Clinical trial NCT02501265
Conditions: Nicotine Dependence
Keywords: Nicotine addiction Cigarette smoking Bupropion Varenicline Adaptive Approach Nicotine Patch Chantix
Sponsor: Duke University
Start date: 2017-06-06; Completion date: 2021-05-12
Enrollment: 188 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess an "adaptive" approach to smoking cessation pharmacotherapy. The protocol is designed to compare adaptive vs. standard approaches to two common smoking cessation pharmacotherapies - Varenicline (commonly known as Chantix) and the Nicotine Patch. The investigators hypothesize that participants allocated to adaptive therapy will show significantly higher biochemically confirmed 30-day continuous abstinence at 12 weeks post-Target Quit Day (TQD).

Detailed description:
The purpose of this study is to assess an "adaptive" approach to smoking cessation pharmacotherapy. The protocol is designed to compare adaptive vs. standard approaches to two common smoking cessation pharmacotherapies (Varenicline and Nicotine Patch). The adaptive treatment approach provides the addition of Bupropion in the pre-quit period for participants who are not "responding" to initial treatment. Little is known about the adaptive use of Varenicline or Nicotine Patch, in which Bupropion is added to Varenicline or Patch for those who do not respond to one of these medications in a pre-quit treatment period. This study attempts to address these knowledge deficits. The study (N=300) is a double-blinded randomized placebo-controlled trial designed to compare biochemically-confirmed abstinence rates in smokers randomized to Varenicline Adaptive Protocol vs. Varenicline (N=150) and for comparison, Nicotine Patch Adaptive Protocol vs. Nicotine Patch (N=150). The "Varenicline Adaptive Protocol" is conducted by starting treatment with Varenicline 4 weeks prior to the quit day and following each participant's response to this pre-treatment medication. After 2 weeks, if the patient shows a reduction greater than 50% in cigarettes smoked per day, then the patient is considered to be a "Varenicline responder" and is continued on Varenicline alone out to 12-weeks post quit day. If the patient does not spontaneously decrease smoking in the pre-quit period by more than 50% cigarettes per day, the patient is considered to be a "Varenicline non-responder" and Bupropion is added to the Varenicline. For comparison, an identical protocol is used with nicotine patch vs. nicotine patch adaptive treatment. The study uses only FDA-approved medications: Varenicline, Nicotine Patch, Bupropion, and placebo controls. To pattern clinical practice, participants will be able to choose whether they would like to use a patch or Varenicline-based treatment. After choosing, however, they will be randomized to adaptive vs. non-adaptive version of that treatment. Placebo medications are matched throughout the study. Participants will be blinded to all medications. All participants will receive behavioral treatment including a single 40-minute visit with a medical provider. The study is designed to provide researchers and clinicians with a better understanding of how to use adaptive pharmacotherapy protocols to improve smoking cessation rates.

Arms: arm 1: Participant choses Varenicline-based treatment and is then randomized to Standard Treatment arm (N=75). Four weeks prior to target quit date (TQD), participant starts placebo Varenicline. Consistent with Varenicline Standard Treatment, 1 week prior to the TQD the participant will switch to active Varenicline and placebo Bupropion. Participant will continue active Varenicline and placebo Bupropion to 12 weeks post-TQD. arm 2: Participant choses Nicotine patch-based treatment and is then randomized to Standard Treatment arm (N=75). Four weeks prior to target quit date (TQD), participant starts placebo Nicotine Patch. One week prior to TQD, participant will start placebo Bupropion. Consistent with Nicotine Patch Standard Treatment, participant will start active Nicotine Patch on TQD. Participant will continue active Nicotine Patch and placebo Bupropion to 12 weeks post-TQD. arm 3: Participant chooses Varenicline treatment and is randomized to Adaptive Treatment arm (N=75). Four weeks prior to target quit date (TQD), participant starts active Varenicline. Two weeks prior to TQD, cigarettes smoked per day is assessed. If the number of cigarettes smoked per day is reduced by \>50%, the participant is considered a Varenicline responder, and starts placebo Bupropion 1 week prior to the TQD. If the participant DOES NOT reduce cigarettes smoked per day by \>50%, the participant is considered a Varenicline non-responder and starts active Bupropion 1 week prior to TQD. Varenicline responders will continue active Varenicline and placebo Bupropion to 12 weeks post TQD. Varenicline non-responders will continue active Varenicline and active Bupropion to 12 weeks post TQD. arm 4: Participant choses Nicotine treatment and is randomized to Adaptive Treatment arm (N=75). Four weeks prior to target quit date (TQD), participant starts active Nicotine Patches. Two weeks prior to TQD, cigarettes smoked per day is assessed. If cigarettes smoked per day is reduced by \>50%, the participant is considered a Nicotine Patch responder and starts placebo Bupropion 1 week prior to the TQD. If the participant DOES NOT reduce cigarettes smoked per day by \>50%, the participant is considered a Nicotine Patch non-responder and starts active Bupropion 1 week prior to the TQD. Nicotine Patch responders will continue active Nicotine Patches and placebo Bupropion to 12 weeks post TQD. Nicotine Patch non-responders will continue active Nicotine Patches and Bupropion to 12 weeks post TQD.
Interventions: intervention 1: Varenicline Standard Protocol intervention 2: Nicotine Patch Standard Protocol intervention 3: Varenicline Adaptive Protocol intervention 4: Nicotine Adaptive Protocol
Intervention descriptions: intervention 1: 4 weeks pre-TQD: Start Placebo Varenicline

1 week prior to TQD: Switch to Active Varenicline

1 week prior to TQD: Start Placebo Bupropion Varenicline + Placebo Bupropion to 12 weeks post TQD intervention 2: 4 weeks pre-TQD: Start Placebo Nicotine Patch TQD: Start active Nicotine Patch

1 week prior to TQD: Start Placebo Bupropion Nicotine Patch + Placebo Bupropion to 12 weeks post TQD intervention 3: VARENICLINE RESPONDER 4 weeks pre-TQD: Start Varenicline 2 weeks pre-TQD: DOES reduce cigs/day by \> 50% 1 week pre-TQD: Start Placebo Bupropion Varenicline + Placebo Bupropion to 12 weeks post TQD

VARENICLINE NON-RESPONDER 4 weeks pre-TQD: Start Varenicline 2 weeks pre-TQD: DOES NOT reduce cigs/day by \> 50%

1 week pre-TQD: Start active Bupropion Varenicline + Bupropion to 12 weeks post TQD intervention 4: NICOTINE PATCH RESPONDER 4 weeks pre-TQD: Start Patch 2 weeks pre-TQD: DOES reduce cigs/day by \> 50% 1 week pre-TQD: Start Placebo Bupropion Patch + Placebo Bupropion to 12 weeks post TQD

NICOTINE PATCH NON-RESPONDER 4 weeks pre-TQD: Start Patch 2 weeks pre-TQD: DOES NOT reduce cigs/day by \> 50%

1 week pre-TQD: Start Bupropion Patch + Bupropion to 12 weeks post TQD

Protocol documents:
Prot_SAP_000.pdf: 
Version Date: 02/26/2020 
 
 
 
 
 
 
 
 
 
Randomized Controlled Smoking Cessation Trial on Adaptive 
Pharmacotherapy 
 
NCT02501265 
 
Document Date: February 26, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version Date: 02/26/2020 
 
A Supportive Care‐Drug Intervention Study 
 
Randomized Controlled Smoking Cessation Trial on Adaptive 
Pharmacotherapy 
 
 
 
 
Sponsor: 
James Davis, MD – Duke 
Cancer Institute 
 
 
Funding Source: 
National Institutes of Health 
 
 
Protocol Source: 
James Davis, MD - Duke 
Cancer Institute 
 
 
Duke IRB#: 
Pro00072077 
 
 
 
 
 
 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  
 
Co‐Investigator 
Santanu Datta, Ph.D. 
santanu.datta@duke.edu 
 
Co‐Investigator 
Jed Rose, Ph.D. 
jed.rose@duke.edu  
 
Statistician 
Frances Wang 
frances.wang@duke.edu  
 
Study Coordinator 
Leah Thomas, MS, CRC, LRT/CTRS 
leah.thomas@duke.edu 
 
 
 
 


Version Date: 02/26/2020 
 
 
 
 
1 
Table of Contents 
2 
LIST OF ABBREVIATIONS .......................................................................................................................................... 6 
3 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY .................................................................................................. 7 
3.1 
Purpose ........................................................................................................................................................... 7 
3.2 
Background and Significance .......................................................................................................................... 8 
3.3 
Design and Procedure ................................................................................................................................... 11 
3.4 
Selection of Subjects ..................................................................................................................................... 11 
3.5 
Duration of study .......................................................................................................................................... 12 
3.6 
Data Analysis and Statistical Considerations................................................................................................. 12 
4 
Study Schema ........................................................................................................................................................ 13 
5 
BACKGROUND AND SIGNIFICANCE ....................................................................................................................... 14 
5.1 
Study Condition ............................................................................................................................................. 14 
5.2 
Study Drug ..................................................................................................................................................... 14 
5.2.1. 
Pre‐clinical experience of study drug .................................................................................................... 16 
5.2.2. 
Clinical experience ................................................................................................................................. 17 
5.3 
Study Purpose/Rationale............................................................................................................................... 17 
6 
OBJECTIVES AND ENDPOINTS ............................................................................................................................... 18 
7 
INVESTIGATIONAL PLAN ........................................................................................................................................ 20 
7.1 
Study Design .................................................................................................................................................. 20 
7.1.1. 
Dose Modification ................................................................................................................................. 20 
7.1.2. 
Safety Considerations ............................................................................................................................ 20 
7.1.3. 
Missed Doses ......................................................................................................................................... 20 
7.1.4. 
Concomitant Medications/Therapies .................................................................................................... 20 
7.1.5. 
Study Drug Blinding ............................................................................................................................... 20 
7.1.6. 
Randomization ...................................................................................................................................... 20 
7.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration............................................................ 20 
7.3 
Rationale for Correlative Studies .................................................................................................................. 21 
7.4 
Definition of Evaluable Subjects, On Study, and End of Study ...................................................................... 21 
7.5 
Early Study Termination ................................................................................................................................ 21 
8 
STUDY DRUG ......................................................................................................................................................... 21 
8.1 
Names, Classification, and Mechanism of Action ......................................................................................... 21 
8.2 
Packaging and Labeling ................................................................................................................................. 21 


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8.3 
Supply, Receipt, and Storage ........................................................................................................................ 22 
8.4 
Dispensing and Preparation .......................................................................................................................... 22 
8.5 
Compliance and Accountability ..................................................................................................................... 22 
8.6 
Disposal and Destruction .............................................................................................................................. 22 
9 
SUBJECT ELIGIBILITY .............................................................................................................................................. 22 
9.1 
Inclusion Criteria ........................................................................................................................................... 22 
9.2 
Exclusion Criteria ........................................................................................................................................... 22 
10 
TRIAL PROCEDURES AND ASSESSMENTS .......................................................................................................... 24 
10.1 
Screening Examination .................................................................................................................................. 25 
10.2 
Treatment Period .......................................................................................................................................... 26 
10.3 
End of Treatment .......................................................................................................................................... 28 
10.4 
Follow‐up Period ........................................................................................................................................... 28 
10.5 
End of Study .................................................................................................................................................. 28 
10.6 
Early Withdrawal of Subject(s) ...................................................................................................................... 29 
10.6.1. 
Criteria for Early Withdrawal ................................................................................................................ 29 
10.6.2. 
Follow‐up Requirements for Early Withdrawal ..................................................................................... 29 
10.6.3. 
Replacement of Early Withdrawal(s) .................................................................................................... 29 
10.7 
Study Assessments ........................................................................................................................................ 29 
10.7.1. 
Medical History ..................................................................................................................................... 29 
10.7.2. 
Physical Exam ........................................................................................................................................ 29 
Subject‐Rated Non‐Standardized Measures  ........................................................................................................ 29 
10.7.3. 
Subject‐Rated Standardized Measures  ................................................................................................ 30 
10.7.4. 
Subject‐Rated Non‐Standardized Measures to Be Collected at All Clinic Visits .................................... 30 
10.7.5. 
Subject‐Rated Standardized Measures to Be Collected at All Clinic Visits ............................................ 30 
10.7.6. 
Subject‐Rated Measures to Be Collected through Phone Assessment ................................................. 30 
11 
SAFETY MONITORING AND REPORTING ........................................................................................................... 30 
11.1 
Adverse Events .............................................................................................................................................. 30 
11.1.1. 
AEs of Special Interest ........................................................................................................................... 31 
11.1.2. 
Reporting of AEs .................................................................................................................................... 31 
11.2 
Serious Adverse Events ................................................................................................................................. 31 
11.2.1. 
Reporting of SAEs .................................................................................................................................. 31 
11.3 
Emergency Unblinding of Investigational Treatment ................................................................................... 32 
11.4 
Other Reportable Information ...................................................................................................................... 32 
11.5 
Special Warnings and Precautions ................................................................................................................ 32 


Version Date: 02/26/2020 
 
11.6 
Stopping Rules ............................................................................................................................................... 32 
11.7 
Safety Oversight Committee (SOC) ............................................................................................................... 33 
11.8 
External Data and Safety Monitoring Board (DSMB) .................................................................................... 33 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................................................ 33 
12.1 
Monitoring .................................................................................................................................................... 33 
12.2 
Audits ............................................................................................................................................................ 33 
12.3 
Data Management and Processing ............................................................................................................... 34 
12.3.1. 
Case Report Forms (CRFs) ..................................................................................................................... 34 
12.3.2. 
Data Management Procedures and Data Verification .......................................................................... 34 
12.3.3. 
Study Closure......................................................................................................................................... 34 
13 
STATISTICAL METHODS AND DATA ANALYSIS ................................................................................................... 34 
13.1 
Analysis Sets ..................................................................................................... Error! Bookmark not defined. 
13.2 
Patient Demographics and Other Baseline Characteristics ............................. Error! Bookmark not defined. 
13.3 
Treatments ....................................................................................................... Error! Bookmark not defined. 
13.4 
Primary Objective .......................................................................................................................................... 34 
13.4.1. 
Variable ................................................................................................................................................. 34 
13.4.2. 
Statistical Hypothesis, Model, and Method of Analysis ........................... Error! Bookmark not defined. 
13.4.3. 
Handling of missing values, censoring, and discontinuations .................. Error! Bookmark not defined. 
13.5 
Secondary Objectives ....................................................................................... Error! Bookmark not defined. 
13.5.1. 
Key Secondary Objective .......................................................................... Error! Bookmark not defined. 
13.5.2. 
Other Secondary Objectives ..................................................................... Error! Bookmark not defined. 
13.6 
Exploratory Objectives .................................................................................................................................. 36 
13.6.1. 
Key Exploratory Objective ..................................................................................................................... 36 
13.6.2. 
Other Exploratory Objectives ................................................................... Error! Bookmark not defined. 
13.7 
Interim Analyses ............................................................................................................................................ 37 
13.8 
Sample Size Calculation ................................................................................................................................. 37 
14 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS .......................................................................................... 38 
14.1 
Regulatory and Ethical Compliance ............................................................................................................... 38 
14.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee ....................................................... 38 
14.3 
Informed Consent ......................................................................................................................................... 38 
14.4 
Study Documentation ................................................................................................................................... 38 
14.5 
Privacy, Confidentiality, and Data Storage .................................................................................................... 39 
14.6 
Data and Safety Monitoring .......................................................................................................................... 39 
14.7 
Protocol Amendments .................................................................................................................................. 39 


Version Date: 02/26/2020 
 
14.8 
Records Retention ......................................................................................................................................... 39 
15 
REFERENCES ...................................................................................................................................................... 40 
16     APPENDICES .......................................................................................................................................................... 44 
16 .................................................................................................................................................................................. 58 
 
2 LIST OF ABBREVIATIONS 
AE 
Adverse event 
AUDIT‐C 
Alcohol Use Disorders Identification Test 
BID 
Twice a day 
CO 
Carbon monoxide 
CPD 
Cigarettes per day 
CRC 
Clinical Research Coordinator 
CSC 
Center for Smoking Cessation 
CTA 
Clinical Trials Assistant 
DSCP 
Duke Smoking Cessation Program 
DSMB 
Data and Safety Monitoring Board 
DUHS 
Duke University Health System 
EMR 
Electronic medical record 
FDA 
Food and Drug Administration 
FTND 
Fagerström Test of Nicotine Dependence 
GAD‐2 
Generalized Anxiety Disorder 2‐item Scale 
GCP 
Good Clinical Practice 
ICS 
        Investigational Chemotherapy Service 
IRB 
Institutional Review Board 
NIDA 
National Institute on Drug Abuse 
NIH 
National Institutes of Health 
MPSS 
Mood and Physical Symptoms Scale 
P 
Placebo (e.g. P‐Varenicline is Placebo Varenicline) 
PHI 
Protected Health Information 
PHQ‐9 
Patient Health Questionnaire‐9 
PSS‐4 
Perceived Stress Scale 
SAE 
Serious adverse event 
TQD 
Target Quit Day 
 
 


Version Date: 02/26/2020 
 
3 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
3.1 Purpose 
   
The purpose of this study is to assess an “adaptive” approach to smoking cessation pharmacotherapy. The protocol is 
designed to compare adaptive vs. standard approaches to two common smoking cessation pharmacotherapies (Varenicline 
and Nicotine Patch). The adaptive treatment approach provides the addition of Bupropion in the pre‐quit period for 
participants who are not “responding” to initial treatment. Little is known about the adaptive use of Varenicline or 
Nicotine Patch, in which Bupropion is added to Varenicline or Patch for those who do not respond to one of these 
medications in a pre‐quit treatment period.  This study attempts to address these knowledge deficits. The study (N=300) is 
a double‐blinded randomized placebo‐controlled trial designed to compare biochemically‐confirmed abstinence rates in 
smokers randomized to Varenicline Adaptive Protocol vs. Varenicline (N=150) and for comparison, Nicotine Patch Adaptive 
Protocol vs. Nicotine Patch (N=150). The “Varenicline Adaptive Protocol” is conducted by starting treatment with 
Varenicline 4 weeks prior to the quit day, then following each participant’s response to this pre‐treatment medication.  
After 2 weeks, if the patient shows a reduction greater than 50% in cigarettes smoked per day then the patient is 
considered to be a “Varenicline responder” and is continued on Varenicline alone out to 12‐weeks post quit day.  If the 
patient does not spontaneously decrease smoking in the pre‐quit period by more than 50% cigarettes per day, the patient 
is considered to be a “Varenicline non‐responder” and Bupropion is added to the Varenicline. For comparison, an identical 
protocol is used with nicotine patch vs. nicotine patch adaptive treatment. The study uses only FDA‐approved medications: 
Varenicline, Nicotine Patch, Bupropion, and placebo controls. To pattern clinical practice, participants will be able to 
choose whether they would like to use a patch or Varenicline‐based treatment.  After choosing, however, they will be 
randomized to adaptive vs. non‐adaptive version of that treatment.  Placebo medications are matched throughout the 
study.  Participants will be blinded to all medications.  All participants will receive behavioral treatment including a single 
40‐minute visit with a medical provider.  The study is designed to provide researchers and clinicians with a better 
understanding of how to use adaptive pharmacotherapy protocols to improve smoking cessation rates.  
 
Primary Objective 
1. Biochemically‐confirmed 30‐day continuous smoking abstinence at 12‐weeks post quit attempt measured by self‐
report and confirmed by carbon monoxide (CO) expired breath testing with CO < 7ppm required to confirm 
abstinence. Subject will be coded as abstinent only if he or she meets criteria for both self‐reported abstinence and 
biochemical abstinence. 
Secondary Objectives 
2. To compare 7‐day point prevalence biochemically confirmed abstinence rates at 2‐ and 12‐weeks post‐TQD in 
participants randomized to adaptive vs standard treatment.  
3. To compare phone‐assessed self‐reported abstinence at 1, 2, 6, 12, 26 and 52 weeks post‐TQD in participants 
randomized to adaptive vs standard treatment. Phone assessments will be compared at specific time points and also 
across multiple time points using multi‐level modeling.   
4. To compare smoking reduction (number of cigarettes per day) at 2 and 12 weeks post TQD in participants randomized 
to adaptive vs standard treatment.  
5. To compare smoking reduction (number of cigarettes per day)  on phone‐based self‐report at 1, 2, 6, 12, 26, and 52 
weeks post‐TQD in participants randomized to adaptive vs. standard treatment. Phone assessments will be compared 
at specific time points and also across multiple time points using multi‐level modeling. 
Exploratory Objectives   
6. To assess potential baseline (pre‐intervention) predictors of abstinence including self‐reported dependence, stress, 
anxiety, depression, alcohol and drug use, and self‐efficacy.  If a baseline variable is found to be associated with 
abstinence, it will be further assessed as a moderator of abstinence.   
7. To assess change in self‐reported measures at baseline (pre‐quit) to 2‐ and 12‐weeks post TQD on repeated 
standardized measures of nicotine dependence, stress, anxiety, depression, alcohol and drug use, and self‐efficacy.  If 
a measure is found to change significantly from baseline to a post quit time point, it will be assessed as possible 
mediator of abstinence outcomes.   
8. To compare phone‐assessed non‐standardized single item questions on urges, withdrawal, motivation to quit smoking 
or remain abstinent, and confidence in ability to quit or remain abstinent at 1, 2, 6, 12, 26 and 52 weeks post‐TQD.  If a 
measure is found to change significantly from baseline to a post quit time point, it will be assessed as a possible 
mediator of abstinence outcomes.  Phone assessments will be compared at specific time points and also across 
multiple time points using multi‐level modeling.   


Version Date: 02/26/2020 
 
9. To compare baseline scores on anxiety, depression, and stress for their effect on allocation to Responder or Non‐
Responder status in the adaptive and standard treatment arms.   
 
10.  To conduct cost‐benefit analyses on allocation to adaptive vs standard treatment from the perspective of multiple 
stake holders:  smokers, healthcare systems (clinics/hospitals), insurance companies, and employers.  
 
 
Hypotheses 
This protocol is hypothesis‐supporting and hypothesis‐testing.  
 
Primary Hypothesis:   
1. Participants allocated to adaptive therapy will show significantly higher biochemically confirmed 30‐day continuous 
abstinence at 12 weeks post TQD.   
 
Secondary Hypotheses:  
2. Participants allocated to adaptive vs standard treatment will show significantly higher biochemically confirmed 7‐day 
point prevalence abstinence at 2 and 12 post TQD assessment visits.   
3. Participants allocated to adaptive vs standard treatment will show significantly higher phone‐assessed self‐reported 
abstinence at 1, 2, 6, 12,26, and 52 weeks post‐TQD.    
4. Participants allocated to adaptive vs standard treatment will show lower number of cigarettes per day (cpd) at 2‐ and 
12‐weeks post TQD. 
5. Participants allocated to adaptive vs standard treatment will show lower number of cigarettes per day (cpd) on phone‐
based self‐report at 1, 2, 6, 12, 26, and 52 weeks post‐TQD.   
Exploratory Objectives 
6. The following baseline self‐report assessment outcomes will predict biochemically confirmed 30‐day continuous 
abstinence at 12 weeks post TQD and 7‐day point prevalence abstinence at 2‐ and 12‐weeks post‐quit:  nicotine 
dependence, depression, anxiety, stress, alcohol use, drug use, motivation, and self‐efficacy.  
7. The following baseline self‐report assessment outcomes will predict lower number of cpd and higher number of days 
abstinent at 2‐ and 12‐ week visits:  urge, withdrawal symptoms, depression, anxiety, stress, alcohol use, drug use, 
motivation, and self‐efficacy. 
8. The following baseline self‐report assessment outcomes will predict abstinence on phone‐based self‐report at 1, 2, 6, 
12, 26, and 52 weeks post‐TQD urges, withdrawal, motivation to quit smoking or remain abstinent, and confidence in 
ability to quit or remain abstinent    
9. Baseline scores on anxiety, depression, and stress will moderate the effect of allocation to Non‐Responder status in 
the adaptive and standard treatment arms. This finding will show that poor response to pharmacotherapy may be 
related to high levels of anxiety, depression, or stress.   
10. A prospective economic analysis of adaptive vs standard treatment will show cost‐benefit outcomes from the 
perspective of people that smoke cigarettes, healthcare systems, insurance companies, and employers.  
11. Feasibility:  Demographics of patients at DSCP and Duke CSC will reflect the recruitment area 
12. Feasibility:  Medications used will show wide variation of use.  
13. Feasibility:   Attendance at DSCP Return Appointments will be favorable.   
14. Feasibility:   Referral Routes to DSCP will reflect recruitment area.  
15. Feasibility:   Medication side effects will be favorable.   
16. Feasibility:  Medication adherence will be favorable.    
3.2 Background and Significance 
Adaptive Treatment Regimens:  The primary study treatment is a medication strategy referred to here as the 
adaptive pharmacotherapy algorithm. This strategy uses FDA‐approved medications for smoking cessation 
(Varenicline, Nicotine Patch and Bupropion). Two weeks after starting these treatments, participants are assessed 
to see how much they have reduced their smoking on these medications.  If, after 2 weeks of treatment, 
participants have reduced their cpd to 50% or less of baseline, they are considered to be “responsive” to 
treatment and are continued on this treatment alone until 12 weeks post‐TQD.  After 2 weeks of treatment, 
participants who have not decreased their cigarette use to 50% or more of their baseline cpd are considered 
“non‐responders”, and Bupropion is added to the treatment regimen 2 weeks prior to the quit attempt and 
continued until 12 weeks post TQD.  Estimates based on prior studies within our lab (see preliminary studies) 
suggest 50% will be non‐responders.   


Version Date: 02/26/2020 
 
 
Pharmacotherapy Control:  The control group used for this algorithm is Varenicline started 1 week prior to TQD (1 
week escalating dose) or Nicotine Patch started on the TQD and continuing to 12 weeks post‐TQD. This is considered 
standard of care treatment. P‐Varenicline and P‐Patch for control participants only will be started 4 weeks prior to 
TQD, and P‐Bupropion will be started 1 week prior to TQD to match study groups  
 
Behavioral Treatments:  All participants will receive one 40‐minute visit with a medical provider who specializes in 
tobacco dependence treatment.    
 
Rationale for Research: The primary disease population is people that smoke cigarettes, with the goal of decreasing 
the incidence of cancer and other smoking‐related illnesses. Smokers are at significantly increased risk of multiple 
forms of cancer (USDHHS, 2014). The unmet need of this treatment is that current methods used to treat smokers 
yield low abstinence rates.  Smoking is the number one cause of preventable morbidity and mortality in the US, 
claiming over 500,000 lives per year (USDHHS, 2014). There is currently compelling evidence from our research center 
(Duke Center for Smoking Cessation) and from other investigators that adaptive treatment of smokers who fail to 
respond to Varenicline or Nicotine patch alone will lead to higher abstinence rates than Varenicline used in usual 
dosing protocols (see below).  If the adaptive approach is found to be effective, it might be implemented as a 
treatment strategy by clinicians.  
 
Existing Evidence for Intervention 
 
A. Use of Adaptive Pharmacotherapy Algorithm:  Trials have shown that a number of pharmacotherapies are 
effective for smoking cessation including Bupropion, Nicotine Lozenge, and Nicotine Patch and have found even 
greater effectiveness for combination nicotine therapy and Varenicline (Mills et al., 2012; Piper et al., 2009). Today, 
however, there is growing evidence that pharmacotherapies might be more effective if they are tailored to specific 
patients based on their early response to a treatment regimen (Pancani et al., 2015). Preliminary studies at Duke 
University have demonstrated a simple method to provide “targeted therapy” to smokers through an adaptive 
pharmacotherapy algorithm, referred to throughout this protocol as the “Algorithm”(Rose, 2011; Rose & Behm, 2013, 
2014; Rose, Herskovic, Behm, & Westman, 2009). Algorithm‐based treatment results show two patterns of response.  
Responders (smokers who decrease their cigarette use by 50% or more during the pre‐quit treatment) show high‐level 
abstinence rates using only the medication on which they were started (see preliminary studies below).  Non‐
Responders (smokers who do not show a 50% decrease in cigarette use during the pre‐quit treatment) show much 
lower abstinence rates overall (see below) with Patch or Varenicline but show significant increases in abstinence rates 
with the addition of Bupropion.  In this study, we will provide non‐responders with Bupropion as an “adaptive 
treatment” with the goal of improving abstinence rates in these individuals.   
 
B. Use of Behavioral Therapies:  It is now well established that the use of pharmacotherapies and behavioral therapies 
together result in higher abstinence rates than either approach alone (Alterman, Gariti, & Mulvaney, 2001; Evins et al., 
2001; Fiore, 2008; Whitlock, Orleans, Pender, & Allan, 2002).  Meta‐analyses across multiple interventions show that 
the effectiveness of behavioral therapy is robustly related to treatment intensity and overall time commitment (Fiore, 
2008; Stead & Lancaster, 2012).  In accordance with these findings, the study will utilize a single 40‐minute treatment 
with encouragement, quit day planning, discussion of prior quit attempts, and smoking triggers.  
 
C. Economic Assessment:  Economic analyses have found smoking cessation interventions to be highly cost‐effective 
when compared to conventional standards of quality‐adjusted life year saved (QALYs), including sub‐populations of 
older smokers, pregnant women, and racial/ethnic minorities (Barnett et al., 2014; Cooper et al., 2014; Dornelas et al., 
2006; Gordon, Graves, Hawkes, & Eakin, 2007; Ronckers, Groot, & Ament, 2005; Ruger & Lazar, 2012; Ruger, 
Weinstein, Hammond, Kearney, & Emmons, 2008). There is growing evidence that the financial gains to employers 
from employee smoking cessation may make employer‐based cost incentives cost‐effective to both employers and 
employees (Berman, Crane, Seiber, & Munur, 2014; Bunn, Stave, Downs, Alvir, & Dirani, 2006; Burton et al., 2005; 
Giles, Robalino, McColl, Sniehotta, & Adams, 2014; Halpern, Shikiar, Rentz, & Khan, 2001). With development of new 
treatment strategies, there is a growing need for studies testing the economic impact of outcomes in healthcare 
systems (Papadakis et al., 2014).  The proposed study includes an economic analysis of adaptive treatment vs. 
standard pharmacotherapy.   
 
Preliminary Studies 


Version Date: 02/26/2020 
 
 
A. Pre‐Treatment Response Delineates Smokers into Groups with Differing Treatment Outcomes: Several studies 
have found an association between pre‐quit smoking reduction and subsequent smoking abstinence (Papadakis et al., 
2014; Rose, 2011; Rose & Behm, 2013, 2014; Rose et al., 2009). In one study, providing 13 weeks of nicotine patch 
therapy with quit day at week 2, 53.8% of the smokers placed on a nicotine patch decreased their cigarette use by 
50% within 1 week (Rose & Behm, 2013). These “responders” showed significantly higher biochemically confirmed 4‐
week continuous abstinence at 11 weeks post‐quit (p = 0.0006, OR = 2.3, 95% CI = 1.43‐3.72) compared to “Non‐
Responders,” who did not decrease their cigarette use by 50% after 1 week of pre‐treatment. Nicotine Patch response 
was assessed via cigarette use at week‐1 and used to determine which testing method allocated subjects in such a way 
as to yield the highest abstinence.  Other studies (Ebbert, 2013) have shown similar responses to pre‐quit Varenicline, 
in which rates of smoking during the pre‐quit period are associated with long‐term abstinence.  The current study 
design is drawn from several studies conducted at the Duke Center for Smoking Cessation as well as studies by others.  
Conclusions drawn from prior NIDA P50‐funded studies initially demonstrated the usefulness of “adaptive treatment” 
(adding bupropion for non‐responders to pre‐quit treatment).    
 
B. Efficacy of Adaptive Treatment:  
 
In this study, 50% of smokers will likely be classified as treatment responders. In a comparison across similar studies, 
treatment responders demonstrated 11‐week post‐quit 4‐week continuous abstinence on nicotine patch at 39.0% and 
36.9%, and 63.9% (p = 0.018) on Varenicline (Rose & Behm, 2013, 2014; Rose et al., 2009). Varenicline alone was not 
significantly different from Varenicline + Bupropion at 70.0% (p = 0.99) (Rose & Behm, 2014). In another P50 Study‐4, 
pre‐treatment Non‐Responders demonstrated biochemically confirmed 11‐week post‐quit, 4‐week continuous 
abstinence rate for: Varenicline + Bupropion = 44.4% vs. Varenicline alone = 18.6% (p = 0.001, OR = 3.51, 95% CI = 
1.64‐7.51).This finding is supported by a recent Mayo Clinic study in which smokers achieved prolonged 12‐week post‐
quit abstinence with Varenicline alone at 34.2% vs. Varenicline + Bupropion at 47.5%, (p = 0.04, OR = 1.74, 95% CI = 
1.04‐2.93).  If they are “treatment responders” they do not benefit significantly from the addition of Bupropion to 
Varenicline, but if they are non‐responders, the addition of Bupropion appears to significantly improve abstinence 
rates, supporting the use of adaptive pharmacotherapy for Varenicline. Regarding use of the nicotine patch, we found 
that smokers did well using nicotine patch if they reduced their cpd by 50% during pre‐quit treatment.  Analysis of 
these “treatment responders” demonstrated biochemically‐confirmed 4‐week continuous abstinence at 11 weeks 
post‐quit attempt of 54.2% in one study (n = 71) and 59.0% in another study (n = 39) (Rose & Behm, 2013, 2014). On 
the other hand, treatment non‐responders showed 11‐week post‐quit attempt biochemically confirmed 4‐week 
continuous abstinence at the following rates:  Patch = 16.8% (n = 45), vs. Patch + Bupropion = 39.5% (n = 38) (p = 0.03, 
OR = 3.0, 95% CI = 1.1‐8.2), vs. Varenicline = 19.0% (n = 42) (p = 0.88, OR = 1.09, 95% CI = 0.37‐3.2). This data suggests 
that it is reasonable to start smokers who choose the nicotine patch with just the patch, and then add Bupropion if 
they do not reduce cpd by 50% (Rose & Behm, 2014). 
 
 
Application of Results 
 
1. Algorithm Testing: The Algorithm developed through the P50 has not been tested as a whole. Prior P50 funded 
studies have assessed the general principle of adaptive treatment (as above) and tested individual quadrants of the 
Algorithm.  The proposed study is designed to test the Algorithm as a whole within a double‐blinded randomized 
placebo‐controlled trial.  If findings are positive, it will influence the use of algorithm‐based treatment and longer 
treatment periods:  4‐week pre‐treatment period with adaptive assessment, followed by 12 weeks of post‐TQD 
treatment.   
 
2. Assessment of Sub‐Populations: There is a growing body of evidence that smokers are a heterogeneous population, 
with variation in treatment response dependent on individual characteristics (Cahill & Perera, 2008; Fiore, 2008; 
Shiffman, Sweeney, & Dresler, 2005; Sussman, Valente, Rohrbach, Skara, & Pentz, 2006; Wagena, Knipschild, Huibers, 
Wouters, & van Schayck, 2005; Wagena, van der Meer, Ostelo, Jacobs, & van Schayck, 2004). The study design 
includes an analysis of baseline characteristics – dependence, depression, anxiety, and stress that show evidence as 
predictors of relapse.   
 
3. Economic Assessment: Economic barriers must always be considered in the successful “real‐world” implementation 
of smoking cessation therapies (Eddy, 2009; Fiore, 2008; Nides, Leischow, Sarna, & Evans, 2007; Warner, Mendez, & 


Version Date: 02/26/2020 
 
Smith, 2004). An economic analysis will be conducted to generate a prospective economic analysis of adaptive vs. 
standard pharmacotherapy treatment to identify cost‐benefit outcomes from the perspective of smokers, healthcare 
systems, insurance companies, and employers. 
3.3 Design and Procedure   
This is an investigational study (n=300) designed to test a Varenicline and Nicotine Patch‐based adaptive 
pharmacotherapy algorithm.  The study is designed to compare two smoking cessation pharmacotherapy strategies: 
Adaptive vs. standard treatment.  Individual arms of this adaptive algorithm have demonstrated compelling results, 
but the algorithm itself has not been studied as an integrated treatment tool. 
 
CHOICE OF VARENICLINE VS. PATCH THEN RANDOMIZATION TO ADAPTIVE VS. STANDARDTREATMENT  
 
 
 
 
 
 
 
ADAPTIVE PHARMACOTHERAPY ALGORITHM (n=300)  
  
VARENICLINE‐BASED TREATMENT  
Participant choses Varenicline‐based treatment and is then 
randomized to Adaptive Treatment arm (N=75)   
NICOTINE PATCH‐BASED TREATMENT  
Participant choses Nicotine patch‐based treatment and is then 
randomized to Adaptive Treatment arm (N=75)   
VARENICLINE NON‐RESPONDER 
4 weeks prior to TQD: Start Varenicline  
2 weeks prior to TQD, DOES NOT reduce cigs/day by > 50% 
1 week prior to TQD: Start Bupropion  
Use Varenicline + Bupropion to 12 weeks post TQD 
NICOTINE PATCH NON‐RESPONDER 
4 weeks prior to TQD: Start Nicotine Patch 
2 weeks prior to TQD, DOES NOT reduce cigs/day by > 50% 
1 week prior to TQD: Start Bupropion  
Use Nicotine Patch + Bupropion to 12 weeks post TQD  
VARENICLINE RESPONDER 
4 weeks pre‐TQD: Start Varenicline  
2 weeks prior to TQD ‐ DOES reduce cigs/day by > 50% 
1 week prior to TQD: Start Placebo Bupropion  
Use Varenicline + Placebo Bupropion to 12 weeks post TQD 
NICOTINE PATCH RESPONDER 
4 weeks pre‐TQD: Start Nicotine Patch   
2 weeks prior to TQD ‐ DOES reduce cigs/day by > 50% 
1 week prior to TQD: Start Placebo Bupropion  
Use Nicotine Patch + Placebo Bupropion to 12 weeks post TQD  
 
STANDARD PHARMACOTHERAPY PROTOCOL: 
VARENICLINE-BASED TREATMENT  
Participant choses Varenicline-based treatment and is then 
randomized to Standard Treatment arm (N=75)   
NICOTINE PATCH-BASED TREATMENT  
Participant choses Nicotine patch-based treatment and is then 
randomized to Standard Treatment arm (N=75)   
VARENICLINE STANDARD TREATMENT 
4 weeks pre-TQD: Start Placebo Varenicline  
1 week prior to TQD – Switch to Active Varenicline 
1 week prior to TQD: Start Placebo Bupropion  
Use Varenicline + Placebo Bupropion to 12 weeks post TQD 
NICOTINE PATCH STANDARD TREATMENT  
4 weeks pre-TQD: Start Placebo Nicotine Patch   
TQD - start Nicotine Patch 
1 week prior to TQD: Start Placebo Bupropion   
Use Nicotine Patch + Placebo Bupropion to 12 weeks post TQD 
 
3.4   Selection of Subjects 
This study will recruit participants through Quit at Duke, also called the Duke Smoking Cessation Program (DSCP), the 
Duke Primary Care Research Consortium, and the Duke Center for Smoking Cessation (CSC). The DSCP is a growing 
multi‐clinic tobacco use treatment program. The Duke CSC is a research center dedicated to researching novel 
 
N=300 
 
RANDOMIZATION WITHIN PARTICIPANTS TO ADAPTIVE VS. STANDARD 
PROTOCOLS  
CHOICE:  
VARENICLINE‐BASED RX  
(n=150) 
VARENICLINE ADAPTIVE PROTCOL  
 (N=75)  
VARENICLINE STANDARD PR0TOCOL  
(N=75)  
CHOICE:  
PATCH‐BASED RX 
(n=150)  
  
NICOTINE PATCH ADAPTIVE 
PROTOCOL 
(N=75)   
NICOTINE PATCH STANDARD 
PROTOCOL 
(N=75)   


Version Date: 02/26/2020 
 
treatments to help smokers break their addiction to nicotine. Subjects for this study will be required to be current 
smokers, confirmed by self‐report and carbon monoxide testing (CO over 7) who are at least 18 years of age. Subjects 
additionally must also be willing to set a Quit Day (day they intend to stop smoking) within the next six weeks and be 
willing to use two medications together – either Varenicline and Bupropion or Nicotine Patch and Bupropion 
depending on their choice of regimen.  Subjects will be excluded if they are currently pregnant or breast feeding, test 
positive for drug or alcohol abuse psychometrically, use a secondary form of tobacco or nicotine, are already taking a 
tobacco use treatment medication, have a symptomatic mental or physical illness, or are unwilling to engage in 
pharmaceutical and behavioral treatments for tobacco use.   
3.5   Duration of study 
All subjects will receive pharmacotherapy +/‐ placebo treatment for 16 weeks (4 weeks pre‐TQD, then 12 weeks post‐
TQD). Subjects will be called for brief phone assessments up to 12‐months post TQD.  Total study duration will be 
approximately 13 months.   
3.6   Data Analysis and Statistical Considerations 
Detailed Data Analysis is provided in Section 13.  A summary of data analysis procedures includes the following:  
Multilevel Modeling: Given repeated observations across multiple individuals, many of the analyses in this study will 
be derived from multilevel modeling (MLM).  Missing Data: Missing data will be examined to determine whether 
missingness is systematic (i.e., associated with individual baseline differences or time‐related changes in observed 
variables). An intent‐to‐treat approach in which subjects lost to follow‐up will be counted as non‐abstinent will also be 
used to analyze univariate outcomes. An alpha criterion of 0.05 (two‐tailed) will be used in all comparisons.   Analysis 
of Primary Outcome:  The primary study outcome is comparison of abstinence rates in adaptive vs standard treatment 
groups. The primary outcome measure is biochemically confirmed 30‐day continuous abstinence at the 12‐week post‐
quit attempt (carbon monoxide breath testing with CO < 7ppm).  Secondary abstinence outcomes: Includes 
comparison of abstinence rates in adaptive vs standard treatment groups via self‐reported 7 and 30‐day continuous 
abstinence at 2‐ and 12‐weeks post‐TQD as well as phone‐based self‐reported abstinence at 1, 2, 6, 12, 26, and 52 
weeks post‐TQD.  Continuous Smoking Outcomes:  In addition to dichotomous outcomes described above, there will 
be an assessment of number of cpd and number of days abstinent at 2‐ and 12‐week post TQD assessment visit (as 
well as phone assessment time points).  Assessment of potential moderators of primary effect: The following 
constructs will be assessed as potential predictors of abstinence: demographics (age, gender, race, education), 
smoking history and heaviness, prior quit attempts, financial status, dependence (FTND), urge rating (MPSS), 
depression (PHQ‐2), anxiety (GAD‐2), alcohol use (AUDIT‐C), stress (PSS‐4), self‐efficacy questions.  Assessment of 
potential mediators of primary effect: The following constructs will be assessed to determine whether assignment to 
pharmacotherapy group is associated with change in these constructs pre‐ and post‐treatment:  urge rating (MPSS), 
depression (PHQ‐2), anxiety (GAD‐2), stress (PSS‐4), self‐efficacy. Economic Analysis:  An economic analysis of the 
Algorithm vs. Standard treatment from multiple perspectives will be provided.   Sample Size Calculation: Total sample 
size required to show differences on primary outcomes between pharmacotherapies and behavioral treatments with 
10% downward adjustment in study group outcomes for possibility of unexpectedly poor outcomes is N = 300.   
 
 
 
 
 
 
 
 
 
 
 
 
 


Version Date: 02/26/2020 
 
 
4 Study Schema 
 
 
 
 


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5 BACKGROUND AND SIGNIFICANCE 
5.1 
Study Condition 
Tobacco use is the number one cause of preventable morbidity and mortality in the US, has a profound economic impact 
nationally, and devastating health effects globally (CDC, 2008; USDHHS, 2014; USSGsACo, 1964; WHO, 2002). The 
contemporary person that smokes cigarettes has greater nicotine dependence, resistance to available therapies, and 
increased need for new, more effective tobacco use treatment therapies (Brandon, 2001; Cokkinides et al., 2009; Fiore, 
2008; J. Hughes, Lindgren, Connett, Nides, & Lung Health, 2004; Irvin, Hendricks, & Brandon, 2003; Orleans, 2007; Warner 
& Burns, 2003) Trials have shown that a number of pharmacotherapies are effective for smoking cessation including 
bupropion, nicotine lozenge, and nicotine patch and have found even greater effectiveness for Varenicline (Mills et al., 
2012; Piper et al., 2009). There is, however, limited evidence on the use of Varenicline or Nicotine patch within adaptive 
pharmacotherapy algorithms.  
5.2 
Study Drug 
There are three smoking cessation medications used in this study:  Nicotine Patch, Varenicline and Bupropion.  All are FDA‐
approved for use as pharmacotherapy for tobacco use treatment.  Below is information on each including mechanism of 
action, rational for use and potential side effects.   
 
Varenicline (Chantix) 
 
Mechanism of Action: Varenicline stimulates nicotinic receptors (partial agonist at α4β2 Nicotinic receptor and full agonist 
at α7) and provides some relief from withdrawal symptoms related to empty receptors with half‐life of over 12 hours (Taly, 
Corringer, Guedin, Lestage, & Changeux, 2009).   The sustained stimulation of nicotinic receptors has a similar effect to 
that of the nicotine patch.  Varenicline does a bit more however: When it binds to a nicotinic receptor, it also blocks that 
receptor from nicotine so that when a person lapses and smokes a cigarette after their quit day, the nicotine does not bind 
to blocked nicotinic receptors.  Because some receptors remain open for nicotine, smoking does have an effect, but a 
diminished one.   While using Varenicline, people often find that it is not satisfying to smoke.  This helps a person return to 
abstinence after a lapse.  Additionally, Varenicline binds nicotinic receptors differently than nicotine. There are a variety of 
nicotinic acetylcholine receptors; α4β2 ‐ 4 alpha subunits, and 2 beta subunits are most common. However, α7, α3β4, 
α3β2, α6 and others play a role in nicotine dependence (Sharples, 2001). Varenicline is a partial agonist at the α4β2 
receptor, but is a strong and full agonist at α7, now thought to be very important to dependence (Mihalak, Carroll, & 
Luetje, 2006).    
Rationale for Use:  Abstinence rates for Varenicline compared to placebo are OR = 2.88.  Because the abstinence rate is so 
high for Varenicline compared to other treatments, Varenicline is considered standard‐of‐care treatment.  The main 
problem with Varenicline is a relatively large number of patients have intolerable side effects; however, most tolerate it 
well (Cahill, Stevens, Perera, & Lancaster, 2013).  
 
Dosing (Pfizer, 2014) 
Begin Chantix 1 week before “Quit Day”. Total duration of treatment is 12 weeks (Pfizer, 2014)(Pfizer, 2014)(Pfizer, 2014) 
Days 1‐3: 0.5mg once daily (total dose 0.5mg/day) 
Days 4‐7: 0.5mg twice daily (total dose 1mg/day) 
Day 8 till end of treatment: 1mg twice daily (total dose 2mg/day) 
Further instructions for use: Take with a full glass of water in order to minimize risk of nausea 
 
Contraindications: In patients with severe renal impairment, dosing of Varenicline needs to be altered. Varenicline is not 
recommended for use in pregnant or breastfeeding women and in patients <18 years (Fagerstrom & Hughes, 2008). 
 
Side effects (Fagerstrom & Hughes, 2008):  
Nausea: 17 ‐ 44% (attributable discontinuation rates between 0.6 – 0.7%) 
Insomnia: 5.1 – 42.9% 
Abnormal dreams: 5.6 – 37.2% 
Headache: 5.5 – 24.2% 
Other side effects include gastrointestinal disturbances such as constipation and flatulence. 
In individuals with pre‐existing psychiatric conditions there is a slightly increased incidence of anxiety and mood related 
disorders. However, important new data shows that there is no increased risk of suicidal behavior in individuals taking 


Version Date: 02/26/2020 
 
Varenicline (Molero, Lichtenstein, Zetterqvist, Gumpert, & Fazel, 2015).  Studies have shown that individuals who are 
treated with Varenicline have a 1.5 greater chance of discontinuing Varenicline compared to those on placebo (Drovandi, 
Chen, & Glass, 2016).  
 
Nicotine Patch  
 
Mechanism of Action:  Nicotine from cigarette smoke causes dependence by working as an agonist at nicotinic 
acetylcholine receptors (nAChRs).  When nAChRs are activated they release different types of neurotransmitters 
depending on the receptor that was activated. When nicotine binds to α4β2 nAChRs it increases the release of dopamine 
which has effects within the reward and addiction centers in the brain. Nicotine patch work as agonists of nAChR type 
α4β2 therefore stimulating the release of dopamine to reduce nicotine withdrawal symptoms.  
 
Rationale for Use: Nicotine patch decreases symptoms of physical withdrawal and eliminates acute reinforcing effects of 
nicotine so that patients are able to concentrate their efforts on behavioral and psychological components of becoming 
tobacco free.  Nicotine patch is now the cornerstone of tobacco use treatment pharmacotherapy.  Patients generally tend 
to be more compliant with nicotine patches than other FDA‐approved nicotine replacement treatment medications as the 
patch requires dosing only once a day and because they are the least conspicuous to administer.  Added benefits are that 
nicotine patches deliver consistent levels of nicotine during a 24‐hour period and can be used with other smoking 
cessation pharmacotherapies.   
 
Dosing:   Dosing is variable depending on cpd:   
EXAMPLE Dosing for 12 weeks of treatment:  Take one 21 mg Patch per day for 8 weeks, then one 14 mg patch per day for 
2 weeks, then one 7 mg patch for 2 weeks. Tapering however is optional and is not evidence‐based. Further instructions 
for use: Patch can be worn 24 hours per day and then move the site of the patch each morning. If the patient experiences 
insomnia or disturbing dreams from wearing a patch at night, the patient can remove the patch before sleep.   
 
Common Side effects: Only 4% of smokers stop using the transdermal nicotine patch due to adverse effects, a lower rate 
than is found in other smoking cessation medications.  The most commonly reported adverse effects for those who quit 
using patch due to a side effect are provided in the table below by Mills, Wu, Lockhart, Wilson, and Ebbert (2010).  
 
 


Version Date: 02/26/2020 
 
 
Bupropion (Zyban) 
 
Mechanism of Action:  Bupropion was originally developed as an anti‐depressant and is still widely used for this purpose 
(Siu & Tyndale, 2007; Slemmer, Martin, & Damaj, 2000). Bupropion provides relief of withdrawal symptoms differently 
than nicotinic medications. The medications described above, Varenicline, patch and immediate release medications, bind 
to and stimulate nicotinic receptors.  Bupropion on the other hand, is an atypical antidepressant with effects on dopamine 
and norepinephrine.  During nicotine withdrawal there are decreased synaptic levels of dopamine (reward, satisfaction), 
norepinephrine (attention, alertness), and serotonin (sense of ease, peace) in neuronal synapses.  Bupropion acts as a 
reuptake inhibitor increasing synaptic levels of dopamine and norepinephrine (but not Serotonin).  As such, bupropion is 
thought to reduce feelings of anhedonia (inability to feel satisfaction/ reward) and concentration difficulties (alertness) 
that are major symptoms of withdrawal.  
 
Rationale for Use:  As a monotherapy, Bupropion vs. placebo shows OR = 1.85, which is roughly as effective as patch with 
OR = 1.9. Direct comparison of bupropion to patch shows no statistically significant difference.  Bupropion in some studies 
produce a higher abstinence rate in smokers with high scores in depression (Stapleton et al., 2013). 
 
Dosing:  Treatment should begin while the patient is still smoking due to delayed treatment effect of 1 week. Patients 
should therefore set a “Quit Day” within the first 2 weeks of treatment with bupropion (GlaxoSmithKline, 2014). Total 
duration of treatment is variable, with some research protocols using 12 weeks and others as much as 6 months.   Dosing 
is as follows (GlaxoSmithKline, 2014): 
Days 1 ‐3: 150mg once daily (total dose 150mg/day) 
Day 4: Remainder of treatment: 150mg twice daily with a minimum interval of 8 hours between doses (total dose = 
300mg/day).   
Further instructions for use: Allow at least 8 hours between doses and avoid taking prior to bedtime to minimize risk of 
insomnia (GlaxoSmithKline, 2014). 
 
Contraindications: The major contraindicated for bupropion are individuals with seizure disorder as bupropion is known to 
lower the threshold for seizures. Those undergoing acute discontinuation of alcohol and sedatives such as benzodiazepines 
should also not be prescribed for the same reason of increased seizure risk. It is also contraindicated in individuals with a 
diagnosis of bulimia or anorexia nervosa (GlaxoSmithKline, 2014). Individuals using Wellbutrin should not be prescribed 
additional bupropion. Bupropion should also not be started in individuals who have been taking Monoamine Oxidase 
inhibitors (MAOi) in the previous 14 days. It should also be avoided in those with hepatic impairment, pregnant women 
and if <18 years old (GlaxoSmithKline, 2014). 
 
Common Side effects: The most commonly reported adverse reactions of bupropion (incidence ≥5% and ≥1% more than 
placebo rate) are: sleep disturbances, dry mouth, rhinitis, dizziness, anxiety, nausea, constipation, and arthralgia 
(GlaxoSmithKline, 2014). 
Insomnia: 30 ‐ 40% 
Dry mouth: 10% 
Constipation, pruritis and pharyngitis: <10% 
 
Approximately 7‐12% of individuals who report these adverse effects discontinue using bupropion, although some studies 
have reported 31 ‐ 33% of individuals on a 300mg dose of bupropion discontinuing medications due to side effects and 
25% of those on 150mg discontinuing medication due to side effects (J. R. Hughes, Stead, Hartmann‐Boyce, Cahill, & 
Lancaster, 2014; Richmond & Zwar, 2003). Allergic reactions such as pruritus, hives, angioedema and shortness of breath 
have been described at a rate of 1‐3 per thousand (J. R. Hughes et al., 2014; Richmond & Zwar, 2003).  
 
5.2.1. Pre‐clinical experience of study drug  
All medications used are FDA‐approved for smoking cessation.  Nicotine patch is provided over the counter without a 
prescription.  Varenicline and Bupropion may be prescribed by primary care medical providers without clinical 
specialization.  No drugs in this study are investigational and all have passed phase 1, 2 and 3 drug trials.  Because only 
FDA‐approved medications are used for this study, and all drugs are commonly used in the general population, drug 
development and safety data has not been provided.   Links to FDA reports are provided below:   
 


Version Date: 02/26/2020 
 
FDA data on Nicotine patch is provided at 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020165Orig1s036lbl.pdf  
 
FDA data on Bupropion (Zyban) is provided at:  
http://www.fda.gov/safety/medwatch/safetyinformation/ucm176815.htm  
 
FDA data on Varenicline (Chantix) is provided at:  
http://www.fda.gov/drugs/drugsafety/ucm436494.htm and at http://www.fda.gov/drugs/drugsafety/ucm330367.htm  
5.2.2. Clinical experience  
All medications used are FDA‐approved for smoking cessation.  Nicotine patch is provided over the counter without a 
prescription.  Varenicline and Bupropion may be prescribed by primary care medical providers without clinical 
specialization.  No drugs in this study are investigational and all have passed phase 1, 2 and 3 drug trials.  Because only 
FDA‐approved medications are used for this study, and all drugs are commonly used in the general population, drug 
development and safety data has not been provided. Links to FDA reports are provided above.    
 
5.3 
Study Purpose/Rationale 
Preliminary studies at Duke University have demonstrated a single method to provide targeted therapy to people that 
smoke through an adaptive pharmacotherapy algorithm (‘Algorithm’)(Christenhusz, Pieterse, Seydel, & van der Palen, 
2007; Rose, 2011; Rose & Behm, 2013, 2014; Rose et al., 2009). Algorithm‐based treatment results show two patterns of 
response to pre‐quit medication treatment: (1) Responders, or those who show a 50% or more drop in cpd during the first 
2 weeks of pre‐quit treatment show higher abstinence rates overall with pre‐quit medication alone, and show minimal or 
no benefit from adding Bupropion; and (2) Non‐Responders, or people who do not decrease their rate of smoking 
substantially on pre‐quit medications show a significant increase in abstinence rates with the addition of Bupropion. 
Subjects are assessed after 2 weeks of pre‐quit treatment, and then non‐responders are given bupropion in addition to 
initial treatment.   
 
 


Version Date: 02/26/2020 
 
6 OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoints 
Analysis 
Primary 
To compare 30‐day continuous 
biochemically confirmed abstinence 
at 12‐weeks post‐TQD in participants 
randomized to adaptive 
pharmacotherapy algorithm vs. 
standard‐of‐care treatment.  
Biochemically confirmed 12‐week post‐TQD 
30‐day continuous abstinence.   
 
This includes Carbon Monoxide Breath Testing 
< 7 ppm and single‐item self‐report of 30‐day 
continuous abstinence.  
 
See Section 13 
Secondary 
To compare 7‐day point prevalent 
biochemically confirmed abstinence 
rates at 2‐ and 12‐weeks post‐TQD in 
participants randomized to adaptive 
pharmacotherapy algorithm vs. 
standard‐of‐care treatment. 
Biochemically confirmed 2‐week and 12‐week 
post‐TQD 7‐day point prevalence abstinence. 
 
This includes Carbon Monoxide Breath Testing 
< 7 ppm and a 7 day diary of cigarette use 
completed prior to in‐person visits.  
 
 
See Section 13 
Secondary 
To compare phone‐based self‐
reported abstinence at multiple time 
points (1, 2, 6, 12, 26 and 52 weeks 
post‐TQD) assessed by phone in 
participants randomized to adaptive 
pharmacotherapy algorithm vs. 
standard‐of‐care treatment. 
Self‐reported 7‐day point abstinence rates via 
phone‐based assessment at 24 hours post‐
TQD, 1‐week post‐TQD, 2‐week post‐TQD, 6‐
week post‐TQD, 26‐week post‐TQD, and 52‐
week post‐TQD. 
 
This includes phone‐based assessment of 
single‐item question on smoking over the last 
24 hours (for 24‐hour and 1‐week phone call 
assessment time points) and over the last 30 
days for 26‐week to 52‐week time points.   
See Section 13 
Secondary 
To compare smoking reduction 
(number of cpd) at 2‐ and 12‐weeks 
post‐TQD in participants randomized 
to adaptive pharmacotherapy 
algorithm vs. standard‐of‐care 
treatment. 
Self‐reported abstinence via diary correlated 
with biochemically‐confirmed 2‐week and 12‐
week post‐TQD 7‐day point prevalence 
abstinence.  
See Section 13 
Secondary 
To compare smoking reduction 
(number of cpd) and on phone‐based 
self‐report at 1, 2, 6, 12, 26 and 52 
weeks post‐TQD in participants 
randomized to adaptive 
pharmacotherapy algorithm vs. 
standard‐of‐care treatment. Phone 
assessments will be compared at 
specific time points and also across 
multiple time points using multi‐level 
modeling.   
Self‐reported abstinence rates via phone‐
based assessment at 24 hours post‐TQD, 1‐
week post‐TQD, 2‐week post‐TQD, 6‐week 
post‐TQD, 26‐week post‐TQD, and 52‐week 
post‐TQD. 
See Section 13 
Exploratory 
To assess demographic variables 
(age, gender, race, education, and 
income) for an association with all 
abstinence outcomes and, if 
significant, will be used as covariates 
in analysis of all abstinence 
outcomes. 
Self‐reported demographic information 
assessed through surveys administered at the 
baseline visit.   
See Section 13 
Exploratory 
To assess potential baseline (pre‐
intervention) predictors of 
abstinence including self‐reported 
dependence, stress, anxiety, 
depression, alcohol and drug use, 
and self‐efficacy.  If a baseline 
variable is found to be associated 
with abstinence, it will be further 
assessed as a moderator of 
abstinence.   
Self‐reported baseline standardized measures 
on these psychological constructs assessed 
through surveys administered at the baseline 
visit.   
See Section 13 
Exploratory 
To assess change in self‐reported 
measures at baseline (pre‐quit) to 2‐ 
and 12‐weeks post‐TQD on repeated 
standardized measures of nicotine 
dependence, stress, anxiety, 
depression, and self‐efficacy.  If a 
Self‐reported baseline and also 2 and 12 week 
post quit standardized surveys on these 
psychological measures assessed through in‐
person surveys 
See Section 13 


Version Date: 02/26/2020 
 
measure is found to change 
significantly from baseline to a post 
quit time point, it will be assessed as 
possible mediator of abstinence 
outcomes.   
 
 
Exploratory 
To compare baseline scores on 
anxiety, depression, and stress for 
their effect on allocation to 
Responder or Non‐Responder in the 
adaptive and standard treatment.   
 
Self‐reported baseline standardized measures 
See Section 13 
Exploratory 
To compare phone‐assessed non‐
standardized single‐item questions 
on urges, withdrawal, confidence and 
motivation at 1, 2, 6, 12, 26 and 52 
weeks post‐TQD.  If a measure is 
found to change significantly from 
baseline to a post quit time point, it 
will be assessed as possible mediator 
of abstinence outcomes.  Phone 
assessments will be compared at 
specific time points and also across 
multiple time points using multi‐level 
modeling. 
Self‐reported response via phone‐based 
assessment at 48 hours post‐TQD, 1‐week 
post‐TQD, 2‐week post‐TQD, 6‐week post‐
TQD, 26‐week post‐TQD, and 52‐week post‐
TQD on individual non‐standardized questions 
on each of these psychological constructs.   
See Section 13 
Exploratory 
To conduct a cost‐benefit analyses on 
allocation to adaptive 
pharmacotherapy algorithm vs. 
standard‐of‐care treatment from the 
perspective of multiple stake holders: 
smokers, healthcare systems 
(clinics/hospitals), insurance 
companies, and employers. 
 
Biochemically confirmed abstinence measures 
as well as phone measures, demographic 
measures and financial questions and work 
questions (see Appendix 3 and 12)   
See Section 13 
Feasibility 
Demographics of patients at DSCP 
and Duke CSC 
Demographic variables assessed 
See Section 13 
Feasibility 
Medications used 
Medication selection at randomization 
See Section 13 
Feasibility 
Attendance at DSCP appointments 
Attendance recorded in EMR 
See Section 13 
Feasibility 
Referral routes to DSCP 
Referral clinic/route recorded 
See Section 13 
Feasibility 
Medication side effects 
Side effects queried during in‐person and 
phone call assessments 
See Section 13 
Feasibility 
Medication adherence 
Medication use as reported via daily diary 7 
days prior to in‐person visits.  
See Section 13 
 
 


Version Date: 02/26/2020 
 
7 INVESTIGATIONAL PLAN 
7.1 
Study Design 
This study is a double‐blinded, randomized‐controlled trial. Participants will be randomized to Varenicline‐ or Nicotine 
Patch‐based adaptive pharmacotherapy algorithm or to standard treatment with Varenicline or the Nicotine patch.  
7.1.1. Dose Modification 
Dosing of medications will follow FDA recommendations. If a participant experiences a side effect or symptom that 
may be ameliorated by dose adjustment (e.g. nausea while using the nicotine patch), the study physician or Physician 
Assistant will make these adjustments. The decisions to make the adjustments will be based on clinical judgment.  
7.1.2. Safety Considerations 
All study participants will be provided with a list of possible common adverse events related to all of the medications 
used within the consent form.  They will be asked to contact the CTA by phone if they experience side effects. They 
will also be given contact information for the study Medical Supervisor (Dr. Davis).  All information on side effects will 
be directed to the study Physician or Physician Assistant.  Additional monitoring will be provided at every phone call by 
the CTA. The participants are asked about possible side effects just after starting medications, before, on and just after 
the quit day and at other time points.   
7.1.3. Missed Doses 
CTA will ask about the use of medications and will enter information about missed doses into their report.  At each 
visit, the CTA will request that the participant bring all of their medication. The CTA will count the remaining pills and 
record this for medication compliance monitoring.    
7.1.4. Concomitant Medications/Therapies  
Participants enrolled in the study will continue on the medications that they are taking at the time they start the 
study.  They will be asked not to take additional tobacco use treatment medications during the study.  If they start 
new medications during the study, they will be asked to report this to the CTA.   
7.1.5. Study Drug Blinding 
Subjects are blinded to their active medications. Study personnel who are in contact with participants, including the 
CTA, study clinician, and PI, are blinded to active medication.    
7.1.6. Randomization 
Randomization will occur through an open source randomization program “Research Randomizer” developed for 
randomization of subjects in psychology and medication trials.  This can be found at https://www.randomizer.org/.  To 
simulate clinical treatment, the study design provides for subject choice into one of two arms: Varenicline‐based 
treatment (n=150) or Nicotine Patch‐based treatment (n=150).  Once the initial treatment arm is chosen, subjects will 
be randomized to Varenicline adaptive pharmacotherapy (n=75) vs. Varenicline alone (n=75), or similarly nicotine 
patch adaptive treatment (n=75) vs. nicotine patch alone (n=75).   
7.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration 
 
All dosing schedules used are based on FDA‐approved dosing for these FDA‐approved medications ‐ but with minor 
modifications to fit study design requirements.  For example:   
 
Varenicline: Varenicline for control group is dosed exactly as normally prescribed but is continued for 12 weeks instead of 
11 weeks post quit.  In study group subjects, Varenicline is also used exactly as normally prescribed but is started 4 weeks 
prior to TQD instead of 1 week prior.   


Version Date: 02/26/2020 
 
Bupropion:  Bupropion is dosed exactly as is described for smoking cessation (started 1 week prior to quit day, continued 
for 12 weeks).   
Nicotine Patch:  Nicotine patch is dosed according to patient’s use of nicotine – smokers who use 10 cpd or fewer will be 
on 14 mg patch, those who smoke 11‐20 cpd will use a 21 mg patch and those who smoke over 20 cpd will be on a 42 mg 
patch.  This parallels findings in our trial on adaptive treatments using nicotine patch in which participants were 
randomized to pre‐quit nicotine patch of 21 mg vs. 42 mg with the finding that high use smokers showed higher abstinence 
(with allocation arms combined) using 42 mg Nicotine Patch, whereas low‐use smokers showed higher abstinence (with 
allocation arms combined) using a 21 mg Nicotine Patch. In a follow‐up study, participants were given a nicotine patch of 
42 mg for CO >30 and 21 mg patch for CO ≤ 30. Post‐hoc regression analysis showed that a CO level of 30 was most highly 
correlated with 23 cigs/day (Rose & Behm, 2013). 
7.3 
Rationale for Correlative Studies 
An observational study is being conducted on all patients of the DSCP, as well as a phone‐based intervention study. 
Enrollment in either of these studies will exclude a participant from enrolling in this trial. 
 
A qualitative study is being conducted on shared‐decision making in lung cancer screening that may include some overlap 
of participants as well. However, this study is purely qualitative and includes no pharmaceutical or behavioral interventions 
so should not interfere with the present study being conducted.  
 
7.4 
Definition of Evaluable Subjects, On Study, and End of Study 
Participants who enroll in the study will be “evaluable.”  De‐identified data from subjects who sign consent for screening 
will also be used for creation of the Consort Diagram – to show which individuals were excluded or did not sign consent vs. 
those who were enrolled.  Data from subjects who withdraw from the study will still be considered evaluable.   
 
7.5 
Early Study Termination 
This study can be terminated at any time for any reason by the PI‐sponsor – the National Institutes on Drug Abuse.  If this 
occurs, all subjects on study will be notified as soon as possible.  Additional procedures and/or follow up should occur in 
accordance with Section 10.6, which describes procedures and process for prematurely withdrawn patients.  
8 STUDY DRUG 
8.1   Names, Classification, and Mechanism of Action 
Varenicline Tartrate 
Alternate names: Varenicline, Chantix 
Type of Study drug class: smoking cessation medication 
Mechanism of action: Acetylcholine‐Nicotinic receptor partial agonist/antagonist  
 
Bupropion Hydrochloride – sustained release 
Alternate names: Bupropion SR, Zyban, Wellbutrin.  
Type of Study drug class: Antidepressant, appetite suppressant, smoking cessation medication  
Mechanism of action: inhibits reuptake of synaptic dopamine and norepinephrine.   
 
Nicotine patch 
Alternate names: Nicoderm, transdermal nicotine patch 
Type of Study drug class: smoking cessation medication  
Mechanism of action:  Acetylcholine‐Nicotinic receptor agonist   
8.2   Packaging and Labeling 
All medications will be labeled according to Investigational Chemotherapy Service (ICS) Standard Operating Procedures to 
include at least: drug name/strength, quantity, lot number, and expiration or retest date.  Placebo medications will be 
provided in non‐descript packaging, similarly to non‐placebo medications.   


Version Date: 02/26/2020 
 
8.3   Supply, Receipt, and Storage 
Pfizer will provide Varenicline and placebo Varenicline; nicotine patches, bupropion and placebo bupropion will be 
provided by Central Compounding Pharmacy Incorporated. CVS brand clear adhesive bandages will be purchased to serve 
as placebo nicotine patches. For individuals who do not have an adhesive allergy, but instead have other forms of skin 
sensitivity such as discoloration, redness, tenderness (which can be related to the adhesive used in specific brands of 
patch), an alternate placebo or active patch will be purchased. This will provide an alternative for participants who express 
concerns about these types of issues but would like to continue using nicotine patch.  ICS will be responsible for managing 
the receipt and storage of all pharmaceuticals and placebo medications.  
8.4   Dispensing and Preparation 
Pharmaceuticals will be prepared and dispensed according to ICS Standard Operating Procedures. Study staff will collect 
the participant’s pharmaceuticals from the ICS once the participant has arrived at the clinic and dispense them during the 
Study Visit.   
8.5   Compliance and Accountability 
Participants will be asked to return un‐used medications at each visit.  There are 4 study assessment visits at which 
medication management (Unused Medication Count and Dispensing Medications) will occur: Enrollment visit, Medication 
Response Visit, 2‐week post quit visit, 12‐week post quit visit:  
Enrollment Visit: Provide 3 weeks of Medications  
Medication Response Visit: (2‐weeks after Enrollment visit): Provide 4 weeks of Medications (through quit day and 
through 2‐week post quit visit) Unused medication count) 
2‐week post Quit Visit: (4 weeks after Medication Visit):  Provide 9 weeks of Medications (through 12‐week post quit 
visit) (Unused medication count)  
12‐week post quit visit: (10 weeks after 2‐week post quit visit) (Unused medication count)  
 
During each Unused Medication Count, the participant will bring unused medications to the study assessment visit.  
The CTA will then count these medications and record the outcome for an assessment of medication adherence.  This 
data will also be recorded at ICS.  In addition, ICS will collect all used medication bottles.  
8.6   Disposal and Destruction 
ICS will be responsible for destruction of unused medications and will follow standard research pharmacy procedures for 
this.  
9 SUBJECT ELIGIBILITY 
Patients who consent to participate in the study will be screened for the following inclusion/exclusion criteria. 
9.1 
Inclusion Criteria (assessed by research staff and/or study medical provider) 
1. Age 18 years or older 
2. Actively smoking 5 or more cigarettes per day for at least one year 
3. Have a median CO of at least 7 ppm (on carbon monoxide breath test) 
4. Willing to set a quit date within 6 weeks 
5. Willingness to take Varenicline OR nicotine patch (patient choice) and Bupropion 
6. Access to a telephone  
9.2       Exclusion Criteria (assessed by research staff and/or study medical provider) 
1. 5 or above for women OR 6 or above for men on the Alcohol Use Disorders Identification Test (AUDIT‐C) are 
considered a “positive” screen and will require additional clinician assessment to determine if an alcohol use disorder 
is present.  
2. Illicit drug use within the last month 
3. 3 or above on Patient Health Questionnaire (PHQ‐2) Depression Scale or >0 in PHQ‐9 question 9 
4. Daily use of a second form of tobacco or nicotine or smoking a product other than combustible cigarettes (e.g. e‐
cigarettes, cigars, chewing tobacco, snuff, hemp) 
5. Current use of a smoking cessation medication (e.g. nicotine replacement, Varenicline, Bupropion) 


Version Date: 02/26/2020 
 
6. Report of pregnancy, attempting to get pregnant, or actively breast feeding or  positive urine pregnancy test (only 
given to females with child bearing potential)  
9.3       Exclusion Criteria (assessed study medical provider) 
 
7. Medical contraindication to the use of Varenicline or Nicotine Patch, or Bupropion (including seizure disorder) 
8. Brain abnormality that would increase the patients risk for a seizure (including but not limited to a stroke or brain 
tumor)  
9. Bulimia or anorexia 
10. Currently undergoing discontinuation of alcohol or sedative (including benzodiazepines, barbiturates, or antiepileptic 
drugs) 
11. Use of MAO‐inhibitor (currently or in the last 14 days) 
12. Taking Linezolid or intravenous methylene blue.  
13. Significant adverse reaction to bupropion in the past 
14. Symptomatic cognitive or emotive disorder such as untreated schizophrenia, severe untreated depression, anxiety.  
15. Uncontrolled hypertension (systolic BP >160 mm Hg, diastolic BP >100 mm Hg) or hypotension 
16. Chest pain in the last month (unless history indicates a non‐cardiac source) or myocardial infarction in the past year 
17. Unstable irregular heart rhythm 
18. Symptomatic cardiac disorder  
19. Moderate renal impairment  or mild hepatic impairment (study provider discretion)  
20. Current symptomatic lung disorder/disease (including but not limited to COPD, emphysema, and asthma) that 
requires oxygen  
21. Migraine headache occurring more than once per week 
22. Unexplained fainting spell within the last month 
23. Uncontrolled diabetes (blood sugars >200 more than once per week, suffering from complications or on insulin) 
24. Current cancer or treatment of cancer in the past 6 months (except basal or squamous cell skin cancer) 
25. History of Tuberculosis or positive PPD 
26. Suicidal ideating within the past 12 months or attempted suicide within the last 10 years.  
27. Psychiatric hospitalization in the past 12 months 
28. Red dye allergy 
29. Any other major medical conditions (study provider discretion) 
 
  
 


Version Date: 02/26/2020 
 
10 TRIAL PROCEDURES AND ASSESSMENTS 
Relationship of this study to the Duke Translational Smoking Cessation Program (TSCP) and Duke Center for Smoking 
Cessation (CSC)  
Study recruitment will take place among a clinical population via three routes ‐ the TSCP Clinics, Duke Primary Care (DPC) 
Clinics, and the Center for Smoking Cessation (CSC).  
 
Duke Translational Smoking Cessation Program (TSCP): Most patients in this study will be recruited through the Duke 
TSCP clinics – a network of six clinics throughout the Duke University Health System (DUHS) that receive roughly 250 
patient referrals per month. The TSCP is a growing program expanding to serve patients across Duke Health. Dr. James 
Davis, the PI for this study, is Director of the TSCP and oversees all TSCP personnel and processes. Each TSCP Clinic site 
contains a provider trained in tobacco cessation treatment (typically an APP (Advanced Practice Provider)) who performs a 
thorough evaluation, conducts physical exams and prescribes medication and a Medical Assistant or Staff Assistant who 
assists with data collection.  The TSCP is designed with a research infrastructure in which data is collected in a standardized 
format and research staff who recruit patients are present on site for studies. The TSCP contains centralized operations 
including a clinic coordinator who calls patients for scheduling and follow up.  Every patient who is scheduled for an 
appointment at a clinic within the TSCP will be  screened for research study eligibility. If a patient could potentially be 
eligible for a research study, a note will be made in their medical chart. Research staff will then attempt to reach out to 
them to see if they are interested in participating in a research study (via MyChart message and then via phone). If the 
patient is interested in the study and meets the inclusion criteria, the patient will be scheduled to meet research staff at 
the TSCP clinic or the CSC for a screening visit.  If the potential participant is not interested in a research study or not 
eligible, a note will be made in their medical record and they will be encouraged to keep their regularly scheduled clinic 
visit.  
 
Duke Primary Care (DPC):  The study will also recruit participants through the Duke Primary Care (DPC) Clinics. 
Authorization has been provided by the DPC Research Consortium, which will provide access to smokers who have 
consented to be contacted for research. The Research Consortium manages multiple studies to avoid conflict between 
studies and will provide access to three DPC Clinics. DPC includes a network of 40 primary care clinics throughout Duke 
University Health System. Patients who attend visits with DPC medical providers at within Duke Primary Care are screened 
to see if they are willing to be contacted to find out about available research. DPC patients who are identified within the 
Electronic Health Record as being “current smokers” will be available for contact for our study. Using a regularly generated 
report, research staff will use participant MRN to look at their medical record to screen for eligibility (name, mailing 
address, email address, phone number, age, smoking history, allergies, emergency department visits for substance use, 
medications, and medical diagnoses). Ineligible participants will not be contacted. If eligible, research study staff will 
contact the eligible participant via phone and MyChart message to describe the study. MyChart messages will include 
information on opting out (center phone number). Any voicemails left will be non‐descript and only including brief 
information that they may be eligible for a research study at Duke and a phone number to reach back out (no information 
provided on smoking status).  If participants have previously opted‐out of research (as noted in their medical record), they 
will not be contacted. If they are interested and meet inclusion criteria, the research staff will schedule them for a 
screening visit at the Duke Center for Smoking Cessation (CSC) (central study site). 
 
Other Research Studies: Potential subjects will be recruited through pre‐screen failures from other studies at the CSC. 
There are currently several studies recruiting smokers from communities in and around Durham, North Carolina through 
newspaper flyers, internet and TV advertisements, and word‐of‐mouth. If potential subjects fail to meet the pre‐screening 
study requirements for these studies (Pro: 00074741, Pro: 00042277) at the CSC, but are still interested in research, they 
will be routed to a CTA to be pre‐screened for this study over the phone. If potential subjects meet the pre‐screening study 
requirements and are still interested in participation, they will attend a physical screening session at the Duke CSC, located 
at 2424 Erwin Road, Suite 201, Durham, NC  27705. At the screening on‐site visit, a CTA will meet with the patient in a 
private area of the CSC (consent room) and provide the patient with the Study Consent Form for review. 
 
Advertisements: Subjects will be recruited through internet‐based ads on free websites (for example, Craigslist). The ad 
will feature a phone number and contact email for potential participants and can be found in the Recruitment section. A 
physical copy of this ad may also be produced to be used as a flyer advertising the study in Durham and the surrounding 
areas.  
 


Version Date: 02/26/2020 
 
Consent: Interested individuals will be provided with the Study Consent Form (CF), which provides a description of the 
study.  The CTA will review the consent form with the potential participant, read key sections out loud, clarify terms as 
needed, and answer questions. Ability to read and understand English will be assessed at this time. If unable, the consent 
process will be discontinued. After reviewing the CF, if the interested individual is interested in participation in the study, 
they will they will be asked to sign consent in order to continue screening (completion of exclusion criteria and pregnancy 
testing). This will include assessment of data collected in EPIC specifically for the Duke Smoking Cessation Program Initial 
Clinic Visit. The study medical staff (PA or MD) will have access to the potential participant’s EPIC record in order to review 
the Duke Smoking Cessation Program Initial Clinic visit for participant eligibility as well as other pertinent elements of the 
patient’s medical record to ensure their safe inclusion in the study.  Individuals who pass Inclusion/Exclusion Criteria will 
be required to take a urine pregnancy test if they are of child‐bearing potential, as defined by the Duke IRB. 
 
SCHEDULE OF ACTIVITIES 
 
Screening 
Phase  
Treatment Phase 
End of 
Treatment  
Phone Follow 
up Period 
End of Study 
 
Screening 
Visit 
Enrollment 
Visit 
Medication 
Response 
Visit  
2-week 
post Quit 
Visit  
12-week Post 
Quit Visit 
(Discontinue 
Medications) 
Calls 1-9 
52-week post 
quit phone 
call  
Assessments/Observations 
 
 
 
 
 
 
 
Assessment in-person 
X 
X 
X 
X 
X 
 
 
Obtain Informed Consent 
X 
 
 
 
 
 
 
Assessment of Inclusion/Exclusion 
Criteria.  Urine pregnancy test 
X 
 
 
 
 
 
 
Vitals and CO breath test 
X 
X 
X 
X 
X 
 
 
Psychometric measures 
X 
 
 
X 
X 
 
 
Dispense Medications  
 
X 
X 
X 
 
 
 
Assess Medications 
 
 
X 
X 
X 
 
 
Phone Call Assessments 
X 
X 
X 
X 
X 
X 
X 
Assess Adverse Events 
 
X* 
X 
X 
X 
X 
X 
Payment  
 
X 
X 
X 
X 
 
X 
*The Adverse Events questionnaire will be administered at the Enrollment visit in order to obtain baseline data on a patient’s 
symptoms to better understand if the development of any SE is related to study drugs.  
10.1 Screening Examination 
The screening examination will take place on the day of the screening visit.  Subject data to be collected at the Screening 
Examination includes the following baseline measures: contact information questionnaire, demographics questionnaire, 
smoking‐related medical history questionnaire, TSCP smoking history questionnaire, recent smoking history questionnaire, 
medication use and intolerance questionnaire, financial questionnaire, work break questionnaire, cost of smoking 
questionnaire, general health questionnaire, cancer questionnaire, self‐efficacy questions, Fagerstrom Test for Nicotine 
Dependence (FTND), Mood and Physical Symptoms Scale (MPSS), Patient Health Questionnaire (PHQ‐2 as well as PHQ‐9 
question 9), Generalized Anxiety Disorder‐2 (GAD‐2), Alcohol Use Disorders Identification Test (AUDIT‐C), and the 
Perceived Stress Test (PSS‐4). The subject will also complete a urine pregnancy test if female and of child‐bearing potential.  
 
The urine pregnancy test will be conducted by the CTA or other study staff with the appropriate training. Most information 
except the urine pregnancy test results will be documented in the EMR because these assessments are all part of standard 
clinical practice within the TSCP. If the screening visit occurs at the CSC, outside of the normal TSCP clinic, all information 
will be collected on paper forms or in REDCap. If the screening visit occurs at the TSCP during a routine clinic visit, the 
study Physician or Physician Assistant will review the visit documentation to assess eligibility. In the event of a screen 
failure, documentation of this will be noted in eResearch. Participants that fail the screening process will receive follow‐up 
from the study physician to ensure the participant has been connected to appropriate clinical care.  
 


Version Date: 02/26/2020 
 
Enrollment/Randomization Visit:  If an individual meets the criteria to be enrolled in the study, they will be asked to come 
to the Enrollment/Randomization Visit.  At this visit, the individual will be enrolled (given a study ID) and randomized to 
adaptive vs. non‐adaptive treatment. The CTA will notify the research pharmacy of the enrollment and randomization 
status and will pick up medications/placebos for the participant then give these to the participant with a description of 
how to use them. The participant will then be scheduled for follow up visits in 2 weeks (Medication Response Visit) and 2‐ 
and 12‐week post quit. They will also be entered into the phone‐based follow up system (see Phone‐based Assessment 
Time Table below).  At the point of Enrollment, all payment for TSCP services will stop, and participants receive free 
treatment, medications etc. through the study.  
10.2 Treatment Period 
The following is an overview of active treatments and then active and placebo treatments for participants allocated to 
adaptive therapy and standard therapy groups:  
 
Figure 2. Adaptive Pharamcotherapy Protocol (n=150) 
VARENICLINE‐BASED TREATMENT  
Participant choses Varenicline‐based treatment and is then 
randomized to Adaptive Treatment arm (N=75)   
NICOTINE PATCH‐BASED TREATMENT  
Participant choses Nicotine patch‐based treatment and is then 
randomized to Adaptive Treatment arm (N=75)   
VARENICLINE NON‐RESPONDER 
4 weeks prior to TQD: Start Varenicline  
2 weeks prior to TQD, DOES NOT reduce cigs/day by > 50% 
1 week prior to TQD: Start Bupropion  
Use Varenicline + Bupropion to 12 weeks post TQD 
NICOTINE PATCH NON‐RESPONDER 
4 weeks prior to TQD: Start Nicotine Patch 
2 weeks prior to TQD, DOES NOT reduce cigs/day by > 50% 
1 week prior to TQD: Start Bupropion  
Use Nicotine Patch + Bupropion to 12 weeks post TQD  
VARENICLINE RESPONDER 
4 weeks pre‐TQD: Start Varenicline  
2 weeks prior to TQD ‐ DOES reduce cigs/day by > 50% 
1 week prior to TQD: Start Placebo Bupropion  
Use Varenicline + Placebo Bupropion to 12 weeks post TQD 
NICOTINE PATCH RESPONDER 
4 weeks pre‐TQD: Start Nicotine Patch   
2 weeks prior to TQD ‐ DOES reduce cigs/day by > 50% 
1 week prior to TQD: Start Placebo Bupropion  
Use Nicotine Patch + Placebo Bupropion to 12 weeks post TQD  
 
Standard Treatment Regimens: Participants who chose either Varenicline or Patch‐based treatment but who are randomized 
to standard treatment will be given Varenicline or Nicotine Patch with what is now considered standard‐of‐care treatment. 
Varenicline Standard Treatment arm will start Varenicline 1 week prior to the TQD and continue for 12 weeks post TQD.  
Nicotine Patch Standard Treatment arm will start nicotine patch on the TQD and continue for 12 weeks post TQD.  Placebo 
medications are used to match Adaptive Treatment Protocols and shown in Figure 3.   
 
Figure 3. STANDARD PHARMACOTHERAPY PROTOCOLS (n=150)  
VARENICLINE‐BASED TREATMENT  
Participant choses Varenicline‐based treatment and is then 
randomized to Standard Treatment arm (N=75)   
NICOTINE PATCH‐BASED TREATMENT  
Participant choses Nicotine patch‐based treatment and is then 
randomized to Standard Treatment arm (N=75)   
VARENICLINE STANDARD TREATMENT 
4 weeks pre‐TQD: Start Placebo Varenicline  
1 week prior to TQD – Switch to Active Varenicline 
1 week prior to TQD: Start Placebo Bupropion  
Use Varenicline + Placebo Bupropion to 12 weeks post TQD 
NICOTINE PATCH STANDARD TREATMENT  
4 weeks pre‐TQD: Start Placebo Nicotine Patch   
TQD ‐ start Nicotine Patch 
1 week prior to TQD: Start Placebo Bupropion   
Use Nicotine Patch + Placebo Bupropion to 12 weeks post TQD 
 
Medication Dosing for Each Group:   
Varenicline Adaptive Treatment Arm (n=75)  
Participants who chose Varenicline‐based treatment and are then randomized to the Varenicline Adaptive Treatment Arm 
will receive the following:   
4 weeks prior to TQD: Begin Varenicline with this schedule:   
Day 1‐3: 0.5 mg q AM for 3 days (with placebo Varenicline in the evening)  
Day 4‐7: 0.5 mg BID  
Day 8 to end of treatment: 1 mg BID  
This group will remain on 1 mg BID Varenicline x 3 weeks pre‐TQD, then 12 weeks post TQD.  
At the 2 week pre‐TQD visit, this group will be assessed for “Response” to Pre‐quit Varenicline:   
 


Version Date: 02/26/2020 
 
a. Varenicline Non‐Responders: Participants who do NOT show > 50% reduction in cigarettes‐per‐day from baseline will be 
continued on Varenicline, and Bupropion will be added as a “rescue medication.”  
Bupropion will be added to their regimen 1 week prior to the TQD with this schedule:  
 
Day 1‐3: 150 mg q AM  
 
Day 4 to end of treatment: 150 mg BID  
Bupropion will be continued for 12 weeks post TQD.   
 
b. Varenicline Responders: Participants who show > 50% reduction in cigarettes per day from baseline will be continued 
on Varenicline as their only active medication.  
1 week prior to the TQD, Placebo Bupropion will be added with this schedule:  
 
Day 1‐3: 1 placebo pill q AM 
 
 
Day 4 to end of treatment: 1 placebo pill BID  
Placebo Bupropion will be continued for 12 weeks post TQD.    
 
Varenicline Standard Treatment Arm (n=75) 
Participants who chose Varenicline‐based treatment and are then randomized to the Varenicline Standard Treatment Arm 
will receive the following:   
4 weeks prior to TQD: start Placebo‐Varenicline 1 pill BID 
1 week prior to TQD: stop placebo Varenicline and start real Varenicline on the following start up schedule:  
Day 1‐3: 0.5 mg q AM for 3 days (with placebo Varenicline in the evening)  
Day 4‐7: 0.5 mg BID  
Day 8 to end of treatment: 1 mg BID  
This group will remain on Varenicline 1 mg BID x 12 weeks post TQD.  
1 week prior to the TQD: Placebo Bupropion will be added: 
 
Day 1‐3: 1 pill q AM 
 
 
Day 4 to end of treatment: 1 pill BID  
Placebo Bupropion will be continued for 12 weeks post TQD.    
 
Nicotine Patch Adaptive Treatment Arm (n=75)  
Participants who chose Nicotine Patch‐based treatment and are then randomized to the Nicotine Patch Adaptive 
Treatment Arm will receive the following:   
4 weeks prior to TQD: start on Nicotine Patch with the following dosing:  
 
14 mg/day for participants smoking 5‐10 cigarettes per day 
21 mg/day for participants smoking 11‐20 cigarettes per day 
42 mg/day for participants smoking 20 or more cigarettes per day  
This group will remain on this treatment for 4 weeks pre‐TQD, then 12 weeks post TQD.  
At the 2 week pre‐TQD visit, this group will be assessed for “Response” to pre‐quit Nicotine Patch:   
 
a. Nicotine Patch Non‐Responders: Participants who do NOT show > 50% reduction in cigarettes‐per‐day from baseline 
will be continued on Nicotine Patch, and Bupropion will be added as a “rescue medication”.  
1 week prior to the TQD: Bupropion will be added to their regimen with this schedule:  
 
Day 1‐3: 150 mg q AM 
 
 
Day 4 to end of treatment: 150 mg BID 
Bupropion will be continued for 12 weeks post TQD.   
 
b. Nicotine Patch Responders: Participants who show > 50% reduction in cigarettes‐per‐day from baseline will be 
continued on Nicotine Patch as their only active medication.   
1 week prior to the TQD: Placebo Bupropion will be added  
 
Day 1‐3: 1 pill q AM 
 
Day 4 to end of treatment: 1 pill BID  
Placebo Bupropion will be continued for 12 weeks post TQD.    
 
Nicotine Patch Standard Treatment Arm (n=75) 
Participants who chose Nicotine Patch‐based treatment and are then randomized to the Nicotine Patch Standard 
Treatment will receive the following:   
4 weeks prior to TQD they will be started on placebo Nicotine Patch once per day. 


Version Date: 02/26/2020 
 
On the TQD, placebo Nicotine Patch will be stopped and real Nicotine patch will be started with this dosing:  
14 mg/day for participants smoking 5‐10 cigarettes‐per‐day 
21 mg/day for participants smoking 11 or more cigarettes‐per‐day 
This group will remain on Nicotine Patch once per day x 12 weeks post TQD.  
1 week prior to the TQD, Placebo Bupropion will be added:  
 
Day 1‐3: 1 pill q AM  
 
 
Day 4 to end of treatment: 1 pill BID  
Placebo Bupropion will be continued for 12 weeks post TQD 
10.3 End of Treatment 
At the end of treatment (12‐week post‐quit study visit) study staff will administer questionnaires (detailed further in 
section 10.7) and a program evaluation questionnaire.  Participants will return all unused medications and empty pill 
bottles.  
10.4 Follow‐up Period 
Following the End of Treatment, participants will receive two follow‐up phone assessments (detailed further in section 
10.7). These phone assessments will occur at 26‐weeks post‐TQD and 52‐weeks post‐TQD.  If participants are not currently 
abstinent from tobacco at the End of Treatment, a referral to clinical resources within the TSCP will be offered.   
 
Follow up Study Assessment Visits:  At each assessment visit, there will be a standardized evaluation.  The screening will be 
provided through the Duke Smoking Cessation Program for clinical purposes.  Later assessments (Enrollment, Medication 
Response, 2‐ and 12‐week post quit) will be provided by the CTA. During these visits there will be multiple self‐report 
assessments (see below) as well as CO testing.  Finally each participant will receive a total of 10 phone calls out to 1 year post 
quit attempt.  Biochemically confirmed 30‐day continuous abstinence at twelve weeks post‐Target Quit Day is the primary 
endpoint to determine abstinence. Other endpoints, including biochemically confirmed 7‐day point prevalent abstinence at 
two and twelve weeks post‐TQD and self‐reported abstinence rates via phone‐based assessment up to 52‐week post‐TQD, will 
also assess abstinence as secondary measures. 
 
Phone‐based Assessment Time Table:  The phone assessments function to collect data on study participants but also to 
check on difficulties with medications, medication side effects and to remind participants of upcoming visits.  The timing is 
as follows:   
 
1 
1 day after the Enrollment Visit  
2 
1 day before the Medication Response Visit  
3 
1 day pre‐TQD  
4 
1 day post‐TQD  
5 
1‐week post‐TQD visit  
6 
1 day before the 2‐week post‐TQD visit  
7 
6‐week post‐TQD time point  
8 
1 day before the 12 week post‐TQD visit  
9 
26 week post‐TQD time point  
10 
52 week post‐TQD time point  
10.5 End of Study 
Study participation will end with each participant after the 52‐week post TQD phone assessment. If participants cannot be 
reached by phone, they will be contacted by additional means including email or other contact methods listed.   If they are 
still not able to be contacted, they will be listed as “lost to follow up” for purposes of analysis of results (see management 
of missing data in analysis).  If participants are not abstinent from tobacco at the End of Treatment, a referral to clinical 
resources within the TSCP will be offered.  After all participants have completed the study, study data collection period will 
be considered over and the team will begin analysis of results.  Analysis may continue for up to 5 years.  This is necessary 
because of multiple sub‐analyses that may be performed on the large quantity of data generated from this trial.  After this 
5‐year period, it is expected that the trial will lock the data.  


Version Date: 02/26/2020 
 
10.6 Early Withdrawal of Subject(s) 
10.6.1.  Criteria for Early Withdrawal 
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 test procedure results 
‐ 
Protocol deviation 
‐ 
Administrative issues 
‐ 
Disease progression 
‐ 
Pregnancy 
10.6.2. 
 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 attend a Premature Withdrawal Visit.  If this occurs before the 12‐week post quit visit (final 
treatment visit), the Premature Withdrawal Visit will essentially mirror the 12‐week post quit visit (if the subject is 
able).  If the premature Withdrawal occurs after the 12‐week visit, then the patient will simply be called on the phone 
for a final phone call assessment then withdrawn with payment for the encounters he/she was able to complete.   
10.6.3. 
 Replacement of Early Withdrawal(s) 
Sample size estimation from this trial is all based on intent‐to‐treat data and attrition is expected and included within 
the calculation of abstinence rates for all outcomes.  As such, there will be no replacement for premature withdrawal 
of subjects or subjects lost to follow up.   
10.7 Study Assessments 
10.7.1. 
 Medical History 
Medical history assessments will be completed by each subject as part of standard clinical practice. A Clinical Trials 
Assistant or other Key Personnel will review this as part of the screening process. Appendix 1 provides an overview of 
medical history information to be collected and is considered a baseline measure.   
10.7.2. 
 Physical Exam 
A physical exam will be conducted as part of standard clinical practice by the Clinical Tobacco Treatment Specialist 
(TTS medical provider) at the initial visit to the TSCP or Duke CSC. Exam findings however, will not be used to 
exclude patients from participation in the study.  The study only uses medications that are FDA approved for 
smoking cessation.   
Subject‐Rated Non‐Standardized Measures  
At each clinic visit, subjects will complete a number of assessments, some standardized and others non‐standardized. 
All of these measures are completed by the subject as part of standard clinical practice. If the subject consents to 
research, the previously completed information will be recorded as Baseline measures. A Clinical Trials Assistant or 
other Key Personnel will review these as part of the screening process.  
 
At the Initial visit to the TSCP or Duke CSC (baseline visit), the subject will complete the Smoking History questionnaire 
(Appendix 2). This non‐standardized questionnaire provides information on the number of pack years, additional 
tobacco product use, and other drug use. 
 
A subject’s financial and insurance status is also assessed using the Financial Questions (Appendix 3). Cost of Smoking 
(Appendix 4) ascertains the amount the participant pays for cigarettes. 
 


Version Date: 02/26/2020 
 
Medication Intolerance Questions (Appendix 5) determines if a participant’s intolerance to a tobacco treatment 
medication or other contraindications to these medications (e.g. pregnancy) may exclude them from the study. Health 
and Surgery (Appendix 6) and Cancer Questions (Appendix 7) also measure if a participant should be excluded from 
the study for current symptomatic medical conditions. Race and ethnicity, are assessed in Demographics (Appendix 8).  
10.7.3. 
Subject‐Rated Standardized Measures  
A participant’s alcohol use is assessed at Baseline using the AUDIT‐C (Appendix 9). A score of 3 or higher (if female) or 
4 or higher (if male) is considered a “positive” screen, and will require additional assessment from the study clinician 
to determine if the participant can be included in the study..  
10.7.4. 
Subject‐Rated Non‐Standardized Measures to Be Collected at All Clinic Visits 
Thirty‐ and 7‐day point prevalence are assessed in Recent Smoking (Appendix 11), as well as compliance with 
prescribed medications and reasons for non‐compliance, if applicable. 
A participant’s employment status is assessed by Work Questions (Appendix 12); this measure also allows the study 
staff to calculate the amount of time spent during smoke breaks during the work day. 
A participant’s self‐efficacy and motivation to stop smoking are assessed with Predictor Questions (Appendix 13). 
10.7.5. 
Subject‐Rated Standardized Measures to Be Collected at All Clinic Visits 
A number of standardized measures are collected at each clinic visit. All references are listed in each respective 
appendix. A participant’s level of physical nicotine dependence is assessed using the FTND (Appendix 14).   
A participant’s current withdrawal symptoms from cigarettes is assessed in the MPSS‐2 (Appendix 15). Depression is 
assessed using the PHQ‐2 (Appendix 16), anxiety is assessed using the GAD‐2 (Appendix 17) and stress is assessed 
using the PSS‐4 (Appendix 18).  
Finally, participants will be given a 7 day daily diary to complete prior to in‐person study visits. This diary will ask about 
the number of cigarettes smoked per day and daily medication adherence. Participants will be asked to complete this 
prior to their visit. If they have not completed the diary prior to the visit, the RA will use the time‐line follow‐back 
approach to complete the 7 day diary with the participant. This form can be found in Appendix 20. 
10.7.6. 
Subject‐Rated Measures to Be Collected through Phone Assessment 
Participants will be followed up with by phone to answer questions about the following: 
 
Abstinence status 
 
Average number of cpd over the past 24 hours, 7 days, and 30 days 
 
Medications they are taking and side effects they are experiencing, if any 
 
Stress level 
 
Experience of urges 
 
Confidence in their ability to become tobacco free 
These questions are also listed in Appendix 19  
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 designee must assess, through non‐suggestive inquiries of the subject or evaluation of study 
assessments, whether an AE or SAE has occurred.   
 
The DCI Safety Surveillance is responsible for tracking and reporting SAEs to external and internal monitors. The DCI Safety 
Team will also manage any external safety reporting required by NIH and Pfizer. The contact for this is Marla Jordan, (919) 681‐
2351. 
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, whether or not 
related to use of the study therapy.  Abnormal laboratory findings without clinical significance (based on the PI’s judgment) 


Version Date: 02/26/2020 
 
should not be recorded as AEs.  But laboratory value changes that require therapy or adjustment in prior therapy are 
considered adverse events. 
 
From the time the subject signs the informed consent form through the End of Study visit (as defined in Section 10.3), all 
AEs must be recorded in the subject medical record and adverse events case report form. The investigator will follow all 
reportable events until resolution, a return to baseline condition or stabilization. 
 
AEs will be assessed according to the CTCAE version 4.0.  If CTCAE grading does not exist for an AE, the severity of the AE 
will be graded as mild (1), moderate (2), severe (3), life‐threatening (4), or fatal (5). 
 
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  
 
11.1.1. 
 AEs of Special Interest 
There are not AEs of particular concern or interest in this study because all medications used are FDA approved for 
smoking cessation.   
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. 
 
 All SAEs must be followed until resolution, a return to baseline condition, stabilization, or 30 
days after the subject’s last dose of study drug whichever occurs first. Any SAEs that are ongoing at the time the 
clinical database is closed will be reported to the supporting company as unresolved. 
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. All SAE’s will be reported to the IRB.  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 
 
Description of SAE 
 
Description of patient’s condition 
 
Indication whether the patient remains of study 
 
Causality or causal relationship 
 


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De‐identified source documentation (i.e. discharge 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 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: 
 
DCI Safety Surveillance must be notified and they will submit to Pfizer of designee within 24 hours of 
Investigator’s awareness, even if it is not felt to be drug related. Report to Pfizer U.S. Clinical Trial 
Department (Fax # 866‐997‐8322) 
 
The investigator agrees to provide supplementary information requested by Pfizer Drug Safety personnel or 
designee.  
 
SAEs will be reported by the P.I. 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 
SAEs will be reported to the NIDA Serious Adverse Event Tracking and Reporting System (SAETRS) within 72 hours. The 
NIDA Program Official will be kept apprised of IRB actions related to SAEs and any plan to modify the protocol as a 
result of IRB recommendation will be subject to NIDA approval. 
 
In accordance with applicable regulations, investigators will submit the SAE report to their local IRB according to local 
IRB institutional guidelines. 
Duke as the lead center 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 must be submitted to the FDA. This will be done by DCI Safety 
Desk and/or coordinate with study team regulatory coordinator. 
 
These reports are to be filed utilizing the Form FDA 3500 (MedWatch Form) completed by the DCI Safety 
Desk. 
 
The final MedWatch Form must be submitted by the study site to Pfizer within one to two business days of 
submission to the FDA to allow Pfizer time to cross‐report to Pfizer IND. 
11.3 Emergency Unblinding of Investigational Treatment 
Study staff in direct contact with participants (Clinical Trials Assistants, Study Clinician) will not be blinded to the selection 
of Varenicline or Nicotine Patch. All study staff in direct contact with participants will be blinded to the randomization to 
adaptive vs standard treatment algorithms. The Clinical Research Coordinator will have access to participant randomization 
for emergency un‐blinding. In the case that Emergency un‐blinding is required, the Principle Investigator will contact the 
Clinical Research Coordinator directly to obtain the necessary information. Emergency contact information for un‐blinding 
will be the email and cell phone number of Leah Thomas, the study CRC:  leah.thomas@duke.edu; 704‐798‐4498.   
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.    
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; or (3) other situations occur that might warrant stopping the study. The P.I. will include an assessment 
of futility in the annual progress report to NIDA and will consult with the study monitors to assess the impact of significant 
data loss due to problems in recruitment, retention, or data. 


Version Date: 02/26/2020 
 
11.7 Safety Oversight Committee (SOC) 
The 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, includes, but may not be limited to review of safety data, enrollment status, stopping rules if applicable, accrual, 
toxicities, reference literature, and interim analyses as provided by the sponsor‐investigator. The SOC oversees the 
conduct of DUHS 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) 
NIDA website describing the criteria for DSMB states “A Data and Safety Monitoring Board (DSMB) is generally required for 
Phase III clinical trials. For earlier medication trials (Phase I or II and some behavioral clinical trials), a DSMB may be 
appropriate if the study has multiple clinical sites, is blinded, tests a high‐risk intervention, or is conducted in vulnerable 
populations.” According to these criteria, this study should not require a DSMB; it is not a Phase III clinical trial, does not 
use multiple clinical sites, is not blinded, does not test a high‐risk intervention, and is not conducted in a vulnerable 
population. 
 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Monitoring 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject safety and to ensure that 
the protocol is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, good 
clinical practice, and applicable regulatory requirements.  As specified in the DCI Data and Safety Monitoring Plan, the DCI 
Monitoring Team will conduct routine monitoring after the third subject is 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.   
 
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or 
unexpected toxicities, or other concerns and may be initiated upon request of DUHS and DCI leadership, the DCI Cancer 
Protocol Committee, the Safety Oversight Committee (SOC), the sponsor, the Principal Investigator, or the IRB.  All study 
documents must be made available upon request to the DCI Monitoring Team and other authorized regulatory authorities, 
including but not limited to the National Institute of Health, National Cancer Institute, and the FDA.  Every reasonable 
effort will be made to maintain confidentiality during study monitoring. 
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 goals of such 


Version Date: 02/26/2020 
 
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 eCRF 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, Principal Investigator, Study Coordinator, and 
Clinical Trials Assistants, are permitted to make entries or corrections in the CRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system in REDCap and Epic. 
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.   Please 
specify them here. 
 
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 Study Coordinator and CTA 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, if applicable 
‐ 
Review of site study records for completeness 
‐ 
Shipment of all remaining laboratory samples to the designated laboratories. 
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 Primary Objective 
1. The primary study outcome is comparison of 30‐day continuous biochemically confirmed abstinence at 12‐weeks post‐
TQD in participants randomized to adaptive pharmacotherapy algorithm vs. standard‐of‐care treatment. This will be 
confirmed by carbon monoxide breath testing with CO < 7 ppm. 
13.2 Secondary Objectives 
2. To compare 7‐day point prevalent biochemically confirmed abstinence rates at 2‐ and 12‐weeks post‐TQD in 
participants randomized to adaptive pharmacotherapy vs. standard‐of‐care treatment (Varenicline/Nicotine patch).  
3. To compare phone‐assessed self‐reported abstinence at 1, 2, 6, 12, 26 and 52 weeks post‐TQD in participants 
randomized to adaptive vs standard treatment. Phone assessments will be compared at specific time points and also 
across multiple time points using multi‐level modeling.   
4. To compare smoking reduction (number of cigarettes per day) at 2 and 12 weeks post TQD in participants randomized 
to adaptive vs standard treatment.  
5. To compare smoking reduction (number of cigarettes per day) on phone‐based self‐report at 1, 2, 6, 12, 26, and 52 
weeks post‐TQD in participants randomized to adaptive vs. standard treatment. Phone assessments will be compared 
at specific time points and also across multiple time points using multi‐level modeling. 


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13.3 Handling of missing values, censoring, and discontinuations 
An intent‐to‐treat approach will be taken in which any subjects lost to follow‐up after the point of randomization will 
be counted as non‐abstinent.  In addition, a sensitivity analysis will be conducted to determine the impact of 
“missingness” and smoking at previously observed time‐points. 
13.4 
Statistical Hypothesis, Model, and Method of Analysis 
Outcomes will be analyzed using generalized linear regression modeling using an ANOVA‐based design; randomization 
status to both pharmacotherapy and behavioral groups will be denoted using a proxy variable to test primary study 
effects. An alpha criterion of 0.05 (two‐tailed) will be used in all comparisons. 
 
Data Management and Statistical Procedures: All data measures collected during study visits (e.g., smoking 
history, demographics, standardized tests on nicotine dependence, anxiety, stress etc.) will be captured in the 
EMR. Phone‐based data will be captured using REDCap, an encrypted, HIPAA compliant, Duke Translational 
Medicine Institute (DTMI)‐based data collection system allowing for multi‐site data entry, direct participant 
electronic data upload through interface with computer terminals or tablets, time‐based data entry (for use in 
calendar‐based Assessment Visits) and capacity for direct upload into statistical programs SAS, SPSS, R, Excel for 
analysis.  Trained staff (Duke CITI certification) will conduct data integrity processes for REDCap data with 
download into SAS (SAS Institute, Cary NC).   
 
Multilevel Modeling: Given repeated observations across multiple individuals, many of the analyses in this study 
will be derived from multilevel modeling (MLM). MLM models hierarchically organized data, in which data at the 
lowest level of the analysis (e.g., measured at a given time point) can be modeled as a function of time point‐
specific (Level 1) variables and person‐specific variables (Level 2). Unlike repeated‐measures ANOVA, MLM is able 
to also handle imbalanced data with unequal variances across clusters/individuals (Searle S., 1992). In addition to 
modeling between‐person differences in momentary levels of an outcome variable (MLM with intercepts as 
outcome), MLM is also able to model individual differences in changes in momentary outcomes over time (MLM 
with intercepts and slopes as outcomes), also known as latent‐growth curve modeling. Because MLM procedures 
are based on maximum likelihood estimation and use all available data, MLM can accommodate data missing at 
random and is often considered favorable to multiple imputation techniques, which can yield results that vary 
substantially depending on the imputation model and iteration (D, 2012; L & K, 1998). Nevertheless, missing data 
will be examined to determine whether missingness is systematic (i.e., associated with individual baseline 
differences or time‐related changes in observed variables). An intent‐to‐treat approach in which subjects lost to 
follow‐up will be counted as non‐abstinent will also be used to analyze univariate outcomes. An alpha criterion of 
0.05 (two‐tailed) will be used in all comparisons.    
 
Analysis of Primary Outcome: The primary outcome measure is biochemically confirmed 30‐day continuous 
abstinence at the 12‐week post‐Target Quit Day (TQD) confirmed by carbon monoxide (CO) breath testing with CO 
< 7ppm. The study hypothesis is that adaptive treatment arms of the study will show higher smoking abstinence at 
12‐weeks post‐quit attempt vs. non‐adaptive treatment. An intent‐to‐treat approach will be taken to analyze 
primary outcomes such that all subjects who are enrolled in the study will be included in the primary analysis of 
outcomes. Outcomes will be analyzed using generalized linear regression modeling using an ANOVA‐based design. 
An alpha criterion of 0.05 (two‐tailed) will be used in all comparisons.  For a conservative estimation of abstinence, 
subjects lost to follow‐up after the point of randomization will be counted as non‐abstinent. Following this, 
however, a sensitivity analysis will be conducted to determine the impact of this assumption, using multiple 
imputation procedures that model smoking outcomes in terms of “missingness” and smoking at previously 
observed time‐points.  
 
Secondary smoking outcomes: Analysis of secondary smoking outcomes will include comparison of abstinence 
rates in Adaptive vs. Non‐Adaptive groups via self‐reported 7 and 30‐day continuous abstinence and number of 
cigarettes smoked per day at 2‐ and 12‐weeks post TQD. Secondary smoking outcomes will be assessed using 
intent‐to‐treat principles with use of multiple imputation to account for missing data.   
 


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13.2 Exploratory Objectives 
Exploration Analysis: The unique aspects of this proposed intervention, related to development of an adaptive 
approach to smoking cessation treatment is expected to provide a rich database for subsequent exploratory 
analyses. Accordingly, we will conduct a number of such analyses primarily – but not restricted to – investigating 
putative associations between primary outcome measures of abstinence, compliance, attrition, with numerous 
demographic, ecological, clinical, physical, and psychological factors (including but not limited to: age, gender, race, 
income, education, insurance status, nicotine dependence, physical and psychiatric comorbidity), measured and 
tested variously across, between, and within conditions. As we are proposing these studies as exploratory, a‐priori 
assumptions on outcomes, although not excluded, are also not mandated. Modeling strategies and details will 
necessarily be assessed through study outcomes with questions and requisite data not outlined herein.  
13.5.1 Key Exploratory Objective Analysis 
Patient demographics and other baseline characteristics: The unique aspects of this proposed intervention, related both 
to development of an adaptive approach to tobacco use treatment and as an exemplar of a large scale translational study 
into the feasibility and efficacy of service engagement and delivery, is expected to provide a rich database for subsequent 
exploratory analyses. Accordingly, we will conduct a number of such analyses primarily, but not restricted to, investigating 
putative associations between primary outcome measures of abstinence, compliance, and attrition with numerous 
demographic, ecological, clinical, physical, and psychological factors (including but not limited to: age, gender, race, 
income, education, insurance status, nicotine dependence, physical and psychiatric comorbidity), measured and tested 
variously across, between, and within conditions. As we are proposing these studies as exploratory, a‐priori assumptions 
on outcomes, although not excluded, are also not mandated. Modeling strategies and details will necessarily be dictated 
by the structures of both the questions and the requisite data and, hence, are not outlined herein. 
Assessment of potential moderators of primary effect: The following constructs will be assessed as potential predictors of 
abstinence: demographics (age, gender, race, education), smoking history and heaviness, financial status, dependence 
(measured by FTND), urge rating (measured by MPSS), depression (measured by PHQ‐2), anxiety (measured by GAD‐2), 
alcohol use (measured by AUDIT‐C), stress (measured by PSS‐4), and self‐efficacy questions. Constructs that demonstrate 
an association with abstinence will be analyzed for potential moderation. Tests for differential associations of effects of 
baseline characteristics by randomization status on week‐12 smoking abstinence will be based on interaction terms 
crossing randomization status (group) with the tested (putative) baseline predictor. Significance of the estimated 
coefficient associated with the interaction term would indicate that the effect of the tested predictor on abstinence varied 
differentially by treatment assignment. For each baseline predictor, we hypothesize that baseline will be equivalent across 
all randomized arms. In a second series of tests, the above protocol will be used to test for differential rates of change in 
abstinence associated with putative constructs (scales): urge (MPSS‐2), stress (PSS‐4), depression (PHQ‐2), anxiety (GAD‐2). 
As above, the primary test statistic will be based on interaction term crossing the tested scale with group.  
Assessment of potential mediators of primary effect: The following constructs will be assessed to determine whether 
assignment to pharmacotherapy group are associated with change in these constructs pre‐post treatment: urge rating 
(MPSS), depression (PHQ‐2), anxiety (GAD‐2), stress (PSS‐4), self‐efficacy. Positive findings for candidate measures would 
also recommend them for subsequent testing as mediators using formal mediation paradigms (VanderWeele TJ, 2014). 
These methods now supersede the methodology advocated by Baron and Kenny (1986), and are based on a four‐way 
decomposition of the effects of exposure on an outcome in the presence of a putative mediator. That is, using standard 
statistical procedures (i.e. regression), effects are decomposed into four components: i) an effect of the exposure in the 
absence of the mediator, ii) an additive effect where both exposure and the mediator affect the outcome but the mediator 
is not affected by exposure, iii) the mediated interaction where exposure has an effect on the mediator, and iv) a pure 
mediated effect where exposure causes the mediator to have an effect although subsequent presence of the mediator is 
not required.  These components are subsequently used to decompose total estimated effect into the proportions of that 


Version Date: 02/26/2020 
 
effect due to neither mediation nor interaction, exclusively to interaction, to a combined effect including both mediation 
and interaction, and exclusively to interaction.  
Economic Analysis:  An economic analysis of Adaptive vs. Non‐Adaptive pharmacotherapy will be conducted. Dr. 
Santanu Datta, PhD, MBA, a Duke University Health Economist with expertise in cost‐benefit analysis for healthcare 
system program operation will conduct this analysis and oversee prospective data‐collection on cost and time for all 
necessary TSCP operations to generate a prospective economic analysis of adaptive vs. non‐adaptive treatment to 
identify cost‐benefit outcomes from the perspective of smokers, healthcare systems, insurance companies, and 
employers. Cost assessments of adaptive treatment will include: 1) Descriptive statistics to compare overall cost of 
medications for adaptive vs. non‐adaptive treatment. 2) ANOVA modeling to analyze cost of medications per abstinent 
smoker comparing adaptive vs. non‐adaptive treatment. 3) ANOVA modeling to analyze the cost of prescribed 
medications as related to medication non‐adherence and attrition. 4) Mediation analysis on how randomization status 
affects medication adherence and how that relationship is mediated by income.   
 
13.3 Interim Analyses 
1. There will be an interim analysis after completion of the 12 week visit for all 300 participants.  This will include data 
from all Clinical Assessment Visits, but exclude data from phone visits out to 1 year and will be sufficient for early 
initiation of manuscript preparation.    
 
13.4 Sample Size Calculation 
Outcomes: The primary outcome for this study is biochemically confirmed 30‐day continuous smoking abstinence at 12 weeks 
post TQD across all enrolled participants (intent‐to‐treat). Secondary outcomes include smoking abstinence at other time 
points (2 week visit), smoking reduction from baseline to follow‐up visits, assessment of baseline variables as potential 
moderators of smoking behavior, assessment of psychological variables as potential mediators of smoking behavior, and 
assessment of economic outcomes. The sample size for this study was calculated based on effect sizes from prior studies on 
Varenicline and nicotine patch. Abstinence within these two arms will be assessed as secondary outcomes and are not 
expected to reach significance on all secondary outcomes.  The study is powered to reach significance on the primary outcome 
(abstinence across the two arms combined).  
 
Nicotine Patch Based Treatment (secondary outcome):  Power calculation for Nicotine Patch Adaptive Treatment vs. Nicotine 
Patch Standard Treatment is based on abstinence rates observed in prior P50‐funded trials.  In one trial (Rose et al 2013), when 
participants received Nicotine Patch prior to their quit attempt, 41.2% showed >50% reduction in cigarettes‐per‐day 
(considered Patch Responders) whereas 58.8% did not show >50% reduction in cigarettes‐per‐day (were considered Patch Non‐
Responders). “Patch Responders” demonstrated biochemically‐confirmed 4‐week continuous abstinence at the 11‐week post‐
quit attempt of 59.2%, whereas “Patch Non‐Responders,” when left on Nicotine Patch alone showed an abstinence rate of 
16.0%.  When however, the Patch Non‐Responders were given Bupropion in addition to Nicotine Patch, they showed an 
increased abstinence of 28.3%.  If our study were to show similar effect sizes as this prior study, the adaptive treatment group 
with 41.2% responders (abstinence rate = 59.2%), and 58.8% non‐responders given Nicotine Patch + Bupropion (abstinence) 
rate = 28.3%), should show an abstinence rate for responders + non‐responders of 41.0%.  Abstinence rates for Nicotine Patch 
Standard Treatment in several CSC trials using the similar recruitment and exclusion criteria range from 17‐26%. With a 
conservative assumption that we will see the higher abstinence rates in our controls (e.g. 26%), our two Nicotine Patch‐Based 
Treatment groups should show abstinence rates of 41.2% vs. 26%. Sample size calculation using 2‐tail test with continuity 
correction assuming p = 0.05 and power = 80%, yields a minimum sample size of 298 in the nicotine patch arm. This study is 
designed with 150 in the Nicotine Patch arm and so it underpowered to reach this secondary outcome.  
 
Varenicline‐Based Treatment (secondary outcome):  Power calculation for Varenicline Based Adaptive treatment vs. 
Varenicline Standard Treatment is based on abstinence rates observed in prior P50‐funded trials as well as other published 
studies. To estimate the effect of adaptive treatment, a critical consideration is that 4 week Varenicline pre‐cessation 
treatment without adaptation was superior to starting 1 week prior to quit day (Hajek et al 2011). Abstinence rate were 20.8% 
1‐week pre‐quit start time.  Hajek further showed that for participants starting 4 weeks prior to the Quit day, 35.4% of 
participants showed >50% reduction in cigs/day with an abstinence rate of 66.7% whereas 64.6% of participants failed to show 
>50% reduction in cigs/day and had an abstinence rate of 22.6%. The weighted average of these groups = 38.2%.  Sample size 
calculation using 38.2% vs. 20.8% with 2‐tail test with continuity correction assuming p = 0.05 and power = 80%, yields a 
minimum sample size of 208 within the Varenicline arm alone.  This study is designed with 150 in the Varenicline arm and so it 
underpowered to reach this secondary outcome.   


Version Date: 02/26/2020 
 
 
Full Sample (Primary Outcome): Based on these calculations, a sample size of 300 for each of these comparisons should be 
sufficient to demonstrate significant differences between randomized arms (150 vs. 150). The Primary Outcome is a 
comparison of 12‐week post‐TQD smoking abstinence across the study sample (N=300). As stated above, the nicotine patch 
arm will require n=298 to reach significance, and the varenicline arm will require n=208 to reach significance. Neither arm (150 
each) is powered to reach significance.  The two arms together (n=300) are powered to reach primary outcomes. For the 
control group (nicotine patch arm = 26.0%; varenicline arm = 20.8%), an equally weighted sample would result in an abstinence 
rate of 23.4%. For the adaptive treatment group (nicotine patch arm = 41.2%; varenicline arm = 38.2%), an equally weighted 
sample would result in abstinence rate of 39.7%. A sample size calculation using 2‐tail test with continuity correction assuming 
p = 0.05 and power = 80% results in sample size of 248. With 300 participants this study as power of 87% power for showing 
significant results on our primary outcome.   
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.).  
 
The Principal Investigator must obtain protocol re‐approval from the IRB within 1 year of the most recent IRB approval.  
The Principal Investigator must also obtain protocol re‐approval from the CPC within 1 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 or understand 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 


Version Date: 02/26/2020 
 
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, 
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 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 (please specify names and/or titles of authorized individuals as 
stated in key personnel), are permitted to make entries, changes, or corrections in the CRF.  For paper CRFs, errors will 
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 systems, 
REDCap and Epic Dashboard.   
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 his 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 dedicated databases: eResearch, REDCap, and Epic Dashboard, which is housed in an 
encrypted and password‐protected (required:  please specify storage device, i.e. laptop computer, desktop computer, DCI 
file server).  Access to electronic databases will be limited to study staff.  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.    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 Section 11 (Sections 11.7 and 11.8 in particular) along with 
section 12. 
14.7 Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB 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 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. 


Version Date: 02/26/2020 
 
15 REFERENCES 
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16     APPENDICES 
Appendix 1: Smoking Related Medical History 
MEDICAL HISTORY pg. l 
Major Medical Conditions 
Have you had any of the following conditions?  
 Yes   No      Uncontrolled high blood pressure (Hypertension) or hypotension with symptoms (<90/60) 
 
 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      Chest pains related to the heart in the last month__________________________________________ 
 Yes   No      Heart failure 
 
 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, or 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      Use of oxygen 
 
 Yes   No      Asthma 
 
 Yes   No      Other chronic lung disorder such as Tuberculosis, Pulmonary Fibrosis, Sarcoid, or other 
 
 Yes   No      Stroke/TIA (mini-stroke)/brain tumor 
 
 Yes   No      Seizure disorder 
 
 Yes   No      Regular headaches or migraines that occur more than one per week 
 
 Yes   No      Unexplained fainting spells 
 
 Yes   No      Insomnia requiring medications 
 
 Yes   No      Other neurologic conditions 
 
 Yes   No      Problems giving blood samples 
 
 Yes   No      Blood disorder or Anemia requiring iron 
 
 Yes   No      Rheumatic Disease such as Rheumatoid Arthritis, Fibromyalgia, or other 
 
 Yes   No      Sinusitis/Seasonal allergies 
 
 Yes   No      Diabetes with uncontrolled blood sugar (>200 more than once/week) or on insulin 
 
 Yes   No      Thyroid disease/condition 
 
 Yes   No      Current cancer or treatment for cancer in the past 6 months 
 
 Yes   No      Depression/Anxiety/Bipolar disorder/psychiatric hospitalization in the past 3 months 
 
 Yes   No      Suicidal ideation (thinking about ways to commit suicide) within the past 10 years 
 
 Yes   No      Suicide attempt during the last year 
 
 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 
 Yes   No      Anorexia or bulimia 


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 Yes   No      Undergoing acute discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic 
drugs 
 
Please list any illnesses that caused you to miss work or have interrupted your life this past year: 
1. _______________________________________________________ Year: __________ 
2. _______________________________________________________ Year: __________ 
3. _______________________________________________________ Year: __________ 
4. _______________________________________________________ Year: __________ 
5. _______________________________________________________ Year: __________ 
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: __________ 
3. _______________________________________________________ Year: __________ 
4. _______________________________________________________ Year: __________ 
5. _______________________________________________________ Year: __________ 
Women Only: 
Date of last menstrual cycle:  __________________ 
Are you menstruating regularly?       Yes       No 
Are you post-menopausal (natural or from surgery)?       Yes       No 
 
Family History 
Has any first degree family member (child, parent, or sibling) had any of the following illnesses? 
Illness 
Which family member? 
Anemia or Blood Disease 
 


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Cancer 
 
Diabetes 
 
Heart Disease 
 
High Blood Pressure 
 
Severe Mental Illness 
 
Stroke 
 
Substance abuse (alcohol, tobacco, or other) 
 
Other serious illness 
 
 
Medications 
Please list any medications you are allergic to: 
1. 
2. 
3. 
  
Please list all medications you are now taking or have used in the last month (include over-the-counter drugs, vitamins, and 
especially prescriptions). It is okay to skip dates for long-term medications:  
Name of Medication 
Dosage 
Start Date 
Stop Date 
Prescribed for what problem? 
1. 
 
 
 
 
2. 
 
 
 
 
3. 
 
 
 
 
4. 
 
 
 
 
5. 
 
 
 
 
6. 
 
 
 
 
7. 
 
 
 
 
8.  
 
 
 
 
 
Are you taking Linezolid or intravenous methylene blue?    Yes    No    
Have you used monoamine oxidase inhibitors (MAOi) in the past 14 days?    Yes    No    
Have you used experimental or investigational drugs in the past 30 days?    Yes    No    
 
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 
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 30 days?    Yes    No 


Review of Systems 
General: 
 None of these apply 
 Unexplained weight loss or 
gain 
 Fever or chills 
 Fatigue / lack of energy 
 Weakness 
 Trouble sleeping 
 
Skin: 
 None of these apply 
 Rashes 
 Lumps 
 Color change 
 Hair and nail changes 
 
Head: 
 None of these apply 
 Headache 
 Head injury 
  
Ears: 
 None of these apply 
 Decreased hearing 
 Earache 
 Ringing in the ears 
 
Eyes: 
 None of these apply 
 Vision problems 
 Specks 
 Blurry or double vision 
 Flashing lights 
 Redness 
 Pain
 
Nose: 
 None of these apply 
 Stuffiness 
 Discharge 
 Itching 
 Sinus pain 
 Nose bleeds 
 
Throat: 
 None of these apply 
 Teeth/gum problems 
 Dentures 
 Hoarseness 
 Sore tongue 
 Dry mouth 
 Sore throat 
 Thrush 
 Non-healing sores 
 Difficulty swallowing 
 
Neck: 
 None of these apply 
 Lumps 
 Stiffness 
 Pain 
 Swollen glands 
 
Respiratory: 
 None of these apply 
 Cough (dry or wet, 
productive) 
 Shortness of breath 
 Coughing up blood 
 Painful breathing 
 Wheezing
 
Cardiovascular: 
 None of these apply 
 Chest pain or discomfort 
 Tightness 
 Heart 
pounding/fluttering/ 
palpitations 
 Difficulty breathing lying 
down 
 Swelling 
 Shortness of breath with  
activity 
 Suddenly awaking from 
sleep 
with shortness of breath 
 
Gastrointestinal: 
 None of these apply 
 Swallowing difficulties 
 Heartburn 
 Constipation 
 Vomiting 
 Change in bowel habits 
 Rectal bleeding 
 Diarrhea 
 Stomach pain 
 Yellow eyes or skin 
 Change in appetite 
 Nausea 
 


Urinary: 
 None of these apply 
 Frequency 
 Urgency 
 Blood in urine 
 Pain with urination 
 Change in urinary 
strength 
 Incontinence 
 
Vascular: 
 None of these apply 
 Calf pain with walking 
 Leg cramping 
 Leg pains 
 
Musculoskeletal: 
 None of these apply 
 Muscle or joint pain 
 Stiffness 
 Back pain 
 Swelling of joints 
 Trauma 
 
Neurologic: 
 None of these apply 
 Dizziness 
 Fainting 
 Tingling 
 Weakness 
 Numbness 
 Tremor 
 Shaking episodes 
 
Hematologic: 
 None of these apply 
 Bruise easily 
 Bleed easily 
 
Endocrine: 
 None of these apply 
 Heat or cold intolerance 
 Sweating 
 Frequent urination 
 Thirst 
 Change in appetite 
 
Psychiatric: 
 None of these apply 
 Nervousness 
 Memory loss 
 Feeling down 
 
Females only 
 None of these apply 
 Pregnant or currently 
breast feeding 
 
 
 
 
 
 
 
 
 


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Appendix 2: Smoking History 
 
Please answer the following questions are about your history of smoking, use of other products 
and medications.   
 
1. How many cigarettes have you smoked per day, on average? _____ [1-99]  
 
2. How many years have you smoked? ________ [1-99] 
 
 
 
3. Do you usually smoke menthol or non-menthol cigarettes?  
1 = Non-Menthol 
2 = Menthol 
3 = Both 
0 = Don’t know  
 
4. Which of the following tobacco products have you used in the last week? (Check all that 
apply) 
 
1 = Cigarettes 
 
2 = Cigars 
 
3 = Pipes 
 
4 = Hookah 
 
5 = Cigarillos 
 
6 = E-cigarettes 
 
7 = Chewing tobacco 
 
8 = Snuff 
 
9 = Other 
 
5. During the last week did you use any of the following drugs? (Check all that apply)  
 
 
 
1 = Marijuana 
 
2 = Cocaine/Crack 
 
3 = Meth 
 
4 = PCP 
 
5 = Heroin 
 
6 = Opiods such as Morphine, Oxycotin, Percocet, Vicodini, Fentanyl 
 
7 = Benzodiazepines such as Valium, Xanax, Klonopin 
 
8 = Other 
 
 
 


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Appendix 3: Financial Questions 
These next 10 questions are about your finances, medical coverage, and benefits.  
 
1. What is your Gross Yearly Income (include all forms of income)?  
1= Less than $10,000 
2= $10,000 – $24,999 
3= $25,000 – $49,999 
4= $50,000 – $74,999  
5= $75,000 – $99,999 
6= Over $100,000 
0 = Don’t know 
 
2. What is your means of paying for medical services?  (Check all that apply) 
1 = Private Insurance: HMO, PPO, CMO  
2 = Medicare  
3 = Medicaid  
4 = Veteran’s Benefit 
5 =No insurance  
6 = Other 
7 = Don’t know  
8= Not retired    
  
3.  Which one of the following statements best describes your personal financial situation? 
1 = I am in good shape.  I am able to save and plan for the future. 
2 = I am okay.  I am saving a little and I am able to provide for my needs.   
3 = I am barely getting by.  I have to budget carefully and am not able to plan for the 
future. 
4 = I am falling behind.  I have to use savings or go further into debt to pay my bills. 
5 = I am in serious financial trouble and can’t quite see how I am going to make it. 
0 = Don’t know  
 
4.  What is the highest grade or year of school you completed? 
 
1= Less than high school 
 
2= GED 
 
3= High School 
 
4= Some college, but no degree 
 
5= Associate’s Degree (2 year degree) 
 
6= Bachelor’s degree (4 year degree) 
 
7= Graduate education  
 


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Appendix 4: Cost of Smoking 
These next questions are about the cost of cigarettes to you.   
 
1. 
How do you usually buy your cigarettes?   
1 = By the Pack  
2 = By the Carton  
 
3 = Individually  
0 = Don’t know  
 
 
IF 1 = go to Question 43a  
IF 2 = go to Question 43b  
IF 3 = go to Question 43c  
 
 
1a.   How much did you pay for the LAST PACK of cigarettes you bought?  
 
$___ __ . ____ ____  $1.00-$10.00)   
 
1b. How much did you pay for the LAST CARTON of cigarettes you bought?  
 
 $___ __ . ___ ___ ($1.00 – $99.00) 
 
1c. How much did you pay for the LAST CIGARETTE you bought?  
 
 . ___ __¢  ( 0-99¢ ) 
 
 
44. Calculate:  Cost of 1 cigarette:  (Pack holds 20 cigs – so divide by 20) (Carton holds 200 so divide 
by 200) (do not report)  
44a. Calculate Cigs per day x cost of each cig = Cost per day.  Report Cost per day  
44b. Calcualte  Cost per week = cost per day x 7.  Report cost per week  
44c.Calcualte Cost per month = cost per day x 30. Report cost per month  
44d. Calculate Cost per year = Cost per day x 365.  Report cost per year.    


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Appendix 5: Medication Intolerance Questions 
The next questions will help us determine which medications might be appropriate for you.  
 
1. Are you willing to use the Nicotine Patch? 
 
1 = I am willing to use 
 
2 = I would consider using it   
 
0 = Don’t know  
 
2. Are you willing to use nicotine gum or nicotine lozenge?    
1 = I am willing to use 
 
2 = I would consider using it   
 
0 = Don’t know  
IF male, skip questions 3&4.  
 
3. Which best describes any potential plans to get pregnant? 
 
1 = Not applicable (post-menopausal, hysterectomy)  
 
2 = I am pregnant now 
 
3 = I hope to get pregnant in the next 12 months 
 
4 = I hope not to get pregnant in the next 12 months  
 
4. Are you currently nursing?  
1 = YES 
2 = NO 
 
5. Have you been diagnosed with any of the following conditions? (Check all that apply) 
 
1 = Schizophrenia 
 
2 = Bipolar Disorder 
 
3 = Closed Angle Glaucoma 
 
4 = Brain Cancer or Cerebral Aneurysm 
 
5 = Stroke 
 
6 = Seizure 
 
0 = I have none of these conditions 
 
6. Do you currently take anti-seizure medications such as Dilantin, Keppra, Depakote, Tegretol, Lyrica, Topamax, or Lamictal?  
1 = YES 
2 = NO 
0 = Don’t know  
 
7. Do you currently take an MAO Inhibitor such as Linezolid, Isoniazid, Selegiline, Rasagiline, Isocarboxazid, Phenelzine, or 
Tranylcypromine?   
1 = YES 
2 = NO 
0 = Don’t know  
 
8. Are you willing to use Chantix (varenicline)? 
 
1 = I am willing to use 
 
2 = I would consider using it   
 
0 = Don’t know  
 
9. Are you willing to use Wellbutrin (bupropion)?  
 
1 = I am willing to use 
 
2 = I would consider using it   
 
0 = Don’t know  
 
 


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Appendix 6: Health and Surgery 
The next several questions are about your health.   
 
1. Are you planning to have surgery?  
1= I am not scheduled for surgery and do not think I will need surgery in the future.  
2= I am scheduled for surgery  
3= I will probably need surgery, but it is not scheduled  
4 = Other  
 
IF the answer to 1 = 2, ask question 2. 
 
2. What is the date of the scheduled surgery _______________  
 
Appendix 7: Cancer Questions 
The next questions are about cancer diagnosis and treatment  
 
1. Are you currently undergoing diagnosis, treatment, or follow up for cancer or possible 
cancer?   
1 = Yes 
2 = No  
 
Appendix 8: Demographics 
These next three questions are about you.   
1. What is your race?  
1 = American Indian or Alaskan Native 
2 = Asian 
3 = Black or African American 
4 = Native Hawaiian or Pacific Islander 
5 = White 
6 = Other 
0 = Don’t know  
 
2. Do you consider yourself to be Hispanic or Latino? 
1=YES 
2=NO 
0 = Don’t know 
 
3. What is your gender? 
 
1= Male 
 
2= Female 
 
 


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Appendix 9: Alcohol Use Disorders Identification Test (AUDIT‐C)(Bush, 
Kivlahan, McDonell, Fihn, & Bradley, 1998) 
 
The next questions are about your alcohol use. 
 
1. How often do you have a drink containing alcohol? 
0= Never 
1= monthly or less 
  
2= 2-4 times a month 
3= 2-3 times a week 
 
2. How many standard drinks containing alcohol do you have on a typical day? 
0= 1 or 2 
1= 3 or 4 
2= 5 or 6 
3= 7 to 9 
4= 10 or more 
 
3. How often do you have six or more drinks on one occasion? 
0 = Never 
1 = Less than monthly 
2 = Monthly 
3 = Weekly  
4 = Daily or almost daily 
 
 
4. Calculate:  Add all scores of 3 question above together.   
Then reference score to gender:  
3 or higher for females = likely alcohol abuse or dependence   
4 or higher for males = likely alcohol abuse or dependence   
  


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Appendix 10: Drug Use Question 
 
1. How many times in the past year have you used an illegal drug or used a prescription 
medication for non-medical reasons? ___________ 
 
Appendix 11: Recent Smoking 
The follow questions are about your recent smoking 
 
 
1. In the last 7 days, have you smoked at all - even a puff?    
1=YES 
2 = No 
0 = Don’t know  
 
 
2. In the last 7 days, how many cigarettes have you smoked per day?  
 
_____ [0-99]  
 
3.  In the last 30 days, have you smoked at all- even a puff?  
1= YES 
2 = No 
4. On average, how many cigarettes have you smoked per day over the last 30 days?  
_______ 
 
Adherence questions- These questions will be used for phone-based assessments. 
Medication adherence for in-person visits will be assessed via diaries, which is found in 
Appendix 20.  
(CTA Dialogue) 
Medications that have been given to you for this study should be taken as follows 
o Patch: put on in AM and wear for 24 hours unless otherwise directed 
o Study pills: are each taken two times per day, in the morning and in the evening unless 
otherwise directed by study personnel  
1. Did you choose to use the nicotine patch or varenicline?  
 
1= Nicotine Patch 
 
2= Varenicline 
If “Nicotine Patch” selected ,go to questions 1a-1c.  


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If “Varenicline” selected, go to questions 2a-2c 
   1a) Over the last seven days, how many days have you used the nicotine patch as 
prescribed? 
   1b) Over the last seven days, how many days have you used the pills as prescribed? 
   1c) If answer to 1a or 1 b is less than 7 (100% adherence), please provide reason why you did 
not follow the directions above.  
   2a) Over the last seven days, how many days have you taken the varenicline pills as 
prescribed above? 
   2b) Over the last seven days, how many days have you taken the bupropion pills as 
prescribed above? 
   2c) If answer to 2a or 2b is less than 7 (100% adherence), please provide reason why 
you did not follow the directions above. 
 
  
 
  
 
 


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 Appendix 12: Work Questions  
The next few questions are about work.  
1. Please describe your employment status. Are you currently…?   
 =  
1 = Working full-time (21-40 hours per week)  
2 = Working Part-time (20 hours per week or less)   
3 = Unemployed and looking for work  
4.  Disability or medical leave 
5 = Retired 
6 = Other 
7 = Don’t know  
 
 
2. If you work,how many days of work have you missed due to illness in the past 30 days? 
_______Days  [1-30]   
 
3. If you work, how many smoke breaks do you take during a typical workday?  
______Breaks (0-9)  
 
4.  How long, on average, does each smoke breaks last? ________ (0-60 minutes) 
 
 
 
 
 


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Appendix 13: Predictor Questions 
 
1. On a scale from 1 to 7 where 1 is “not at all confident” and 7 is “extremely confident,” how 
confident are you that you can quit?  
16 
 
Not at all 
confident 
 
 
 
 
 
 
Extremely 
confident 
1 
2 
3 
4 
5 
6 
7 
 
  
 
 
 
 
2. On a scale from 1 to 7 where 1 is “not at all” and 7 is “a lot,” how much do you want to quit? 
 
Not at 
all 
 
 
 
 
 
A lot 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
3. Calculate:  Add scores of questions above together.   
2-5 = Low Efficacy  
6-10 = Moderate Efficacy 
11-14 = High Efficacy   


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Appendix 14: Fagerström Test of Nicotine Dependence 
(FTND)(Heatherton, Kozlowski, Frecker, & Fagerstrom, 1991) 
 
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 
 
  
 
 
  
  
 
 
   
 
Calculate:  Add scores of all 6 items.   
 
1-2 = low dependence 
3-4 = low-moderate dependence 
5-7 = moderate dependence 
8+ = high dependence 


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Appendix 15: Mood and Physical Symptoms Scale‐2 (MPSS‐
2)(West & Hajek, 2004) 
 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=A lot of the time 
3=Almost all of the time 
4= 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  
 
 
 
 
 
 
3.  Calculate:  Please add scores of questions above   
 
0‐2 = Mild 
3‐6 = Moderate 
7‐10 = Severe  
 


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Appendix 16: Patient Health Questionnaire‐2 (PHQ‐2)(K. 
Kroenke, Spitzer, & Williams, 2003) and question 9 of Patient 
Health Questionnaire‐9 (K. Kroenke et al., 2003; Kroenke, 
Spitzer, & Williams, 2001) 
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 
every 
day 
1. Little interest or 
pleasure in doing things 
0 
1 
2 
3 
2. Feeling down, 
depressed or hopeless 
0 
1 
2 
3 
9. Thoughts that you would 
be better off dead or 
hurting yourself in some 
way 
 
 
 
 
 
 
Scoring 
If the sum of the answers to 1 and 2 are ≥ 3, a mood disorder is indicated. 
If the sum of the answers to 1 and 2 are < 3, a mood disorder is not indicated. 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 17: Generalized Anxiety Disorder 2‐item Scale (GAD‐2) 
(Plummer, Manea, Trepel, & McMillan, 2016) 
 
GAD-7  
Over the last 2 weeks, how often have you been 
bothered by any of the following problems?  
Not at all 
Several 
days 
More 
than half 
the days 
Nearly 
every 
 day 
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. Calculate:  Add scores of GAD-7 Responses together for total  
0-2= Negative screen 
3-6= Positive screen 
 
 
 


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Appendix 18: Perceived Stress Scale (PSS‐4)(Cohen, Kamarck, & 
Mermelstein, 1983) 
The next set of questions asks 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  
 
 
 
5.  Calculate: Add scores of above responses 
 
0‐5 = Low Stress 
6‐11 = Moderate Stress 
12‐16 = High Stress 
 


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Appendix 19: Phone‐Based Assessments  
 
Abstinence Status 
 
1. Have you smoked any cigarettes in the last 24 hours? (Call 4) 
2. How many cigarettes have you smoked in the last 24 hours? (Call 4) 
3. Have you smoked cigarettes in the last 7 days? (Call 1,2,3, 4, 5, 6, 7, 8, 9, 10) 
4. On average, how many cigarettes have you smoked per day in the 7 days week? (Call 1,2,3, 4, 5, 6, 7, 
8, 9, 10) 
5. Have you smoked cigarettes in the last 30 days? (Calls 7, 8, 9, 10 ) 
6. On average, how many cigarettes have you smoked per day over the last 30 days? (Calls 7, 8, 9, 10 ) 
 
 
Medications and Side Effects 
 
 
1. Are you experiencing any side effects from the medications? Yes  
No 
2.  If yes, what side effect(s) are you experiencing? 
 
Abnormal Dreams 
Constipation                       
Rash                                       
Dry Mouth 
Dizziness/Lightheadedness 
Headache 
Insomnia 
Nausea 
Seizures 
Anxiety 
Agitation/Anger 
Vomiting 
Gas 
Other (Please describe) 
 
 
3. How severe? 
1. Mild  
2.  
3.  
4.  
5.  
 
6. 
7. 
8. 
9. 
10. Severe 
 
4. When did it start? 
5. How long did it last (in days)? 
6. Did you stop medication? 
 
If more than one side effect reported, repeat questions 3‐6. 
 
 
Withdrawal and Urge Questions 
1. On a scale from 1 to 10, how strong have your urges to smoke been over the last week?  
1. Not at all strong 
2.  
3. A little strong 
4.  
5. Moderately strong 
6.  
7.  
8. Very strong 
9.  
10. Extremely strong 


 
2. On a scale from 1‐10, how bad have your withdrawal symptoms (for example, irritability or agitation 
that occur when you don't smoke) been over the last week?
1. Not at all stressed 
2.  
3. A little stressed 
4.  
5. Moderately stressed 
6.  
7.  
8. Very stressed 
9.  
10. Extremely stressed 
 
 
 
Confidence in Ability and Motivation to Become Tobacco-Free 
 
1. On a scale of 1‐10, how motivated are you to quit smoking or stay quit if abstinent?  
1. Not at all motivated 
2.  
3. A little motivated 
4.  
5. Moderately motivated 
6.  
7.  
8. Very motivated 
9.  
10. Extremely motivated 
 
2. On a scale of 1‐10, how confident are you that you can quit if abstinent or stay quit if abstinent?  
1. Not at all confident 
2.  
3. A little confident 
4.  
5. Moderately confident 
6.  
7.  
8. Very confident 
9.  
10. Extremely confident 
 
26- and 52-Week Call Questions 
 
1. Since completing your last visit with us, have you used any smoking cessation 
medications? (Nicotine patches, gum/lozenge, inhaler, Chantix, Wellbutrin, bupropion, 
or Zyban) Yes      No 
 
 
2. Since completing your last visit with us, have you smoked at all, even a puff? Yes     No 
 
 
 


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Appendix 20: 7 Day Smoking History and Medication Adherence Diary  
Please record your medication use and smoking each day, starting seven days before your next visit. 
(Will be adjusted based on medication regimen chosen and specific in-person visit) 
 
Date 
# cigs 
smoked? 
Did you take your 
Chantix pills today? 
Did you take your 
Bupropion/placebo pills 
today? 
First 
Dose 
Second 
Dose 
First Dose 
Second 
Dose 
1 
____/____ _____ 
Pill 1:   
 YES   
 NO 
Pill 2:   
 YES    
 NO 
Pill 1:    
YES     
NO 
Pill 2:    
YES     
NO 
2 
____/____ _____ 
Pill 1:  
 YES   
 NO 
Pill 2:   
YES    
NO 
Pill 1:    
YES     
NO 
Pill 2:    
YES     
NO 
3 
____/____ _____ 
Pill 1:  
 YES   
 NO 
Pill 2:   
YES    
NO 
Pill 1:    
YES     
NO 
Pill 2:    
YES     
NO 
4 
____/____ _____ 
Pill 1:  
 YES   
 NO 
Pill 2:   
YES    
NO 
Pill 1:    
YES     
NO 
Pill 2:    
YES     
NO 
5 
____/____ _____ 
Pill 1:  
 YES   
 NO 
Pill 2:   
YES    
NO 
Pill 1:    
YES     
NO 
Pill 2:    
YES     
NO 
6 
____/____ _____ 
Pill 1:  
 YES   
 NO 
Pill 2:   
YES    
NO 
Pill 1:    
YES     
NO 
Pill 2:    
YES     
NO 
7 
____/____ _____ 
Pill 1:  
 YES   
 NO 
Pill 2:   
YES    
NO 
Pill 1:    
YES     
NO 
Pill 2:    
YES     
NO 
Next Visit 
____/____ 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 1 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
You are being asked to take part in this research study because you smoke cigarettes.  Research studies 
are voluntary and include only people who choose to take part.  Please read this consent form carefully 
and take your time making your decision. As study staff discusses this consent form with you, please ask 
him/her to explain any words or information that you do not clearly understand.  We encourage you to 
talk with your family and friends before you decide to take part in this research study.  The nature of the 
study, risks, inconveniences, discomforts, and other important information about the study are listed 
below.  
Please tell study staff if you are taking part in another research study. 
A grant from the National Institutes of Health (NIH) will sponsor this study.  Portions of Dr. James 
Davis's and his research team’s salaries will be paid by this grant. Pfizer will be supplying the active and 
placebo Varenicline.  All other study drugs will be paid for by the grant.  
Concise Summary
The purpose of this study is to evaluate a new method for using smoking cessation medications, each 
of which is FDA approved for use alone, but investigational when used together according to a study 
protocol. You will be asked to choose to take either the nicotine patch or varenicline (Chantix). You 
will be randomized (like flipping a coin) and you may receive active drug or placebo. Depending on 
how you respond (based on cigarettes smoked per day), you may be asked to take bupropion 
(Wellbutrin) or placebo for the remainder of your study visits. There will be a total of 5 study visits 
over a 16 week period. The screening visit may last up to 2 hour and the remainder of the study visits 
will last about 30-45 minutes. There will be 10 follow-up phone calls that will occur over a 1 year 
period (after target quit day). During study visits, you will be asked to complete self-report 
assessments and you will be asked to complete smoking diaries prior to study visits. 
The most common side effects of the nicotine patch include insomnia and/or abnormal dreams. Less 
likely side effects of the patch include dizziness, nausea/vomiting, light headedness, and/or fainting. 
The most likely common side effects of varenicline (Chantix) are nausea/vomiting, gas, constipation, 
insomnia, and/or vivid dreams. Less common side effects of varenicline include changes in behavior, 
agitation, depressed mood and/or suicidal thoughts/actions. The most common side effects of 
bupropion are insomnia, agitation, headache, and/or dry mouth. Less common side effects of 
bupropion include changes in behavior, hostility, depressed mood, and/or suicidal thoughts/actions.  
You may also experience nicotine withdrawal when trying to quit. Symptoms are listed below in the 
consent form. There is also a risk to confidentiality, although we will take all steps to prevent this 
from happening. 
If you are interested in learning more about this study, please continue to read below.
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 2 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, Dr. James Davis will be your doctor for the study and will be in contact with 
your regular health care provider throughout the time that you are in the study and afterwards, if needed. 
Dr. Davis or one of the Physician Assistants working on the study will perform your initial physical 
exam and follow your progress through the study. They may access your medical record if deemed 
medically necessary. 
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to evaluate a new method for using smoking cessation medications, each of 
which is FDA approved for use alone, but investigational when used together according to a study 
protocol.
The medications used in this trial are Varenicline, Nicotine Patch, and Bupropion. All are approved 
individually by the U.S. Food and Drug Administration (FDA) for quitting smoking. Varenicline 
(Chantix) is considered standard of care. The investigational aspects of this trial are the use of two of 
these medications together, and the use of these medications before quitting smoking. The word 
“investigational” means that using these drugs in these ways is still being tested in research studies and 
are not approved by the U.S. Food and Drug Administration (FDA).  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
We will consent up to 780 subjects with the target of enrolling approximately 300 people. Participants 
consist of individuals who smoke cigarettes, are ages 18 and older, and meet our eligibility criteria.   
WHAT IS INVOLVED IN THE STUDY?
If you agree to be in this study, you will be asked to sign and date this consent form.  After you sign the 
consent form, study staff will review your medical chart and physical exam results to make sure you are 
eligible. Study participation will be documented in your medical chart/record. You will have the 
following tests and procedures to make sure that you are eligible: 

Self-report measures will be assessed on the following: smoking heaviness, use of other tobacco 
products, depression, anxiety, drug and alcohol use, and willingness to take study medications.

Urine sample: to be used to test for pregnancy (females only). If this test is positive, you will not 
be allowed to continue in this study.  
Depending on the results of the screening procedures you may not be eligible for the study. If you are 
pregnant, you will not be allowed to participate in this study. 
Enrollment and Randomization:  If you sign consent and pass screening criteria, you may enroll in the 
study. If you enroll in the study you will be randomized to one of two groups. Randomization is like 
flipping a coin; there is a 50/50 chance of ending up in either group.  All participants will be able to choose a 
smoking cessation drug: either Varenicline or Nicotine Patch. One randomization group will receive a single 
active medication, guided by their choice, and placebo Bupropion. The other group will receive the 
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 3 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
medication they choose in combination with Bupropion if they do not respond to their chosen medication.  
During the study you will not be told if you are receiving active or placebo Bupropion. The dose of 
Varenicline, Bupropion, and the Nicotine Patch will follow accepted FDA guidelines.  All tablets must 
be swallowed whole, and not crushed, divided, or chewed.  You may also be given placebo medications 
during the first few weeks of your treatment.  A placebo looks like the real drug but has no effect on the 
body, and is used to maintain the integrity of the study.  All drugs will be provided in unmarked 
containers.  Study staff will call you within the first week of starting study drugs to assess effects and address 
questions you may have.  However, please call us immediately if you have questions or concerns.  
You will be blinded to what medications you are taking. Blinding means you will not know if the drug you 
have been prescribed is active or a placebo. The study staff will also be blinded to what treatment group you 
are in, unless there is an emergency and they need to know if the medication you are taking is active or a 
placebo. After the end of the study, you can contact the study physician for information on which active 
medications you were taking during the study. In the case of a health care need during the study, your 
healthcare provider can also contact the study physician for information on the active medications you are 
taking. 
You will be assigned a Quit Smoking Day that is approximately four weeks from your Enrollment Visit. 
You will also be required to attend four study visits, each lasting approximately 30 minutes.   

Study Visit 1 will occur approximately 1 week after your Screening Visit. At this visit, study 
staff will review the results of your urine tests to determine whether you are eligible to 
participate.  If you are able to participate, you will be enrolled in the study, and randomized to a 
study group.  Study staff will also provide you with active and placebo medications (study 
drugs).   

Study Visit 2 will occur approximately 2 weeks after Study Visit 1 (about 2 weeks before your 
Quit Day). At this Visit, study staff will give you additional medications and instructions on how 
to take them. Study staff will also collect any of your empty prescription medication bottles.

Study Visit 3 will occur 2 weeks after your Quit Day.  During this visit, you will be asked to 
complete questionnaires that will take approximately 20 minutes. You will receive the remainder 
of your medications. Study staff will also collect your empty prescription medication bottles.   

Study Visit 4 will occur 12 weeks after your Quit Day. During this visit, you will be asked to 
complete questionnaires that will take approximately 20 minutes. Study staff will also collect any 
empty prescription medication bottles that you have.  
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 4 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
A member of the study staff will call you at the following times:
During these calls, we will answer any further questions you may have.  However, please call us 
immediately if you have any questions or concerns.   
We will also ask you to complete a 7 day diary before your Study Visits. This diary will include 
information on how many cigarettes you have smoked and if you are taking the medications you are 
given through the study.
Participation in this trial is voluntary and refusal to participate will involve no penalty or loss of benefits 
to which you are otherwise entitled. If you choose not to participate or wish to withdraw from the study, 
we encourage you to talk to study staff. If you do not sign this consent form, you will continue to receive 
care, but not as part of this study.
HOW LONG WILL I BE IN THIS STUDY?
You will be in this study for 13 months; but you will only receive the study drugs for 16 weeks, 4 weeks 
before your Quit Date and 12 weeks after your Quit Date. Follow-up will be conducted up to 1 year after 
your Quit Day if you are abstinent at Study Visit 4. Your entire study participation, including one-year 
follow-up, will last approximately 13 months. If you are still smoking at Study Visit 4, you will be in the 
study for approximately 16 weeks, and we will not call you after the last study visit. You can choose to 
stop participating at any time without penalty or loss of any benefits to which you are entitled. However, 
if you decide to stop participating in the study, we encourage you to talk to study staff first. 
WHAT ARE THE RISKS OF THE STUDY?
There is in any study a potential risk of loss of confidentiality. Every effort will be made to keep your 
information confidential; however, this cannot be guaranteed. Some of the questions we will ask you as 
part of this study may make you feel uncomfortable. You may refuse to answer any of the questions, and 
you may take a break at any time during the study. You may stop your participation in this study at any 
time. 
Call Timing
1-2 Days after Study Visit 1 
1-2 Days before Study Visit 2 
1-2 Days prior to Quit Day 
1-2 Days After the Quit Day 
1 Week after the Quit Day
1-2 days before Study Visit 3
6 Weeks after Quit Day 
1-2 Days before Study Visit 4 
 26 Weeks after Quit Day 
 52 Weeks after Quit Day
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 5 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
As a result of your participation in this study, you are at risk for the side effects described below. You 
should discuss these with the study doctor or nurse practitioner and your regular health care provider if 
you choose. Since Varenicline has been associated with severe mood changes, if either you or your 
family notices any changes in mood or behavior, or if you develop suicidal thoughts or actions, you 
should stop taking your tablets and capsules and report these side effects to study staff. If medical study 
staff is not immediately available then you should call your primary physician or go to the nearest 
emergency department. Any other side effects should be reported to study staff immediately before 
making any changes to your use of these drugs. Symptoms will be evaluated by the study medical staff. 
Depending on how severe the side effects are, you may be given a reduced dose of the study drugs or 
given the option of discontinuing use of these study drugs entirely.
Nicotine Skin Patch
The use of nicotine patches for the thirty days of the study, prior to quitting smoking, is investigational 
and is not standard practice. Risks of nicotine from the patch as well as from smoking include 
cardiovascular risks such as high blood pressure and increased heart rate as well as stroke.  Using the 
patch at the same time as you continue smoking may also increase your risk of experiencing the side 
effects listed below.  The amount of nicotine you receive from the patch will be less than you would 
receive from smoking one or two medium strength cigarettes every 30 minutes.  The rate at which the 
nicotine will enter your system will be slower than the rate from smoking cigarettes.  Nicotine skin 
patches may cause some, all or none of the side-effects listed below:
More likely
Insomnia 
Abnormal dreams 
If you experience either, please call us so that we can determine whether you should remove the patches 
at bedtime and apply new ones in the morning upon waking.  Please do not make any changes to your 
use of the patches without contacting study staff.  Skin irritation may occur, although the likelihood of 
this will be reduced by changing the site of the patch application daily.  Notify us if you have skin 
irritation so that we may recommend treatment to help reduce the irritation.
Less likely
Dizziness
Nausea/Vomiting
Light Headedness 
Fainting
There is no evidence that normal healthy smokers will be exposed to a major risk of the nicotine toxicity 
side effects listed above when using nicotine patch.
Bupropion:
Bupropion may cause some, all or none of the side-effects listed below:
More likely
Insomnia
Agitation
Headache
Dry mouth
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 6 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Less likely
Changes in behavior
Hostility
Depressed mood
Suicidal thoughts or actions
Some people had these symptoms when they began taking Bupropion, and others developed them 
after several weeks of stopping Bupropion.
Varenicline:
Varenicline may cause some, all or none of the side-effects listed below:
More likely
Nausea
Vomiting
Gas
Constipation
Insomnia
Vivid dreams
Less likely
Changes in behavior
Agitation
Depressed mood
Suicidal thoughts or actions
Some people had these symptoms when they began taking Varenicline, and others developed them 
after several weeks of stopping Varenicline.
If you develop thoughts of wanting to hurt yourself, you should contact the study doctor immediately. 
The study doctor or one of the physician assistants will evaluate you, and may refer you for further 
treatment if needed. If you develop strong thoughts of suicide, and feel you cannot keep yourself safe, 
you should immediately go to your local emergency room.
If you develop heart problems during your participation in this study, you should contact the study 
doctor immediately. The study doctor or one of the physician assistants will evaluate you, and may refer 
you for further treatment if needed.  Get emergency medical help right away if you have any symptoms 
of a heart attack. 
If you are receiving Varenicline with Bupropion the side effects may be greater.  In addition, there may 
be side effects that are currently not known with the use of this combination.
When quitting smoking you may experience some, all or none of the withdrawal symptoms listed below:
Headache 
Nausea 
Constipation or diarrhea 
Decrease in heart rate and blood pressure 
Fatigue, drowsiness, and insomnia 
Irritability 
Difficulty concentrating 
Anxiety 
Depression 
Tobacco cravings 
Increased desire for the taste of sweets 
Increased hunger and caloric intake leading to 
weight gain
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 7 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Female
Being a part of this study while pregnant may expose the unborn child to significant risks, some of 
which may be currently unforeseeable.  Therefore, pregnant women will be excluded from the study.  If 
you are a woman of childbearing potential, a urine pregnancy test will be done, and it must be negative 
before you can continue in this study.  If sexually active, you must agree to use appropriate 
contraceptive measures for the duration of the study and for one week after the last dose. Medically 
acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) 
approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) 
barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device 
(IUD). Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected sex, are 
not acceptable methods for routine use.  If you do become pregnant during this study or if you have 
unprotected sex, you must inform your study physician immediately.
Risk to the fetus if you become pregnant include the following: nicotine has been shown to lead to pre-
term delivery, low birth weight, and birth defects. Varenicline and bupropion have not been approved or 
studied for use during pregnancy, and risks to the fetus are unknown.
Drug and Food Interactions:
For your safety, you must tell the study doctor or staff about all the prescribed medical foods and drugs, 
herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are 
taking before you start the study and before starting to take any of these products while you are on the 
study.  There may be risks, discomforts, drug interactions or side effects that are not yet known.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may be a direct medical benefit to you. A possible benefit 
from participation in this study is quitting smoking. We also hope the information learned from this 
study will benefit people that smoke in the future.
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THE STUDY?
If you do not wish to participate in this study, there are other alternatives to treat tobacco use.  You can 
talk with your doctor about prescription medicines that may help you quit (including Varenicline or 
Bupropion), or nicotine-replacement products offered outside of this study, both over-the-counter and by 
prescription.  You can also participate in other quit-smoking programs, such as the Duke Smoking 
Cessation Program, which can be reached by calling 919-613-7848.  Information about these resources 
is available through the North Carolina Tobacco Use Quit line at http://www.quitnownc.org or by 
calling (800) 784-8669.  
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 8 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
information may be viewed by individuals involved in this research and may be seen by people 
including those collaborating, funding, and regulating the study. We will share only the minimum 
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law. 
As part of the study, results of your study-related laboratory tests, x-rays, and procedures may be 
reported to research staff and its affiliates. In addition, your records may be reviewed in order to meet 
federal or state regulations. Reviewers may include representatives from the Food and Drug 
Administration, the Duke University Health System Institutional Review Board, the Duke Cancer 
Institute, the Duke Office of Audit, Risk and Compliance, NIH, and others as appropriate. If any of these 
groups review your research record, they may also need to review your entire medical record.
As part of this study, you will be asked to have certain tests or procedures performed. Some of these 
would have been done as part of your regular care. The study doctor will use these test results both to 
treat you and to complete this research.  These test results will be recorded in your medical record and 
will be reported to the representatives and affiliates of NIH. Results of tests and studies done solely for 
this research study and not as part of your regular care will also be included in your medical record.
The study results will be retained in your research record for at least seven years after the study is 
completed. At that time either the research information not already in your medical record may be 
destroyed or information identifying you will be removed from such study results at DUHS.  Any 
research information in your medical record will be kept indefinitely.
This information may be further disclosed by the sponsor of this study.  If disclosed by the sponsor, the 
information is no longer covered by federal privacy regulations.  If this information is disclosed to 
outside reviewers for audit purposes, it may be further disclosed by them and may not be covered by 
federal privacy regulations.
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed.
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information.
A representative from the sponsor may be present at certain study visits/procedures.
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 9 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
The Department of Health and Human Services (HHS) has issued a Certificate of Confidentiality to 
further protect your privacy.  With this Certificate, the investigators may not disclose research 
information that may identify you in any Federal, State, or local civil, criminal, administrative, 
legislative, or other proceedings, unless you have consented for this use. Research information protected 
by this Certificate cannot be disclosed to anyone else who is not connected with the research unless:  
1)
there is a law that requires disclosure (such as to report child abuse or communicable diseases 
but not for legal proceedings); 
2)
you have consented to the disclosure, including for your medical treatment; or 
3)
the research information is used for other scientific research, as allowed by federal regulations 
protecting research subjects. 
4)
Disclosure is required, however, for audit or program evaluation requested by the agency that is 
funding this project or for information that is required by the Food and Drug Administration 
(FDA).
 
You should understand that a Confidentiality Certificate does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your involvement in this research. If you 
want your research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. This means 
that you and your family must also actively protect your own privacy.
Finally, you should understand that the investigator is not prevented from taking steps, including 
reporting to authorities, to prevent serious harm to yourself or others.
WHAT ARE THE COSTS?
You or your insurance provider will be responsible and billed for all costs related to your routine 
medical care, including copayments and deductibles. Routine medical care services are those that you 
would have received for your condition if you were not participating in this research study. Not all 
services are covered by insurance.  Some procedures or scans may require pre-authorization by your 
insurance plan. We will notify you if we learn that a service is not covered by your insurance plan as 
part of the pre-authorization process. If it is not covered, you will be responsible for paying for it.  The 
amount of your out-of-pocket expense will depend on your insurance plan.  For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study.  You 
may have more or higher co-pays than with a Medicare Advantage plan.  Please discuss the costs of the 
study with Dr. James Davis.  At your request, a Financial Counselor in the clinic may provide you with 
an estimate of costs for routine services.
The study sponsor, NIH, has agreed to pay for services and procedures that are done solely for research 
purposes.  Please talk with the PI/study team about the specific services and procedures that the sponsor 
will pay for, and the ones for which you or your insurance will be responsible.
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 10 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
We will monitor your DUHS patient care charges to make sure that costs are directed appropriately.  If 
you have any questions or concerns about appropriate billing, contact your study team coordinator so 
that he/she can help find a resolution.
NIH and Pfizer will provide the study drug/biologic free of charge to you. At the end of the study, or if 
you decide to withdraw from the study before it ends, you may be asked to return all unused study drug.  
Your study doctor may request that you return for a checkup before you stop your study drug/biologic if 
he/she thinks that stopping it suddenly may harm you and may ask you to complete the tests that would 
ordinarily occur when a person completes the study.
WHAT ABOUT COMPENSATION?
You will be compensated up to $210 for your participation in the study. After completing Visit 1, you 
will be compensated $20. After completing Visit 2, you will be compensated $20. After Visit 3, you will 
be compensated $50, and after Visit 4, you will be compensated $100.  You will also receive $20 at the 
end of the study for completion of the phone call assessments ($2 for each of the 10 calls). You will 
receive payment through a rechargeable debit card called ClinCard.  
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., or your Duke physicians to provide monetary 
compensation or free medical care to you in the event of a study-related injury.
For questions about the study or research-related injury, contact Dr. James Davis at (919) 668-5055 
during regular business hours. After hours and on weekends and holidays, please call Dr. Davis at 608-
217-9405.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the 
study at any time. If you withdraw from the study, no new data about you will be collected for study 
purposes unless the data concern an adverse event (a bad effect) related to the study.  If such an adverse 
event occurs, we may need to review your entire medical record.  
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke.  If you do 
decide to withdraw, we ask that you contact Dr. James Davis in writing and let him know that you are 
withdrawing from the study.  His mailing address is 2424 Erwin Road, Suite 201, Durham, NC 27705.
Nonparticipation or withdrawal from this study will not affect your job status if you are a Duke 
employee and will not affect your grades if you are a Duke student.  If you do decide to withdraw, we 
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 11 of 12                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
ask that you contact study staff by phone or Dr. Davis in writing and let him know that you are 
withdrawing from the study.  His mailing address is 2424 Erwin Road, Suite 201, Durham, NC, 27705.  
The study may be stopped at any time without your consent.  If this occurs, you will be notified and your 
study doctor or nurse practitioner will discuss other options with you.   In addition, you must return all 
unused study drug to Dr. Davis or his staff. Dr. Davis may ask you to return for a checkup before you 
stop your study drug if he thinks that stopping the drug suddenly may harm you.  We will tell you about 
new information that may affect your health, welfare, or willingness to stay in this study. 
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if your study doctor determines that it is no longer in your best interest to continue.  The 
sponsor or regulatory agencies may stop this study at any time without your consent. Reasons why this 
might occur include difficulty in study recruitment or retention that will significantly impact the ability 
to evaluate the study endpoints or any new information becomes available during the study that 
necessitates stopping the study.  If this occurs, you will be notified and your study doctor will discuss 
other options with you.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will 
include a summary of the results.  You can search this Web site at any time.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. James Davis at (919) 668-5055 during regular business 
hours. After hours and on weekends and holidays, please call Dr. Davis at 608-217-9405.
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111.
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021


Consent to Participate in a Research Study
Adaptive Pharmacotherapy Study
Pro00072077 Randomized-Controlled Smoking Cessation Trial 
on Adaptive Pharmacotherapy 
Page 12 of 12
                                                  *
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this consent form."
__________________________________________
___________     ____________
Signature of Subject
Date
   Time
__________________________________________
___________     ____________
Signature of Person Obtaining Consent
Date
   Time
DUHS IRB
IRB NUMBER: Pro00072077
IRB REFERENCE DATE: 06/28/2020
IRB EXPIRATION DATE: 07/20/2021