 
 
Extremely 
 
2) On a scale from 1-10, how motivated are you to quit smoking?  
1 
      
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not at all 
 
A little  
Moderately 
 
Very 
 
Extremely 
 
 
 
 


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APPENDIX 5: Patient Health Questionnaire-964,65 
Over the past two weeks, how often have you been bothered by any of the following problems? 
 
Not at all 
Several Days 
More than half 
the days 
Nearly 
Everyday 
1. Little interest or pleasure in 
doing things 
0 
1 
2 
3 
2. Feeling down, depressed or 
hopeless 
0 
1 
2 
3 
3. Trouble falling or staying 
asleep, or sleeping too much 
0 
1 
2 
3 
4. Feeling tired or having little 
energy 
0 
1 
2 
3 
5. Poor appetite or overeating 
0 
1 
2 
3 
6. Feeling bad about yourself – or 
that you are a failure or have let 
yourself or your family down.  
0 
1 
2 
3 
7. Trouble concentrating on 
things, such as reading the 
newspaper or watching 
television.  
0 
1 
2 
3 
8. Moving or speaking so slowly 
that other people could have 
noticed? Or the opposite – being 
so fidgety or restless that you 
have been moving around a lot 
more than usual 
0 
1 
2 
3 
9. Thoughts that you would be 
better off dead or hurting 
yourself in some way 
0 
1 
2 
3 
 
 
 
 
 
 
 
Total: __________ + ____________ + _____________ 
 
 
 
 
 
 
 
 
 
 
Total Score: ________ 
Scoring (add sum of total scores):  
0-4: Minimal Depression 
5-9: Mild Depression 
10-14: Moderate Depression 
15-19: Moderately Severe Depression 
20-27: Severe Depression 


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APPENDIX 6: Columbia Suicide Severity Rating Scale-Screener (C-SSRS)64 
 
 
 
 


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APPENDIX 7: Generalized Anxiety Disorder 7-item Scale (GAD-7)93,94  
Over the last 2 weeks, how often have you been bothered by any of the following problems?  
 
 
 
Not at all 
Several days 
Over half the 
days 
Nearly 
everyday 
1. Feeling nervous, anxious, or 
on edge 
0 
1 
2 
3 
2. Not being able to stop or 
control worrying 
0 
1 
2 
3 
3. Worrying too much about 
different things 
0 
1 
2 
3 
4. Trouble relaxing 
0 
1 
2 
3 
5. Being so restless that it’s 
hard to sit still 
0 
1 
2 
3 
6. Becoming easily annoyed or 
irritable 
0 
1 
2 
3 
7. Feeling afraid as if 
something awful might happen 
0 
1 
2 
3 
 
 
 
 
 
 
Total:  ___________+ __________+ ___________ 
 
 
 
 
 
 
 
 
Grand Total: __________ 
 
Scoring (add sum of columns) 
0-5: Minimal to no anxiety 
6-10: Moderate anxiety  
11 or above: High anxiety 
 
 


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APPENDIX 8: Alcohol Use Disorders Identification Test (AUDIT)67  
 
 
 


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APPENDIX 9: Medical History 
Major Medical Conditions: 
 Yes   No      High blood pressure (Hypertension) 
 
 Yes   No      Heart attack OR heart disease diagnosis by coronary angiogram 
 
 Yes   No      Problems with heart valves such as regurgitation, stenosis, or artificial valve 
 
 Yes   No      Heart rhythm problem such as atrial fibrillation, tachycardia, or pacemaker 
 
 Yes   No      Heart failure requiring a diuretic (water pill) 
 
 Yes   No      Skin problems requiring medication 
 
 Yes   No      Liver cirrhosis (with jaundice or swollen abdomen) 
 
 Yes   No      Liver problems other than cirrhosis (e.g. hepatitis, fatty liver) 
 
 Yes   No      Kidney failure requiring dialysis 
 
 Yes   No      Chronic Kidney Disease not requiring dialysis 
 
 Yes   No      Chronic diarrhea due to Irritable Bowel Syndrome, Crohn's Disease, Inflammatory Bowel 
 
 Yes   No      Stomach/ Duodenal Ulcer (Gastrointestinal Ulcer) 
 
 Yes   No      Chronic Bronchitis (cough every morning) 
 
 Yes   No      Chronic Obstructive Pulmonary Disease (COPD) (Emphysema) 
 
 Yes   No      Asthma 
 
 Yes   No      Other chronic lung disorder such as Tuberculosis, Pulmonary Fibrosis, Sarcoid, or other 
 
 Yes   No      Stroke/TIA (mini-stroke) 
 
 Yes   No      Seizure disorder 
 
 Yes   No      Regular headaches 
 
 Yes   No      Unexplained fainting spells 
 
 Yes   No      Insomnia requiring medications 
 
 Yes   No      Other neurologic conditions 
 
 Yes   No      Problems giving blood samples 
 
 Yes   No      Anemia requiring iron 
 
 Yes   No      Blood disorder 
 
 Yes   No      Rheumatic Disease such as Rheumatoid Arthritis, Fibromyalgia, or other 
 
 Yes   No      Sinusitis/ Seasonal allergies 
 
 Yes   No      Diabetes requiring insulin or other medications 
 


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 Yes   No      Thyroid disease/condition 
 
 Yes   No      Cancer 
 
 Yes   No      Depression/Anxiety/Bipolar disorder 
 
 Yes   No      Suicidal ideation (thinking about ways to commit suicide) within the past year 
 
 Yes   No      Suicide attempt during your lifetime 
 
 Yes   No      Schizophrenia 
 
 Yes   No      Post-Traumatic Stress Disorder (PTSD) 
 
 Yes   No      Other Psychiatric problems (Borderline, Schizoaffective, Hypomania, ADHD) 
 
 Yes   No      Chronic infections syndrome such as HIV, CMV, Epstein Barr 
 
 
 
 
 
 
MEDICAL HISTORY 
 
Please list any hospitalizations in the past 10 years.  If possible, include the year: 
1. _______________________________________________________ Year: __________ 
2. _______________________________________________________ Year: __________ 
3. _______________________________________________________ Year: __________ 
4. _______________________________________________________ Year: __________ 
5. _______________________________________________________ Year: __________ 
Please list any serious injuries or accidents.  If possible, include the year: 
1. _______________________________________________________ Year: __________ 
2. _______________________________________________________ Year: __________ 
3. _______________________________________________________ Year: __________ 
4. _______________________________________________________ Year: __________ 
5. _______________________________________________________ Year: __________ 
Please list any surgeries or major procedures.  If possible, include the year: 
1. _______________________________________________________ Year: __________ 
2. _______________________________________________________ Year: __________ 


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3. _______________________________________________________ Year: __________ 
4. _______________________________________________________ Year: __________ 
5. _______________________________________________________ Year: __________ 
 
      
Women Only: 
Date of last menstrual cycle:  __________________      Not Applicable   
Are you menstruating regularly?       Yes       No 
Are you post-menopausal (natural or from surgery)?       Yes       No 
 
Are you willing to use medically acceptable contraceptive measures for the duration of the study?    
  Yes       No        (  Not Applicable – PA/MD Initials: ___________)     
 
Acceptable methods of contraception include (1) surgical sterilization (such as tubal ligation or hysterectomy, (2) 
approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier 
methods (such as condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). 
Contraceptive measures such as rhythm method or Plan B™, sold for emergency use after unprotected sex, are 
not acceptable methods for routine use. 
 
 
 
 
 
 
 
 
MEDICAL HISTORY 
 
Family History 
Has any first degree family member (child, parent, or sibling) had any of the following illnesses? 
Illness 
Circle One 
Which family member? 
Anemia or Blood Disease 
Yes    or    No 
 
Cancer 
Yes    or    No 
 


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Diabetes 
Yes    or    No 
 
Heart Disease 
Yes    or    No 
 
High Blood Pressure 
Yes    or    No 
 
Severe Mental Illness 
Yes    or    No 
 
Stroke 
Yes    or    No 
 
Substance Abuse (alcohol, tobacco, or 
other) 
Yes    or    No 
 
Other Serious Illness 
Yes    or    No 
 
 
Social History 
Do you drink alcohol (e.g. beer, wine, liquor)?    Yes     No    
If YES, how many days per week do you have a drink containing alcohol? _________ 
How many drinks do you have on your heaviest drinking day of the week? _________ 
Do you currently drink coffee and / or tea?    Yes     No 
If YES, how many cups per day? __________ 
Have you used a non-prescription drug such as marijuana, cocaine or heroin in the last month?    Yes     No 
 
If YES, what drug / substance? ____________________________________ 
 
 
General Health 
1. Do you use oxygen?     No     Yes, continuously     Yes, for exertion or sleep 
 
2. Can you walk up two flights of stairs?  
 No     Yes, without stopping     Yes, but I would need to stop along the way                
 
3. How well do you walk? 
 I walk independently     I walk with a cane     I walk with a walker     I use a wheelchair 
 


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4. Have you ever experienced a seizure or a seizure like activity?   Yes    No 
 
 
 
 
 
 
MEDICAL 
HISTORY 
Medications 
Please list any medications you are allergic to: 
1. 
2. 
3. 
 
Please list all medications you are taking or have used in the last month (includes over-the-counter drugs, 
vitamins, and prescriptions).  
 
 
 
 
 
 
 
 
 
 
 
Have you participated in a research study in the past 30 days where you were given medications?    
 Yes    No    
Name of Medication 
Dosage 
Start Date 
Stop Date 
What is the medication 
used for? 
1. 
 
 
 
 
2. 
 
 
 
 
3. 
 
 
 
 
4. 
 
 
 
 
5. 
 
 
 
 
6. 
 
 
 
 
7. 
 
 
 
 
8.  
 
 
 
 


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Smoking Cessation Medications    
For each of the following, mark if you have used the medication, experienced any side effects, allergy or 
intolerance with usage, or had to stop taking the medication due to side effects. 
 
 
Not Used Used 
Side Effects 
Please list any side effects you experienced while 
taking any of the medications. 
Stopped due to 
side effects? 
Yes 
No 
Nicotine Patch 
 
 
 
 
 
Nicotine Gum 
 
 
 
 
 
Nicotine Lozenge 
 
 
 
 
 
Nicotine Inhaler 
 
 
 
 
 
Zyban (Wellbutrin, 
Bupropion) 
 
 
 
 
 
Chantix (Varenicline) 
 
 
 
 
 
Have you used any of these medications in the past 7 days?    Yes    No 
 
 


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APPENDIX 10: Physical Exam/Review of Systems (ROS) 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 10: Physical Exam/Review of Systems (ROS) cont… 
 
 
 
 


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APPENDIX 11: Minnesota Nicotine Withdrawal Scale (MNWS)65  
Behavior Rating Scale- Self-Report 
Please rate yourself for the period for the last 24 hours. 
DSM – 5 Symptoms 
None 
Slight 
Mild 
Moderate 
Severe 
1. Angry, irritable, frustrated 
0 
1 
2 
3 
4 
2. Anxious, nervous 
0 
1 
2 
3 
4 
3. Depressed mood, sad 
0 
1 
2 
3 
4 
4. Difficulty concentrating 
0 
1 
2 
3 
4 
5. Increased appetite, hungry, weight gain 
0 
1 
2 
3 
4 
6. Insomnia, sleep problems, awakening at night 
0 
1 
2 
3 
4 
7. Restlessness 
0 
1 
2 
3 
4 
Other Validated Symptoms 
None 
Slight 
Mild 
Moderate 
Severe 
8. Desire or craving to smoke 
0 
1 
2 
3 
4 
Other Possible Symptoms 
None 
Slight 
Mild 
Moderate 
Severe 
9. Constipation 
0 
1 
2 
3 
4 
10. Coughing 
0 
1 
2 
3 
4 
11. Decreased pleasure from events 
0 
1 
2 
3 
4 
12. Dizziness 
0 
1 
2 
3 
4 
13. Drowsy 
0 
1 
2 
3 
4 
14. Impatient 
0 
1 
2 
3 
4 
15. Impulsive 
0 
1 
2 
3 
4 
 
TOTAL Score Questions 1-15: _____ 
 
 


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APPENDIX 12: Fagerström Test of Nicotine Dependence66 
1. How soon after you wake up do you smoke your first cigarette? 
 
3 = Within 5 minutes 
 
2 = 6-30 minutes  
 
1 = 31-60 minutes  
 
0 = More than 60 min 
 
2. Do you find it difficult to refrain from smoking in places where it is forbidden, (e.g. in church, at the library, in the 
cinema)?  
    
0 = No 
   
    
1 = Yes 
 
3. Which cigarette would hate most to give up? 
   
1 = The first one in the morning 
   
0 = All others  
 
4. How many cigarettes per day do you smoke? 
   
0= 10 or less  
   
1= 11-20   
   
2= 21-30   
   
3= 31 or more 
 
5. Do you smoke more frequently during the first hours after waking than the rest of the day? 
    
0 = No  
    
1 = Yes 
 
6.  Do you smoke when you are so ill that you are in bed most of the day? 
    
0 = No  
    
1 = Yes 
 
Total Score: _______________ 


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Scoring (add sum of all scores):  
 
1-2: Low dependence 
3-4: Low-moderate dependence 
5-7: Moderate dependence 
8+: High Dependence 
 
 


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APPENDIX 13: Positive and Negative Affect Schedule (PANAS)67 
 
Scoring: Positive Affect Score: Add the scores on items 1, 3, 5, 9, 10, 12, 14, 16, 17, and 19. Scores can range from 10 – 
50, with higher scores representing higher levels of positive affect. Mean Scores: 33.3 (SD±7.2)  
Negative Affect Score: Add the scores on items 2, 4, 6, 7, 8, 11, 13, 15, 18, and 20. Scores can range from 10 – 50, with 
lower scores representing lower levels of negative affect. Mean Score: 17.4 (SD ± 6.2)  
Your scores on the PANAS: Positive: ____ Negative:  
 


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APPENDIX 14: Center for Epidemiologic Studies Depression Scale (CESD)68 
Below is a list of the ways you might have felt or behaved. How often you have felt this way during the past week? 
 
Rarely or none of 
the time (less 
than 1 day ) 
Some or a little of 
the time (1-2 days) 
Occasionally or a 
moderate 
amount of time 
(3-4 days) 
Most or all of the 
time (5-7 days) 
1. I was bothered by things that usually 
don’t bother me. 
 
 
 
 
2. I did not feel like eating; my appetite 
was poor. 
 
 
 
 
3. I felt that I could not shake off the blues 
even with help from my family or friends. 
 
 
 
 
4. I felt I was just as good as other people. 
5. I had. 
 
 
 
 
5. I had trouble keeping my mind on what 
I was doing.  
 
 
 
 
6. I felt depressed.  
 
 
 
 
7. I felt that everything I did was an effort.   
 
 
 
8. I felt hopeful about the future.  
 
 
 
 
9. I thought my life had been a failure.  
 
 
 
 
10. I felt fearful.  
 
 
 
 
11. My sleep was restless.  
 
 
 
 
12. I was happy.  
 
 
 
 
13. I talked less than usual.  
 
 
 
 
14. I felt lonely.  
 
 
 
 
15. People were unfriendly.  
 
 
 
 
16. I enjoyed life.  
 
 
 
 
17. I had crying spells.  
 
 
 
 
18. I felt sad.  
 
 
 
 
19. I felt that people dislike me.  
 
 
 
 
20. I could not get “going.” 
 
 
 
 
SCORING: zero for answers in the first column, 1 for answers in the second column, 2 for answers in the third column, 3 
for answers in the fourth column. The scoring of positive items is reversed. Possible range of scores is zero to 60, with 
the higher scores indicating the presence of more symptomatology. 
 
 


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APPENDIX 15: Perceived Stress Scale (PSS-4)69,70  
Instructions: The questions in this scale ask you about your feelings and thoughts during the last month.  In each case, 
please indicate with a check how often you felt or thought a certain way.  
  
1.  In the last month, how often have you felt that you were unable to control the important things in your life? 
 ___0=never ___1=almost never ___2=sometimes ___3=fairly often ___4=very often  
 
2.  In the last month, how often have you felt confident about your ability to handle your personal problems? 
 ___0=never ___1=almost never ___2=sometimes ___3=fairly often ___4=very often 
 
3.  In the last month, how often have you felt that things were going your way? 
 ___0=never ___1=almost never ___2=sometimes ___3=fairly often ___4=very often 
 
4.  In the last month, how often have you felt difficulties were piling up so high that you could not overcome them? 
 ___0=never ___1=almost never ___2=sometimes ___3=fairly often ___4=very often 
 
 


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APPENDIX 16: Recent Smoking Questionnaire 
 
The follow questions are about your recent smoking 
1. In the last 30 days, have you smoked at all - even a puff?  
1 = Yes 
0 = No 
99 = Don’t know  
 
2. In the last 7 days, have you smoked at all - even a puff?    
1 = Yes 
0 = No 
99 = Don’t know  
 
3.  In the last 7 days, how many days did you smoke cigarettes? _________   [0-7]  
 
  
4. In the last 7 days, how many cigarettes have you smoked per day?  __________ [0-99]  
 
 
 


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APPENDIX 17: Mood and Physical Symptoms Scale-2 (MPSS-2)71 
The next questions are about how you have been feeling over the past 24 hours.  
1.  How much of the time have you felt the urge to smoke in the past 24 hours?   
0=Not at all 
1=A little of the time 
2=Some of the time 
3=A lot of the time 
4=Almost all of the time 
5= All of the time 
 
2.  How strong have the urges been?  
     0=No urge 
     1=Slight  
     2=Moderate  
     3=Strong 
     4=Very Strong  
     5=Extremely Strong  
 
 
Total: _________________ 
 
Scoring (sum of questions): 
0-2: Mild 
3-6: Moderate 
7-10: Severe 
 
 


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APPENDIX 18: Modified Cigarette Evaluation Questionnaire (mCEQ)72  
 If you have smoked since you last completed this questionnaire, please mark the number that best represents how 
smoking made you feel. 
 (1—not at all, 2—very little, 3—a little, 4—moderately, 5—a lot, 6—quite a lot, 7—extremely). 
1. Was smoking satisfying? _____ 
2. Did cigarettes taste good? _____ 
3. Did you enjoy the sensations in your throat and chest? _____ 
4. Did smoking calm you down? _____ 
5. Did smoking make you feel more awake? _____ 
6. Did smoking make you feel less irritable? _____ 
7. Did smoking help you concentrate? _____ 
8. Did smoking reduce your hunger for food? _____ 
9. Did smoking make you dizzy? _____ 
10. Did smoking make you nauseous? _____ 
11. Did smoking immediately relieve your craving for a cigarette? _____ 
12. Did you enjoy smoking? _____ 
 
Scoring Subscales:  
 
1.  "Smoking Satisfaction" (items 1, 2, 12) 
2.  "Psychological Reward" (items 4-8) 
3. "Aversion" (items 9, 10) 
4. "Enjoyment of Respiratory Tract Sensations" (item 3) 
5. "Craving Reduction" (item 11).  
 
Scores for each subscale are calculated as the average of its individual item responses.  
 
Higher scores indicate greater intensity of each smoking effect with, for example, greater satisfaction or psychological 
reward after smoking. 
 


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APPENDIX 19: QUESTIONNAIRE OF SMOKING URGES (QSU-BRIEF)73,74 
 
Please rank each item on a scale from 1-7 
 
1 = Strongly Disagree 
2 
3 
4 = Agree 
5 
6 
7 = Strongly Agree 
 
1. I have a desire for a cigarette right now. 
2. Nothing would be better than smoking a cigarette right now.  
3. If it were possible, I probably would smoke now.  
4. I could control things better right now if I could smoke.  
5. All I want right now is a cigarette.  
6. I have an urge for a cigarette.  
7. A cigarette would taste good now.  
8. I would do almost anything for a cigarette right now.  
9. Smoking would make me less depressed.  
10. I am going to smoking as soon as possible.  
 
Factor 1 (Intention/Desire to Smoke) included items 1, 3, 6, 7, and 10 
Factor 2 (Relief of Negative Affect and Urgent Desire to Smoke) included items 2, 4, 5, 8, and 9 
Factor 3 (Combined) included 1, 6 (from Factor 1) and 4, 8, 9 (from Factor 2).  
 
Sum answers and higher score indicates stronger smoking urges.  
 


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APPENDIX 20: SMOKING AND MEDICATION USE75,76 
 
*Will be modified for the ramp up period as necessary.  
 


 
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APPENDIX 21: MEDICATION SIDE EFFECTS QUESTIONNAIRE 
 
 
Medication Side Effects Questionnaire  
Have you experienced any side effects from the study drugs you are taking?   Yes   
No 
If yes, and fill out the information below.  
Side Effect 1:  
Frequency 
Just 
once 
A Few 
Times 
Several 
Times 
Every Day 
More 
than 
Once a 
Day 
 
Severity 
1  
Not at 
All 
2  
Very Little 
3  
A Little 
4  
Moderately 
5  
A Lot 
6  
Quite a 
lot 
7  
Extremely 
When did it 
start? 
(mm/dd/yy) 
 
How long 
did it last 
(number of 
days)? 
 
 
 
 
 
 
Side Effect 2:  
Frequency 
Just 
once 
A Few 
Times 
Several 
Times 
Every Day 
More 
than 
Once a 
Day 
 
Severity 
1  
Not at 
All 
2  
Very Little 
3  
A Little 
4  
Moderately 
5  
A Lot 
6  
Quite a 
lot 
7  
Extremely 
When did it 
start? 
(mm/dd/yy) 
 
How long 
did it last 
(number of 
days)? 
 
 
 
 
 
 
Side Effect 3:  
Frequency 
Just 
once 
A Few 
Times 
Several 
Times 
Every Day 
More 
than 
Once a 
Day 
 
Severity 
1  
Not at 
All 
2  
Very Little 
3  
A Little 
4  
Moderately 
5  
A Lot 
6  
Quite a 
lot 
7  
Extremely 
Duke Center for Smoking Cessation; Study Name:  
Principal Investigator: James M. Davis M.D. 
Subject Number:  _________________ 
Subject Initials:  ___________________ 
Date of Visit: ____________________ 


 
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When did it 
start? 
(mm/dd/yy) 
 
How long 
did it last 
(number of 
days)? 
 
 
 
 
 
 
Side Effect 4:  
Frequency 
Just 
once 
A Few 
Times 
Several 
Times 
Every Day 
More 
than 
Once a 
Day 
 
Severity 
1  
Not at 
All 
2  
Very Little 
3  
A Little 
4  
Moderately 
5  
A Lot 
6  
Quite a 
lot 
7  
Extremely 
When did it 
start? 
(mm/dd/yy) 
 
How long 
did it last 
(number of 
days)? 
 
 
IF YOU REPORTED SIDE EFFECTS ABOVE:  
Did you stop the study medication as a result of the side effect(s) you listed above? О YES  О NO      
 
 


 
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APPENDIX 22: TEXT BASED MESSAGING 
Introduction 
Description 
Question 
Answer options 
Introduction 
Thank you for being in the 
Project Q - a program to help 
light smokers quit. 
NA 
Date Reminder1 
Starting on DATE, please text us 
the letter S every time you 
smoke. 
 
Date Reminder 2 
Starting on DATE, please text us 
the letter C every time you have 
a craving. 
 
 
 
Texted “S” 
Description 
Question 
Answer options 
Confirm 
Smoking1 
You just smoked?  Text back Y or N. 
 
YES or NO 
Craving1 
How much did you crave the cigarette 
you just smoked? On a scale from 1-
10.  
Range: 1 = Not at all, 10 = Very, very much 
 
Stress1 
How stressed did you feel just before 
you smoked? On a scale from 1-10.  
Range: 1 = Not at all, 10 = Very, very stressed 
Mood1 
What is your mood? On a scale from 
1-10.  
Range: 1 = Extremely bad, 10 = Extremely good 
 
Satisfaction1 
How satisfying was the cigarette you 
just smoked? On a scale from 1-10.  
Range: 1 = Not at all, 10 = Very satisfying 
 
People1 
Are you by yourself? Text back Y or N.  
YES or NO 
People1.1 
If not alone, how many people are 
you with? Enter number between 1-
100.  
Range 1-100.  
Place 1 
Where are you:  1= home; 2 = work, 3 
= public place; 4 = driving/walking; 5 = 
other  
1-5  


 
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Food1 
Did you eat or drink anything in the 
past 15 minutes? Text back Y or N.  
YES or NO 
Alcohol1 
Did you consume alcohol in the past 2 
hours? Text back Y or N.  
YES or NO 
Thank you1 
Thanks for answering those 
questions.  
NA 
 
Texted “C”  
Description 
Question 
Answer options 
Craving2 
How strong is your craving? On a scale 
from 1-10.  
Range: 1 = Not at all, 10 = Very, very strong 
 
Stress2 
How stressed are you?  On a scale 
from 1-10.  
Range: 1 = Not at all, 10 = Very, very stressed 
Mood2 
What is your mood? On a scale from 
1-10.  
Range: 1 = Extremely bad, 10 = Extremely good 
 
People2 
Are you by yourself? Text back Y or N.  
YES or NO 
People2.1 
If not alone, how many people are 
you with? Enter number between 1-
100.  
Range 1-100.  
Place 2 
Where are you:  1= home; 2 = work, 3 
= public place; 4 = driving/walking; 5 = 
other 
1-5  
Food2 
Did you eat or drink anything in the 
past 15 minutes? Text back Y or N.  
YES or NO 
Alcohol2 
Did you consume alcohol in the past 2 
hours? Text back Y or N.  
YES or NO 
Smoke2 
Did you smoke a cigarette in response 
to this episode of craving? Text back Y 
or N.  
YES or NO 
Thank you2 
Thanks for answering those questions.  NA 
 
 
Overall (End of Day)  
Description 
Question 
Answer options 


 
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Overall 
How many cigarettes did you 
smoke today?  
#0-100 
Adherence AM 
Did you take the morning dose of 
your study medication today?  
YES or NO 
Adherence PM  
Did you take the evening dose of 
your study medication today? 
YES or NO 
 
 
 


 
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APPENDIX 23: PHONE CALL FOLLOW-UP QUESTIONS  
1. Have you smoked at all in the last 7 days       YES or NO 
2. In the past 7 days, have you smoked at least 1 cigarette?        YES or NO 
a. (If YES) In the past 7 days, how many cigarettes have you smoke each day on average?    
__________ 
b. (If NO) How many cigarettes have you smoked in total in the past 7 days? 
__________ 
3. Have you taken your medication as directed?        YES or NO 
4. Are you having side effects associated with the medication you received in this study?  YES  or  
NO 
5. If so - what side effects?  (notes box)