Behavioral Activation for Smoking Cessation and the Prevention of Post-Cessation Weight Gain
Phase: NA
Conditions: Smoking Cessation, Weight Loss
Sponsor: Abramson Cancer Center at Penn Medicine

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CLINICAL RESEARCH PROTOCOL 
Behavioral Activation for Smoking Cessation and the 
Prevention of Post-Cessation Weight Gain
Regulatory Sponsor: 
Funding Sponsor: 
Supplement Funding 
Sponsor: 
IRB Protocol Number: 
Version # (Date): 
Nct Code: 
Janet Audrain-McGovern, Ph.D. 
Psychiatry- Center for Interdisciplinary Research on Nicotine 
Addiction (CIRNA)  
3535 Market St.-Suite 4100 
215-746-7145
National Cancer Institute (NCI) 
NCI 
825425 
Version 20 (8.14.2020) 
NCT02906787
Initial version # (Date): Version 1 (6.27.2016) 
Amended: Version 2 (8.1.2016) 
Amended: Version 3 (8.11.2016) 
Amended: Version 4 (10.10.2016) 
Amended: Version 5 (10.26.2016) 
Amended: Version 6 (7.10.2017) 
Amended: Version 7 (8.16.2017) 
Amended: Version 8 (10.2.2017) 
Amended: Version 9 (1.23.2018) 
Amended: Version 10 (5.30.2018) 
Amended: Version 11 (10.12.2018) 
Amended: Version 12 (3.15.2019) 
Amended: Version 13 (6.4.2019) 
Amended: Version 14 (6.7.2019) 
Amended: Version 15 (9.10.2019) 
Amended: Version 16 (10.31.2019) 
Amended: Version 17 (2.17.2020) 
Amended: Version 18 (4.28.2020) 
Amended: Version 19 (5.19.20)  
Amended: Version 20 (8.14.20) 

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Table of Contents 
 
1 
INTRODUCTION .................................................................................................................................. 1 
1.1 
BACKGROUND - PARENT (MAIN) STUDY........................................................................................... 1 
1.2 
BACKGROUND - NEUROIMAGING SUB-STUDY ................................................................................... 2 
1.3 
BACKGROUND- MICROBIOME SUB-STUDY ....................................................................................... 2 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
2.1 
PARENT (MAIN) STUDY ................................................................................................................... 3 
2.2 
NEUROIMAGING SUB-STUDY ........................................................................................................... 4 
2.3 
MICROBIOME SUB-STUDY ............................................................................................................... 5 
3 
STUDY DESIGN ................................................................................................................................... 5 
3.1 
GENERAL DESIGN - PARENT (MAIN) STUDY ..................................................................................... 5 
3.2 
GENERAL DESIGN - NEUROIMAGING SUB-STUDY ............................................................................. 6 
3.3 
GENERAL DESIGN - MICROBIOME SUB-STUDY ................................................................................. 6 
3.4 
STUDY DURATION – PARENT (MAIN) STUDY .................................................................................... 7 
3.5 
STUDY DURATION- NEUROIMAGING SUB-STUDY .............................................................................. 7 
3.6 
STUDY DURATION- MICROBIOME SUB-STUDY .................................................................................. 7 
4 
CHARACTERISTICS OF THE STUDY POPULATION ....................................................................... 7 
4.1 
TARGET POPULATION ..................................................................................................................... 7 
4.2 
ACCRUAL - PARENT (MAIN) STUDY ................................................................................................. 7 
4.3 
ACCRUAL - NEUROIMAGING SUB-STUDY .......................................................................................... 7 
4.4 
ACCRUAL – MICROBIOME SUB-STUDY ............................................................................................. 8 
4.5 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.6 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.7 
VULNERABLE POPULATIONS ......................................................................................................... 11 
4.8 
SUBJECT RECRUITMENT ............................................................................................................... 12 
4.9 
EARLY WITHDRAWAL OF SUBJECTS............................................................................................... 12 
4.9.1 
When and How to Withdraw Subjects............................................................................... 12 
5 
STUDY DRUG (TRANSDERMAL NICOTINE [TN]) .......................................................................... 12 
5.1 
DESCRIPTION ............................................................................................................................... 12 
5.2 
TREATMENT REGIMEN .................................................................................................................. 12 
5.3 
PREPARATION AND PACKAGING OF STUDY DRUG........................................................................... 13 
5.4 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 13 
5.5 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 13 
5.5.1 
Receipt of Drug Supplies .................................................................................................. 13 
5.5.2 
Storage .............................................................................................................................. 13 
5.5.3 
Dispensing and Reconciliation of Study Drug ................................................................... 13 
5.5.4 
Return or Destruction of Study Drug ................................................................................. 14 
6 
STUDY PROCEDURES ..................................................................................................................... 14 
6.1 
TELEPHONE ELIGIBILITY SCREEN .................................................................................................. 14 
6.2 
IN-CENTER VISITS ........................................................................................................................ 14 
6.2.1Visit Reminders .......................................................................................................................... 14 
6.2.2 
Intake Visit (~Week -3) ...................................................................................................... 14 
6.2.3 
Baseline Visit (~Week -2) .................................................................................................. 16 
6.2.4 
Pre-Quit Visit (~Week -1) .................................................................................................. 17 
6.2.5 
Target Quit Day Visit (Week 0) ......................................................................................... 17 
6.2.6 
Mid-Treatment 1 Visit (Week 1) ........................................................................................ 18 
6.2.7 
Mid-Treatment 2 Visit (Week 2) ........................................................................................ 18 
6.2.8 
Mid-Treatment 3 Visit (Week 4) ........................................................................................ 19 

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6.2.9 
Mid-Treatment 4 Visit (Week 6) ........................................................................................ 20 
6.2.10 
End of Treatment Visit (Week 8) ....................................................................................... 20 
         6.2.11       COVID-19 Quitting Experiences Survey …………………………………………...……….. 19 
6.2.12 
Follow-Up Visits 1 and 2 (Week 12 and Week 26) ........................................................... 20 
6.2.13 
fMRI Scan Visits 1 & 2 (~Week -2 and ~Week 7-8) .......................................................... 21 
6.3 
MICROBIOME SUB-STUDY ............................................................................................................. 24 
6.4 
TABLE 2. STUDY MEASURES AND TIME POINTS .............................................................................. 27 
6.5 
DESCRIPTION OF STUDY MEASURES ............................................................................................. 28 
6.5.1 
Treatment .......................................................................................................................... 28 
6.5.2 
Screening/Covariates ........................................................................................................ 30 
6.5.3 
Moderators ........................................................................................................................ 36 
6.5.4 
Mechanisms ...................................................................................................................... 36 
6.5.5 
Microbiome Variables........................................................................................................ 37 
6.5.6 
Outcomes .......................................................................................................................... 38 
6.6 
TISSUE SPECIMENS ...................................................................................................................... 39 
6.7 
SAMPLE SIZE DETERMINATION- PARENT (MAIN) STUDY ................................................................. 39 
6.8 
SAMPLE SIZE DETERMINATION - NEUROIMAGING SUB-STUDY ......................................................... 40 
6.9 
SAMPLE SIZE DETERMINATION - MICROBIOME SUB-STUDY ............................................................. 41 
6.10 
STATISTICAL METHODS - PARENT (MAIN) STUDY ........................................................................... 41 
6.11 
STATISTICAL METHODS - NEUROIMAGING SUB-STUDY ................................................................... 42 
6.12 
STATISTICAL METHODS - MICROBIOME SUB-STUDY ....................................................................... 43 
7 
RISKS / BENEFITS ............................................................................................................................ 44 
7.1 
POTENTIAL STUDY RISKS ............................................................................................................. 44 
7.2 
POTENTIAL STUDY BENEFITS ........................................................................................................ 47 
7.3 
RISK/BENEFIT ASSESSMENT ......................................................................................................... 47 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 47 
8.1 
DEFINITIONS ................................................................................................................................ 47 
8.2 
COLLECTION AND RECORDING OF ADVERSE EVENTS ..................................................................... 49 
8.2.1 
AE Collection Methods ...................................................................................................... 49 
8.2.2 
AE/SAE Documentation and Internal Reporting Procedures ........................................... 50 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 52 
8.3.1 
Investigator reporting: notifying NCI and FDA .................................................................. 52 
8.3.2 
Investigator reporting: notifying the Penn IRB .................................................................. 52 
8.4 
MEDICAL MONITORING ................................................................................................................. 54 
9 
DATA MANAGEMENT ...................................................................................................................... 54 
9.1 
DATA MANAGEMENT SYSTEM DEVELOPMENT ................................................................................ 54 
9.2 
DATA SECURITY ........................................................................................................................... 54 
9.3 
DATA PROCESSING ...................................................................................................................... 55 
9.4 
DATA QUALITY ASSURANCE .......................................................................................................... 55 
9.5 
SUBJECT AND SPECIMEN TRACKING .............................................................................................. 55 
9.6 
RETAINING DATA AND BIOSPECIMENS FOR FUTURE RESEARCH USE ............................................... 56 
9.7 
DATA HANDLING AND RECORD KEEPING ....................................................................................... 56 
9.7.1 
Confidentiality .................................................................................................................... 56 
9.7.2 
Subject Privacy/Protected Health Information .................................................................. 57 
10 
DATA AND SAFETY MONITORING ................................................................................................. 58 
10.1 
RESEARCH ROLES ....................................................................................................................... 58 
10.2 
STAFF TRAINING .......................................................................................................................... 58 
10.3 
MONITORING ACTIVITIES............................................................................................................... 59 
10.3.1 
AE/SAE Monitoring ........................................................................................................... 59 
10.3.2 
Initial Assessment (Intake) Monitoring .............................................................................. 59 
10.3.3 
Protocol Monitoring ........................................................................................................... 59 
10.3.4 
Database Auditing ............................................................................................................. 60 

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10.3.5 
Data Security ..................................................................................................................... 60 
10.4 
FREQUENCY OF DATA AND SAFETY MONITORING ........................................................................... 60 
10.5 
AUDITING AND INSPECTING ........................................................................................................... 60 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 60 
11.1 
INFORMED CONSENT .................................................................................................................... 61 
12 
RESOURCES NECESSARY FOR HUMAN RESEARCH PROTECTION ........................................ 61 
12.1 
RESEARCH STAFF ........................................................................................................................ 61 
12.2 
STUDY FACILITIES ........................................................................................................................ 62 
13 
STUDY FINANCES ............................................................................................................................ 62 
13.1 
FUNDING SOURCE – PARENT (MAIN) STUDY .................................................................................. 62 
13.2 
FUNDING SOURCE – NEUROIMAGING SUB-STUDY .......................................................................... 62 
13.3 
FUNDING SOURCE – MICROBIOME SUB-STUDY .............................................................................. 62 
13.4 
CONFLICT OF INTEREST ................................................................................................................ 62 
13.5 
SUBJECT COMPENSATION............................................................................................................. 63 
Table 3. Study Compensation ............................................................................................................ 64 
14 
REFERENCES ................................................................................................................................... 64 

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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted in 
compliance with this research protocol, as well as according to US and international standards 
of Good Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations, and institutional research policies and 
procedures.  
1.1 Background - Parent (Main) Study  
Smoking cessation and the prevention of obesity are two of the most significant cancer 
prevention outcomes.  Smokers who want to quit smoking and minimize weight gain have few, if 
any treatment options, despite two decades of post-cessation weight gain (PCWG) research.  
Identifying effective PCWG prevention approaches has the potential to remove a major barrier 
to the initiation and maintenance of smoking cessation, and to reduce the overweight and 
obesity problem in the US. To advance the science and practice of interventions to reduce 
PCWG, we propose to evaluate a novel application of a behavioral activation (BA) intervention 
to prevent PCWG in men and women. To date, PCWG prevention research has focused on 
women, even though 25% of the increase in the proportion of overweight men has been 
attributed to quitting smoking. If the hypotheses are supported, the findings would suggest that 
targeting reward-related mechanisms common to both smoking and eating: (1) is an effective 
approach to promoting smoking cessation, while minimizing PCWG; (2) is a viable approach for 
addressing two rewarding behaviors concurrently, without risking compensatory responses; and 
(3) can be used as an adjunct to pharmacotherapy.  Finally, the findings have implications for 
improved treatments for multiple co-morbid health risk behaviors (obesity, alcohol, substance 
use), supporting a wide-ranging impact on the prevention of cancer and other diseases. 
 
Behavioral theories, such as Behavioral Economic and Incentive Salience Theories suggest that 
PCWG may stem, in part, from the reward deficit produced by smoking cessation. Upon quitting, 
smokers lose a significant reinforcer, increasing the motivational salience of available alternative 
reinforcers.  However, smokers typically have fewer alternative reinforcers from which to choose 
and may experience less pleasure from these reinforcers after quitting smoking. Compensatory 
increases in between-meal snacking on foods high in fat and sugar may offset the reward deficit 
due to quitting smoking.  Highly palatable snack food is a readily available reinforcer that shares 
common reward mechanisms with nicotine. Behavioral Economic Theory indicates that the 
reinforcing value of snacking can be enhanced, or reduced, based on the availability of 
alternative reinforcers. Fewer alternative reinforcers and a reduction in pleasure derived from 
available reinforcers forge an over-reliance on palatable snack foods to substitute for the 
reinforcement previously derived from cigarettes. After quitting smoking, individuals may 
become more responsive to snack food cues, find snack foods more pleasant to eat and more 
reinforcing. Indeed, our research group has shown that smoking cessation increases the 
reinforcing value of snack foods, which predicts subsequent food intake and weight gain.  To 
avoid smoking cessation-induced increases in food intake and weight gain that precipitate 
smoking relapse, it is key to evaluate novel behavioral interventions that target involvement in, 
and subjective reward derived from, alternative reinforcers.   
 
To advance the science and practice of interventions to reduce PCWG, we propose to target 
reward-related mechanisms common to smoking and palatable food intake.  Through a novel 
application of a behavioral activation intervention to smoking cessation and to PCWG (BAS+), 
we will increase opportunities for reinforcement and enhance the pleasure obtained from typical 
reinforcers.  We propose a randomized clinical trial of BAS+ plus transdermal nicotine (TN) vs. 
Standard Smoking Cessation Counseling (SC) plus TN in treatment seeking smokers (ages 18-
65). Participants will receive 8 individual BAS+ or SC sessions plus TN over a 10-week period. 

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The primary outcomes will be PCWG and 7-day point prevalence abstinence at 26 weeks after 
the target quit date. Food intake (secondary outcome) will be measured via 24-hour food recalls 
conducted over 3 consecutive days at pre-treatment, mid-treatment, end of treatment, and 
follow-up. Mediating mechanisms (e.g., alternative reinforcers, relative reinforcing value of food, 
food reward, and food cue-induced craving) will be assessed before, during, and at the end of 
treatment (week 8). Potential moderators include gender, depression symptoms and weight 
concerns. 
1.2 Background - Neuroimaging Sub-Study  
The parent randomized clinical trial of behavioral activation intervention (BAS+) integrates 
Behavioral Economic Theory and cognitive neuroscience research. The basic premise is that 
smoking cessation produces a reward dysregulation that increases the reward value of other 
reinforcers, such as highly palatable foods. Because food is a readily available reinforcer --and 
palatable foods increase in their incentive salience after quitting-- food cue-elicited reactivity in 
the brain’s reward system would increase with smoking cessation. Food reward and reinforcing 
value also increases in the context of cessation leading to increased food intake. Cessation-
induced increases in food reward are paralleled by decreases in the ability to control the 
consumption of palatable food. Research by our group and others shows that cessation impairs 
aspects of executive function that are critical to self-control. Abstinence reduces engagement of 
brain regions essential for cognitive control and individuals with lower levels of response 
inhibition are less able to resist palatable foods, and are more vulnerable to overeating. Working 
memory is important to keep goals in mind and for efficient use of behavior change tools, yet it 
can be depleted by efforts to manage cravings. This will be the first study to integrate these 
concepts and to explore brain mechanisms underlying a behavioral activation intervention 
(BAS+) to promote smoking cessation and mitigate PCWG. 
 
This neuroimaging study will aim to examine a sub-set of the randomized clinical trial 
participants. Functional magnetic resonance imaging (fMRI) can identify mechanisms underlying 
behavior change beyond self-report and behavioral measures. We will examine neural 
responses in three parallel pathways including: cognitive control, food cue reactivity, and food 
reinforcement. As in the parent study, the primary outcomes will be food intake and 7-day point 
prevalence abstinence at 12 weeks post target quit date. BOLD signal (secondary outcome) will 
be measured at pre-treatment (week -2) and end of treatment (week 8). Our three aims 
address: 1) identifying putative brain mechanisms underlying BAS+ (vs. SC) treatment for 
smoking cessation and PCWG; 2) evaluating the relative contribution of treatment-induced 
changes in task related brain signal (Food Cue Response, Food Reinforcement/Choice) in 
prediction of post treatment food intake; and 3) testing whether BAS+ (vs. SC) induced change 
in neural responses to food cues and food reinforcement is a stronger predictor of food intake 
among smokers with greater cognitive control. The findings will address why BAS+ may be 
effective in managing PCWG and provide insight into which patients are best supported by this 
treatment. We also test whether cognitive control processes moderate the influence of BAS+ 
treatment on food intake.  
1.3 Background- Microbiome Sub-Study 
The Gut Microbiome May Underpin the Substitution of Food for Cigarettes After Smoking 
Cessation: Converging research suggests that the gut microbiome may play an important role 
in modulating post-cessation increases in food intake and set the stage for smoking relapse. 
Gut bacteria and the brain have a bi-directional route of communication through the 
microbiome-gut-brain (MGB) axis. As such, smoking cessation-induced perturbations in the gut 
microbiome have the potential to impact the brain as well as behavior. Preliminary research has 
shown that smoking cessation results in profound changes in gut microbial abundance within 4 

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to 8 weeks after quitting smoking (see Aim 1). These smoking cessation-associated changes 
(e.g., reduced Bacteroides, increased Firmicutes) are similar to those observed in obesity.  
 
Smoking cessation-induced changes in the abundance of gut bacteria likely have functional, 
downstream consequences for dietary intake and smoking abstinence. Gut microbes secrete 
neurotransmitters and other neuroactive metabolites that regulate reward-seeking behavior by 
communicating pleasure and satiety to the brain via the vagus nerve. For example, dopamine, 
serotonin, and gamma-aminobutyric acid (GABA), as well as their precursors (tyrosine, 
tryptophan, and glutamate, respectively), are secreted by multiple genus. Indeed, the gut is a 
significant source of these key neurotransmitters that are also active in the brain. The gut 
microbiome also produces neuroactive metabolites (e.g., indole and short chain fatty acid 
propionate) that impact appetite by stimulating the production of gut hormones with anorectic 
functions. Shifts in the abundance of bacteria that produce these neurotransmitters and 
metabolites likely translate to a reduction in these molecules that are involved in reward and 
appetite regulation. In turn, reduced reward and appetite regulation may drive the substitution of 
cigarettes with palatable snack foods, as well as smoking relapse. 
 
Can BAS+ Mitigate the Effects of Gut Microbiome Changes on Dietary Intake and 
Smoking Relapse? Smoking cessation induced changes in the composition of the gut 
microbiome along with downstream reductions in neuroactive metabolites involved in reward 
regulation and appetite control likely result in increased food intake (and ultimately weight gain) 
and smoking relapse. As such, the gut microbiome may provide a biological basis for the 
observation that smoking cessation heightens the reinforcing value of snack foods, which 
predicts subsequent food intake and weight gain. In the context of fewer alternative reinforcers 
and diminished sensitivity to these reinforcers, there is little to compete with food or cigarettes 
as a reinforcer. BAS+ focuses on increasing the number of, and pleasure derived from, 
alternative reinforcers to improve cessation rates, mitigate increases in dietary intake, and 
lesson PCWG. We will explore whether BAS+ (versus SC) mitigates the effects of gut 
microbiome changes on dietary intake and smoking abstinence at 12 weeks post TQD. 
2 Study Objectives 
2.1 Parent (Main) Study 
Aim 1: To evaluate the efficacy of BAS+ versus SC when delivered in conjunction with TN.  
H1a:  Compared to SC, participants in the BAS+ group will have less post-cessation food intake 
and gain less weight at week 26.  
H1b: Compared to SC, participants in the BAS+ group will have higher smoking cessation rates 
at the end of treatment and at the 12- and 26-week follow-up time points.  
 
Aim 2: To examine the mechanisms by which BAS+ reduces PCWG and promotes smoking 
cessation.   
H2a: BAS+ vs. SC will increase engagement in and enjoyment from alternative reinforcers, and 
reduce the relative reinforcing value of food, food reward, and food cue-induced craving after 
smoking cessation. 
H2b: Changes in these measures will predict reduced food intake and weight gain, which in turn 
will predict increased quit rates.  
Exploratory Aim: We will explore whether women, or smokers with greater pre-treatment 
weight concerns or depression symptoms are more likely to exhibit PCWG and more likely to 
benefit from BAS+ vs. SC.  

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The proposed study breaks new conceptual and empirical ground by: (1) providing the first 
evaluation of the efficacy of BAS+ for smoking cessation and PCWG as an adjunct to the most 
widely used pharmacotherapy for smoking cessation and (2) examining the mechanisms by 
which BAS+ reduces food intake and weight gain.  If the hypotheses are supported, the findings 
would suggest that targeting reward-related mechanisms common to both smoking and eating: 
(1) is an effective approach to promoting smoking cessation, while minimizing PCWG; and (2) is 
a viable approach for addressing two rewarding behaviors concurrently, without risking 
compensatory increases in one of those behaviors. Pretreatment assessments will enable the 
identification of potential individual differences in intervention efficacy.  
2.2 Neuroimaging Sub-Study 
Aim 1: Identify putative brain mechanisms underlying BAS+ (vs. SC) treatment for smoking 
cessation and PCWG.  
H1a: BAS+ (vs. SC) will decrease food cue-induced activity in insula, anterior cingulate cortex 
(ACC), orbitofrontal cortex (OFC), and ventral striatum/accumbens (VS/NAC);  
H1b and H1c: (Hb) BAS+ (vs. SC) will decrease food reinforcement choice-related activity in 
VS/NAC and ventromedial prefrontal cortex (vmPFC); and (H1c) will produce corresponding 
decreases in food craving, reward, and reinforcement at the behavioral level (task 
performance). 
 
Aim 2: To evaluate the relative contribution of treatment-induced changes in task related brain 
signal (Food Cue Response, Food Reinforcement/Choice) in prediction of post treatment food 
intake. 
H2a: Brain network response (H1a-b) in the BAS+ (vs. SC) group will characterize treatment-
induced changes in caloric intake (and quit success) more accurately than clinical (age, sex, 
nicotine dependence, BMI) and behavioral (withdrawal, craving, food reinforcement) measures 
alone. 
H2b: The relative contribution of domain specific brain signal (food cue reactivity and food 
reward) to the prediction of treatment-induced change in caloric intake will be evaluated 
(regression model). 
 
Aim 3: Test whether BAS+ (vs. SC) induced change in neural responses to food cues and food 
reinforcement is a stronger predictor of food intake among smokers with greater cognitive 
control. 
We predict that the relationship of food cue and choice-related neural activity (e.g., VS/NAC 
BOLD signal; BAS+ vs. SC) will be a stronger predictor of caloric intake among smokers who 
also show greater working memory-related neural activity (i.e., DLPFC BOLD signal) at baseline 
and post treatment. Regions of interest for food cue and choice-related neural activity will be 
selected from those shown to be sensitive to cessation in Aim 1. 
Utilizing fMRI, we can identify the neural underpinning of a novel behavioral activation (BAS+) 
intervention for smoking and related PCWG. The findings will address why BAS+ may be 
effective in managing PCWG and provide insight into which patients are best supported by this 
treatment. We also test whether cognitive control processes moderate the influence of BAS+ 
treatment on food intake. If our cognitive control hypothesis is supported, combining 
neurocognitive training with BAS+ could improve treatment efficacy. The integration of concepts 
and tools from behavioral economics and cognitive neuroscience tackles PCWG in a highly 
novel way, with implications for validating new treatments. 

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2.3 Microbiome Sub-Study 
Aim 1: To identify earlier (4-weeks post TQD) and persistent (8-weeks post TQD) smoking 
cessation associated changes in gut microbiome composition and function. 
H1a: Smoking cessation will result in decreases in Prevotella and Bacteroides species from the 
Bacteroidetes phylum, decreases in β- and ʸ- Proteobacteria, increases in Clostridium clusters 
IV and XIV from the Firmicutes phylum, and increases in Bifidobacteria and HGC bacteria from 
the Actinobacteria phylum.  
H1b. We expect to observe decreases in neurotransmitters implicated in reward (dopamine, 
serotonin, GABA) as well as their precursors (tyrosine, tryptophan, glutamate), and microbial 
metabolites involved in appetite regulation (indole and propionate). 
 
Aim 2: To evaluate the relationship between post-cessation changes in the gut microbiome, 
dietary intake, and smoking abstinence. 
H2: Greater post-cessation changes in the gut microbiome will predict increased dietary intake 
and lower smoking abstinence rates 12 weeks post TQD. 
 
Aim 3: To explore whether BAS+ (vs. SC) mitigates the effect of gut microbiome changes on 
dietary intake and smoking abstinence.  
 
H3: Because BAS+ promotes alternative, non-food sources of reinforcement, BAS+ (vs SC) will 
mitigate the effects of microbiome changes on dietary intake and smoking abstinence 12 weeks 
post TQD. 
3 Study Design 
3.1 General Design - Parent (Main) Study 
This is a randomized clinical trial of the efficacy of BAS+ plus TN compared to SC plus TN in 
treatment-seeking smokers. After completing an Intake Visit (~week -3), eligible smokers will be 
randomized (stratified by nicotine dependence, BMI and gender) to participate in 8 individual 
sessions of BAS+ or SC over a 10-week treatment period with two sessions prior to the target 
quit date (weeks -2, -1) and six sessions post-target quit date (TQD [week 0] and weeks 1, 2, 4, 
6, and 8). Standard, 8-week; open-label TN will begin on the TQD. Moderators will be assessed 
pre-treatment. Mediating mechanisms will be assessed before, during, and at the end of 
treatment (EOT, week 8). Smoking will be assessed by self-report and biochemically confirmed 
(Carbon Monoxide [CO] < 5 or absence of Urine Cotinine) at all in-center visits (for CO ONLY) 
after quitting, at EOT (week 8), and at the 12- and 
26-week follow-ups. Weight will be assessed at 
these same time points.  Food intake will be 
measured by three consecutive days of 24-hour 
food recalls at Baseline [week -2] and 4-, 8-, and 
12- and 26-weeks post-TQD. Smoking cessation 
and PCWG are the primary outcomes and food 
intake is a secondary outcome at 26-weeks post-
TQD. Consistent with intent-to-treat (ITT) analyses, 
we will measure smoking cessation and weight gain 
in the full sample at the 26-week follow-up, 
evaluating 
a 
smoking 
status 
by 
treatment 
interaction for the PCWG analysis.  
 
Time points (i.e. study weeks) displayed in Figure 

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1 and included within the Study Procedures Section represent approximations. Participants will 
follow a study schedule similar to that designated in Figure 1 and the Study Procedures, but will 
be permitted a degree of flexibility based on the maximum/minimum amount of time allowed 
between each time point established by the Principal Investigator. If a participant is unable to 
attend an in-person visit within the permissible window of time allotted between time points, 
counseling and applicable study measures may be completed/collected via telephone. In-person 
completion of the Intake and Baseline Visits are considered mandatory for study participation. 
3.2 General Design - Neuroimaging Sub-Study  
We 
propose 
to 
study 
a 
sub-sample 
of 
consecutively 
recruited 
participants 
(N=~50) 
enrolled in the parent randomized clinical trial. As 
displayed in Figure 2, an equal number of fMRI 
eligible smokers from the BAS+ or SC treatment 
group will be studied before treatment (~week -2) 
and during the final week of nicotine patch therapy  
(~week 7-8). As part of the parent study, smoking 
will be assessed by self-report and biochemically 
confirmed weekly after quitting, at EOT (week 8), 
and at the 12 and 26 week follow-ups. Weight will 
be assessed at these same time points. Food 
intake will be measured by three consecutive days 
of 24-hour food recalls at baseline and 4-, 8- 12- 
and 26-weeks post-TQD. 
 
Scans identified in Figure 2 and included within the Study Procedures Section represent 
approximations. Participants will complete scans as designated in Figure 2 and the Study 
Procedures, but will be permitted a degree of flexibility at the discretion of the Principal 
Investigator due to extenuating circumstances. 
 
3.3 General Design - Microbiome Sub-Study  
We will study a subsample of up to 60 consecutively recruited smokers enrolled in the parent 
trial. The microbiome study subgroups will be balanced for age, sex, and BMI. In addition to the 
exclusion criteria for the parent trial, we will exclude individuals with current and recent (last 3 
weeks) use of non-topical antibiotics, antifungals, antivirals, and psychotropic drugs. 
Participants who are initially eligible based on telephone screening will complete an in- person 
Intake session as part of the parent study. Before or during the Intake session, consent for 
participation in the sub-study will be obtained and final sub-study eligibility will be confirmed. An 
equal number of microbiome eligible smokers from the BAS+ or SC treatment groups will be 
instructed to provide a stool sample on Week -2 (Baseline Visit), Week 4 (Mid-Tx 3 Visit), and 
Week 8 (End of Treatment Visit after completing TN treatment). Participants will be 
instructed to collect a stool sample within 24 hours (up to ~36 hours is permissible) of the target 
time points. Directions and supplies for stool specimen collection will be provided at the visit 
prior to collection.  
 
We will assess within-subjects changes in the gut microbiome across time and explore between 
treatment group comparisons at week 12. As part of the main study, smoking is assessed by 
self-report and is biochemically confirmed (CO < 5) weekly after quitting, at EOT (week 8), and 
at the 12- week follow-up. Food intake is measured by three consecutive days of 24-hour food 
recalls at baseline and 4- 8- 12- week post-TQD. 

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3.4 Study Duration – Parent (Main) Study 
Recruitment/enrollment began in earnest in September 2016 and will continue for ~44 months. 
We anticipate that ~340 participants will have completed the study by December 2020. We 
estimate that it will take ~30 weeks/8 months for a participant to complete the entire study. 
3.5 Study Duration- Neuroimaging Sub-Study  
Recruitment/enrollment for the neuroimaging sub-study is anticipated to begin in late July or 
August 2017 and will continue for ~18 months. We estimate that up to 50 participants will have 
completed the neuroimaging sub-study by ~April 2019. We estimate that it will take ~10 
weeks/2.5 months for a participant to complete the neuroimaging sub-study (i.e. both fMRI 
scans). 
3.6 Study Duration- Microbiome Sub-Study 
Recruitment/enrollment for the microbiome sub-study is anticipated to begin in late September 
or October 2019 and will continue for ~8-10 months. We estimate that up to 60 participants will 
have completed the microbiome sub-study by ~July 2020. 
 
4 CHARACTERISTICS OF THE STUDY POPULATION  
4.1 Target Population 
Participants will be treatment-seeking males and females between the ages of 18-65 who report 
smoking at least 5 cigarettes/day for at least the past 6 months. 
4.2 Accrual - Parent (Main) Study 
We will enroll ~625 participants (i.e., provide consent) to achieve a sample of ~340 who enter 
treatment (i.e., randomized) and remain enrolled through the 26-week assessment. To achieve 
this goal over a ~44-month enrollment period, we will complete 55 telephone screens monthly to 
obtain 25 smokers who meet criteria. Of these smokers, we expect ~15 to attend the Intake 
Visit, and ~10 per month to be confirmed eligible to be randomized after completing the Intake 
Visit.  
In order to increase retention throughout the study we will: (1) educate subjects about the 
benefits of participation and the knowledge gained from the study; (2) schedule sessions at 
times convenient for participants; (3) provide reminder calls; and (4) provide payment for 
completion of all study visits. As is the convention in smoking cessation trials, smokers who are 
lost to follow-up will be included in the analysis and counted as smokers. 
4.3 Accrual - Neuroimaging Sub-Study  
Eligible participants enrolled in the parent study who meet the fMRI eligibility criteria will have 
the opportunity to participate in the neuroimaging sub-study. We estimate that in order to 
achieve a sample of ~50 participants who complete the neuroimaging sub-study with usable 
data, we will need to enroll ~75 participants into the sub-study. Accrual estimates are based on 
our extensive experience conducting neuroimaging studies and specifically recruitment of fMRI 
subsamples from larger clinical trials. To ensure retention, we: (1) educate subjects about the 
benefits of participation and knowledge gained from the study; (2) schedule sessions at 
convenient times; (3) provide reminder calls; and (4) provide incentives for completion of 
sessions and assessments. This accrual rate is highly feasible based on our prior work. 

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4.4 Accrual – Microbiome Sub-Study 
Eligible participants enrolled in the parent study who meet the microbiome eligibility criteria will 
have the opportunity to participate in the microbiome sub-study. We estimate that in order to 
achieve a sample of up to 60 participants who complete the microbiome sub-study with usable 
data, we will need to enroll ~75 participants into the sub-study as our retention rate through 12 
weeks is ~80%. To ensure retention in the sub-study, we will offer monetary incentives for 
providing stool samples per the study instructions. 
4.5 Inclusion Criteria 
1. Male and female treatment-seeking smokers who are between 18 and 65 years of age 
and self-report smoking at least 5 cigarettes (menthol and/or non-menthol) per day for at 
least the last 6 months. 
2. Plan to live in the area for the duration of the study (i.e. ~30 weeks/8 months). 
3. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the combined consent and HIPAA form. 
4. Smokers who wish to make a permanent quit attempt in the next 1-2 months (treatment-
seeking), because our prior work suggests that motivated subjects are more sensitive to 
medication effects on smoking behavior. Using a scale from 0 to 100 (100, being 
extremely interested), subjects must rate their interest in quitting smoking within the next 
1-2 months greater than 50. 
5. Able to communicate fluently in English (i.e. speaking, writing, and reading). 
6. Participants will provide a Urine Cotinine sample that is present at a sensitivity of 100 
ng/mL at the Intake Visit. If deemed safe by the Principle Investigator under federal and 
University guidelines, participants will provide a Carbon Monoxide (CO) breath test 
reading greater than or equal to 5 parts per million (ppm) at the Intake Visit 
4.6 Exclusion Criteria 
Subjects who present and/or self-report with the following criteria will not be eligible to 
participate in the study:  
 
Smoking Behavior 
1. Regular use of nicotine containing products other than cigarettes (e.g. chewing tobacco, 
snuff, snus, cigars, e-cigs, etc.). Participants agreeing to abstain from using nicotine 
containing products other than cigarettes and the study-provided TN for the duration of 
trial will be considered eligible. 
2. Current enrollment or plans to enroll in another research and/or smoking cessation 
program over the duration of the study (i.e. ~30 weeks/8 months). 
3. Anticipated use (within the next ~30 weeks/8 months) of any nicotine substitutes and/or 
smoking cessation treatments/medications unless provided through the study.  
4. 
Participant who provide a Urine Sample that is absent of Cotinine at a sensitivity 
of 100 ng/mL at the Intake Visit. If deemed sage by the Principle Investigator under 
federal and University guidelines, if participants provide a CO breath test reading less 
than 5 ppm at Intake will not be eligible to participate in the study.  
Alcohol and Drug  
1. History of substance abuse (other than nicotine) in the past 12 months and/or currently 
receiving medical treatment for substance abuse. Counseling and support groups (e.g. 
Alcoholics Anonymous and Narcotics Anonymous) will not be considered medical 
treatment for the purposes of this protocol.  
2. Current alcohol consumption that exceeds 25 standard drinks/week. 
3. Breath alcohol reading (BrAC) greater than .000 at the Intake Visit for participants who 
complete an in-person consent. Participants who completed a virtual REDCap consent 

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and telephone Consent Discussion will not be required to complete a BrAc reading for 
the safety of the participant and the staff members due to the risk of exposure to COVID-
19. Further, a BrAc reading is unnecessary in this case because the participant would 
have consented at a different time prior to coming into the center for their Intake Visit.  
4. A 
positive 
urine 
drug 
screen 
(UDS) 
for 
cocaine, 
opiates, 
amphetamines, 
methamphetamines, 
phencyclidine 
(PCP), 
ecstasy 
(MDMA), 
barbiturates, 
benzodiazepines, methadone, and/or oxycodone at the Intake Visit.   
 
 
Medical  
1. Women who are pregnant, breast feeding, or planning a pregnancy over the duration of 
the study period. Women must agree to use an adequate form of contraception or 
abstain from sexual intercourse for the duration and for at least one month after the end 
of the study. 
2. Current treatment of cancer or diagnosed with cancer (except basal or squamous-cell 
carcinoma not treated with chemotherapy and/or radiation) in the past 6 months.  
3. Poorly controlled, brittle, or pump-dependent Type I diabetes. 
4. Current peptic ulcer bleeding. 
5. Allergy to adhesive tape. 
6. Skin problems or sensitivities. Eligibility will be evaluated on a case-by-case basis by the 
Study Physician. 
7. Active hepatitis or poorly controlled kidney and/or liver disease. 
8. Uncontrolled hypertension (systolic blood pressure [SBP] greater than 159 and/or 
diastolic blood pressure [DBP] greater than 99; see Blood Pressure Procedures under 
Screening/Covariates). 
9. History of abnormal heart rhythms, tachycardia, and/or cardiovascular disease (e.g. 
stroke, angina, heart attack) may result in ineligibility. These conditions will be evaluated 
on a case-by-case basis by the Study Physician. 
10. History of epilepsy or seizures. Eligibility will be evaluated on a case-by-case basis by 
the Study Physician. 
11. Serious or unstable disease within the past 6 months. Notable diseases will be 
evaluated on a case-by-case basis by the Principal Investigator and/or the Study 
Physician. 
12. Any impairment including, but not limited to, visual, physical, and/or neurological 
impairments preventing proper completion of the study procedures. Notable impairments 
will be evaluated on a case-by-case basis by the Principal Investigator and/or the Study 
Physician. 
13. Low or borderline intellectual functioning – determined by receiving a score of less than 
75 on the Shipley Institute of Living Scale (SILS), which correlates with the Wechsler 
Adult Intelligence Scale-Revised (WAIS-R) Estimated IQ Test.  
14. Applicable food allergies or disorders:  
• 
Galactosemia a 
• 
Notable milk allergy (lactose intolerant participants may proceed unless they 
experience severe symptoms) b  
• 
Notable soy allergy c 
• 
Peanut allergy d 
a,b,c Boost® Original Very Vanilla Nutritional Shake: Contains milk and soy ingredients. Suitable for Lactose Intolerance. 
a,b,c,d M&M’s® (Milk Chocolate): Contains milk and soy ingredients (MAY CONTAIN PEANUTS) 
Lay’s® Classic Potato Chips (Gluten Free): Potatoes, vegetable oil, and salt  
 
Psychiatric 

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1. Current diagnosis of major depression. Subjects with a history of major depression, in 
remission for 6 months or longer (may be stable on antidepressant medications), are 
eligible. 
2. Lifetime history of a suicide attempt. 
3. Lifetime history of schizophrenia, psychosis, and/or bipolar disorder. 
 
Medication  
Current use or recent discontinuation (within the last 14 days) of: 
1. Smoking cessation medication (e.g., Zyban, Wellbutrin, Wellbutrin SR, Chantix).  
2. Anti-psychotic medications. 
3. Prescription stimulants (e.g., Provigil, Ritalin, Adderall). 
4. Systemic steroids. 
Current use of:  
5. Nicotine replacement therapy (NRT). 
6. Heart medications such as digoxin, quinidine, and nitroglycerin. 
Daily use of: 
7. Benzodiazepines and/or Barbiturates.  
8. Opiate-containing medications for chronic pain. 
9. Inhaled corticosteroids. 
 
Subjects will be instructed to refrain from using any study prohibited drugs/medications (both 
recreational and prescription) throughout their participation in the study.  After final eligibility is 
confirmed, subjects who report taking contraindicated medication(s) over the course of the study 
period may only remain eligible if the Study Physician and Principal Investigator determine that 
the contraindicated medication(s) do/did not significantly impact the study design, data quality, 
and/or subject safety and welfare. Subjects are permitted to take necessary prescription 
medications not included within the exclusion list during the study.  
 
General Exclusion 
1. Past, current, anticipated, or pending enrollment in another research program over the 
study period that could potentially impact subject safety, study data, and/or the study 
design as determined by the Principal Investigator and/or Study Physician. 
2. Any medical condition, illness, disorder, adverse event (AE), or concomitant medication 
that could compromise participant safety or significantly impact study performance as 
determined by the Principal Investigator and/or Study Physician. Subjects may be 
deemed ineligible for any of the aforementioned reasons at any point throughout the 
study, as well as during the initial telephone screen. 
3. Significant non-compliance with protocol and/or study design as determined by the 
Principal Investigator and/or Study Physician.  Subjects may be deemed ineligible at any 
point throughout the study.  
4. Subjects failing to complete an in-person Baseline Visit will be excluded (no Principal 
Investigator determination required).  
 
fMRI Exclusion Criteria  
The following fMRI exclusion criteria are only pertinent to the neuroimaging sub-study sample – 
subjects who are not eligible to complete the neuroimaging sub-study may still complete the 
parent study if appropriate per protocol: 
1. History of claustrophobia. 
2. Being left-handed. 
3. Lifetime history of stroke. 
4. Having a cochlear implant or wearing bilateral hearing aids. 

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5. History of notable head trauma. Although notable head trauma is typically defined as 
being knocked unconscious for a period of three minutes or longer, notable head trauma 
will be evaluated on a case-by-case basis by the appropriate personnel prior to an 
eligibility decision considering exceptions can be made based on the nature and severity 
of the trauma.   
6. History of brain or spinal tumor. 
7. Pacemakers, certain metallic implants or objects, or presence of metal in the eye as 
contraindicated for MRI. 
8. Any circumstances (e.g., exclusionary metal implants, certain dental work, and/or 
physical impairments) and/or conditions that may interfere with MRI and MRI-related 
study visit procedures. All potential exclusionary circumstances and/or conditions will be 
evaluated on a case-by-case basis by the appropriate personnel prior to an eligibility 
decision. 
9. History of gunshot wounds. Injuries from BB guns will be evaluated on a case-by-case 
basis by the appropriate personnel prior to an eligibility decision. 
10. History of epilepsy and/or recurrent or uncontrolled seizures. 
11. Weight greater than 250 lbs at Intake Visit or self-reported at phone screen. If a 
participant weighs less than or equal to 250 lbs at Intake, but presents with a weight 
greater than 250 lbs at either Scan 1 and/or Scan 2, the participant may be permitted to 
proceed with the scan as long as the participant’s weight does not exceed 300 lbs. 
12. A 
positive 
urine 
drug 
screen 
(UDS) 
for 
cocaine, 
opiates, 
amphetamines, 
methamphetamines, 
phencyclidine 
(PCP), 
ecstasy 
(MDMA), 
barbiturates, 
benzodiazepines, methadone, and/or oxycodone at either Scan Visit. Depending on the 
substance and circumstances, a subject may be deemed ineligible for the main study at 
the discretion of the Principal Investigator as well. 
13. A BrAC greater than 0.010 at either Scan Visit.  Depending on the circumstances, the 
Principal Investigator may permit the participant to remain in the sub-study and 
reschedule a neuroimaging scan to another day. 
Microbiome Sub-Study Exclusion Criteria  
The following exclusion criteria only pertain to inclusion within the microbiome sub-study. 
Subjects who are not eligible to participate the microbiome sub-study may still complete the 
parent study if appropriate per protocol. 
Current use or recent discontinuation (within the last 21 days) of the following medications: 
1. Antibiotics (topical antibiotics are permissible) 
2. Antifungals (topical antifungals are permissible) 
3. Antivirals (topical antivirals are permissible) 
4. Psychotropics 
 
Once a participant is confirmed as eligible for the microbiome sub-study at the Intake Visit, they 
may remain enrolled in the sub-study even if they report the use of sub-study exclusionary 
medications listed above. This caveat is in recognition that the impact of certain medications 
may be unknown until the completion of analyses.  
4.7 Vulnerable Populations 
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research 
study. Educationally or economically disadvantaged persons are included but not solely 
targeted for recruitment. Because of our recruitment efforts for this study, it is possible that 
University of Pennsylvania employees and students may be invited to participate. Status of 
participation in the current study will be independent of the participant’s work or school activities.  

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4.8 Subject Recruitment  
Participants may be recruited from television, radio, internet advertisements, social media, 
newspaper, flyers, transit posters, referrals, and/or from our database of previous participants 
who have agreed to be re-contacted for future studies.  All advertising materials will be 
submitted to the UPENN IRB for approval prior to distribution/posting. Interested participants will 
first complete a telephone screen to assess their initial eligibility.  Participants who are initially 
eligible will be screened against our registration database to confirm that they are not currently 
participating in another research study at our Center and have not previously reported a 
condition or circumstance that would make them ineligible for the current study. . If the PI 
deems it is safe for the participant and research staff, based upon federal and University 
COVID-19 guidance, then eligible research participants will be invited to the center to complete 
an Intake Visit during which they will be presented with the IRB approved Informed Consent 
Form in-person and have their final eligibility confirmed.  
 
Prior to the Principle Investigator’s approval, those participants who remain initially eligible at 
phone screen will then be invited to review the entire IRB approved Informed Consent Form 
virtually via REDCap to minimize the participants time spend in the research center during the 
COVID-19 pandemic. After reviewing the IRB approved Informed Consent Form, the participant 
will complete a telephone Consent Discussion with a member of the research staff. After the 
participant has had the opportunity to have their questions answered, signed the consent, and 
agreed to participate, the participant will complete a Shipley Institute of Living Scale (SILS) 
virtually via REDCap. Participants whose estimated IQ is 75 according to the WAIS-R 
conversion based upon the exam will be deemed Ineligible per the Exclusion Criteria above. 
Participants whose WAIS-R estimated IQ is at least a 75 based upon the Shipley will then be 
invited to the center to have their final eligibility confirmed at an Intake Visit. Early Withdrawal of 
Subjects 
4.8.1 When and How to Withdraw Subjects 
Subjects are free to withdraw from the study at any time.  Subjects may be deemed “ineligible” 
at any time per the exclusion criteria listed in section 4.5. No follow-up data collection is required 
for participants who withdraw or are deemed ineligible throughout the study. 
5 Study Drug (Transdermal Nicotine [TN]) 
5.1 Description 
The medication utilized in this trial, open-label TN (NicoDerm® CQ® - Clear), will be used in 
accordance with FDA-approved labeling except participants smoking at least 10 cigarettes per 
day will only utilize TN for 8 weeks instead of 10 weeks. This shortened dosing regimen is 
neither a significant change nor does it pose an increased risk to subjects. The results of this 
trial will not be reported to the FDA to support a new drug indication. This study is not intended 
to support a significant change in the advertising for TN. This study will not involve a route of 
administration or dosage level, use in a subject population, or other factor that would 
significantly increase the risks (or decrease the acceptability of the risks) associated with TN.  
5.2 Treatment Regimen 
All eligible subjects receiving Study Physician approval will receive 8 weeks of open-label TN 
patches (NicoDerm® CQ® - Clear). TN treatment will commence week 0 (TQD) and conclude 
week 8 (EOT). All participants who report smoking 10 or more cigarettes a day at the Intake 
Visit will receive the 21mg dose for the first 4 weeks, 14mg for the subsequent 2 weeks, and 

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7mg for the final 2 weeks. Participants who report smoking 5-9 cigarettes a day at the Intake 
Visits will receive the 14mg dose for 6 weeks and the 7mg dose for the final 2 weeks.   
 
Participants included within the neuroimaging sub-study will be instructed to remove their 7mg 
TN patch prior to entering the MRI environment during their Scan 2 Visit only (no patch worn 
during the pre-treatment scan). Participants will be provided with a loose, sealed 7mg 
(NicoDerm® CQ® - Clear) patch to reapply after exiting the MRI environment. 
5.3 Preparation and Packaging of Study Drug 
A trained member of the research team will distribute TN patches (NicoDerm® CQ® - Clear) per 
a standard distribution schedule. For every two weeks of treatment, participants will receive an 
unopened box of TN patches (n=14) of the appropriate dose, as well as two extra “loose” 
patches of the appropriate dose in an opaque storage bag. A label containing the participant’s 
study I.D. number, dosage (mg), counselor name and phone number, Study Physician name 
and phone number, as well as additional safety and storage instructions will be secured to all 
unopened boxes and loose storage bags of TN prior to distribution. 
5.4 Subject Compliance Monitoring 
TN patch adherence data will be collected and recorded at every applicable time point. The 
research staff will collect all unused patches and attempt to ensure the amount of unused 
patches matches the patch adherence data. All discrepancies will be explored and recorded as 
appropriate. 
5.5 Receiving, Storage, Dispensing and Return 
5.5.1 Receipt of Drug Supplies 
TN will be shipped directly to the CIRNA. Upon receipt of TN to the CIRNA, an inventory will be 
performed and a drug receipt log filled out and signed by the person accepting the shipment. 
Study staff will verify that the shipment contains all the items noted in the shipment inventory. 
Any damaged or unusable TN in a given shipment will be documented in the study files.    
5.5.2 Storage 
TN patches will be stored in a double locked location (i.e., in a locked cabinet in a locked room) 
at room temperature (68-77ºF).  Temperature will be verified and recorded on a temperature log 
at regular intervals. Any readings outside the desired range will be documented and the 
temperature adjusted accordingly. 
5.5.3 Dispensing and Reconciliation of Study Drug 
The appropriate amount of TN patches will be distributed to eligible participants at week -1 
(PQ), week 1 (Mid-Tx.1), and week 4 (Mid-Tx. 3) according to a standardized patch distribution 
schedule. TN dosage (see section 5.2: Treatment Regimen) will be dependent on the 
participant’s daily smoking rate reported at the Intake Visit.  
 
Regular study drug reconciliation will be performed to document drug dispensed, drug used, 
and drug returned. This reconciliation will be logged on both a subject-specific drug 
reconciliation form maintained in the subject’s study chart, as well as an overall study drug 
accountability form. Returned or expired TN will be secured and logged into onsite quarantine. 
UPENN Environmental Health & Radiation Safety (EHRS) will make periodic pick-ups of the 
quarantined TN for incineration.  Records of EHRS pick-ups will be maintained in the study files. 

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5.5.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug received, drug 
consumed, and drug remaining. This reconciliation will be logged on a study completion drug 
reconciliation form, signed and dated.  Any notable discrepancies will be investigated, resolved, 
and documented prior to destruction of unused study drug. Unused or expired TN will be 
secured and logged into onsite quarantine.  UPENN EHRS will make a final pick-up of the 
quarantined TN for incineration.  A record of EHRS final pick-up will be maintained in the study 
files. 
6 Study Procedures 
6.1 Telephone Eligibility Screen  
Individuals interested in study participation will be screened by a qualified member of the 
research team to determine initial study eligibility. If the participant meets preliminary eligibility, 
they will be invited to schedule an Intake Visit at which their final eligibility will be confirmed. 
6.2 In-Center Visits  
6.2.1 Visit Reminders 
Participants will typically receive study visit reminders 24 – 48 hours prior to their scheduled 
study visits via phone call, email, and text message (if applicable).  Prior to the Follow-Up visits, 
participants may receive reminder letters, emails, and/or phone calls up to two weeks in 
advance. 
6.2.2 Intake Visit (~Week -3) 
During the Intake Visit (Duration: ~3 hours) participants will: 
 
1. In order to limit the number of people in the research center and their study visit duration 
during the COVID-19 pandemic, the PPT will complete a virtual IRB approved informed 
consent and HIPAA presentation via REDCap where all the study procedures and 
institutional policies will be reviewed prior to coming in to complete the remainder of their 
Intake Visit until the Principle Investigator deems it is safe for the participant and 
research staff to conduct in-person consenting, based upon federal and University 
COVID-19 guidelines.  
• 
The participant will be required to view the entire combined informed consent and 
HIPAA form prior to signing the document. Upon completing their reading of the 
consent, the PPT will be offered the opportunity to indicate if they have any 
questions and a staff member will call the participant to complete a consent 
discussion via the telephone.All participant questions will be recorded and 
answered as appropriate after which the combined informed consent and HIPAA 
form will be completed (virtually signed and dated) by both the participant and a 
qualified member of the research team.  
• 
The staff will print a signed copy of this completed record and provide a copy to 
the participant and save a copy for our records. 
• 
If the Principle Investigator grants approval, the participant may complete the 
informed consent and HIPAA presentation in-Person to review the study 
procedures and institutional policies. All of their questions will be recorded and 
answered as appropriate after which the combined informed consent and HIPAA 
form will be completed (signed and dated) by both the participant and a qualified 

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member of the research team. The participant and the research study will each 
maintain a completed copy for their records.  
2. Confirm the accuracy of information (i.e. name, address, phone number, email [if 
applicable], date of birth, age, gender, ethnicity, and race) provided during the initial 
Telephone Eligibility Screen. 
3. Complete a UDS (at least 30ml [two tablespoons] of urine). The UDS will assess the use 
of any study-prohibited medications/recreational drugs (See Key Exclusionary Criteria; 
Alcohol and Drug).  
• 
Participants who test positive for any exclusionary medications or recreational 
drugs per this protocol will be deemed ineligible..  
4. Female participants only: Self-administer a CLIA-waived urine pregnancy test.  
• 
Female participants are informed that the participation of pregnant women in this 
study is prohibited and that if they believe they are pregnant they should 
withdraw from the study immediately. 
 
 
5.  The Participant’s urine sample will be used to administer a Urine Cotinine screen with a 
sensitivity of 100 ng/mL to confirm their smoking status in the absence of a CO reading 
in order to maintain the safety of the research staff and research participant during the 
ongoing COVID-19 pandemic.   
• 
Participants who fail to indicate the presence of cotinine of at least 100 ng/mL in 
their urine will be deemed ineligible per this protocol.  
 
6.  May perform a BrAC assessment to control for alcohol consumption if participants 
completed an in-person consent and the Principle Investigator deems it is safe for 
researchers and research participants according to federal and University guidelines. 
• 
Participants with a BrAC greater than 0.000 at Intake Visit will be ineligible. 
7. May perform a CO breath assessment and self-report smoking behavior over the past 24 
hours to control for prior tobacco exposure the Principle Investigator deems it is safe for 
researchers and research participants according to federal and University guidelines  
• 
Participants with a CO reading less than 5 ppm will be deemed ineligible. 
8. Complete a blood pressure measurement (See Blood Pressure Procedures under 
Screening/Covariates section) 
9. Complete height and weight measurements. 
10. Complete a Medical History Form with a member of the research team to review for 
applicable contraindications previously listed under the Inclusion and Exclusion Criteria 
sections. 
11. Participants who meet the microbiome sub-study eligibility criteria at telephone 
screening and elect to participate in the microbiome sub-study only: Complete a 
Microbiome Medication Review form 
• 
Participants who do not meet the microbiome eligibility criteria will be deemed 
ineligible for the microbiome sub-study. Participants may still participate in the 
parent study per protocol. 
12. Complete a baseline concomitant medication review (if applicable).  
13. Participants who meet neuroimaging eligibility criteria at telephone screening and 
elect to participate in the neuroimaging sub-study only: Complete an fMRI Medical 
History Form, Magnet Safety Form, and Emergency Contact Form. 

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• 
Participants who do not meet the fMRI eligibility criteria will be deemed ineligible 
for the neuroimaging sub-study. Participants may still participate in the parent 
study per protocol.  
14. Complete the Shipley Institute of Living Scale IQ test in-person if the Principle 
Investigator deems it is safe for researchers and research participants according to 
federal and University guidelines, or virtually via REDCap 
• 
Participants earning less than an estimated WAIS-R IQ score of 75 will be 
deemed ineligible and will not be invited to complete the remainder of their Intake 
Visit in-person if they completed their exam on REDCap Participants who 
complete their SILS via REDCap will not receive travel reimbursement, because 
they did not travel to the center.  
15. Complete paper and pencil questionnaires: 
• 
Demographics 
• 
Smoking History/Nicotine Dependence (FTND) 
• 
ETOH History 
• 
Cigarette Brand Form (staff will record cigarette brand information) 
• 
Program Referral Form 
16. Complete the Individualized Food (Pre-FCQ-S) task. Foods rated least appetizing (n=20) 
and foods rated most appetizing (n=20) will be selected to create personalized food cue 
stimuli for the Food Cue-Induced Craving (FCQ-S) task administered over the course of 
the study. 
17. Select either the salty (Lay’s® Classic Potato Chips) or sweet (M&M's® [Milk Chocolate]) 
snack food as the snack to “work for” in the Relative Reinforcing Value of Food (RRVF) 
task over the course of the study. 
18. Schedule the Baseline Visit with a member of the research team. Participants who are 
eligible for the neuroimaging sub-study and elect to participate may schedule their Scan 
1 Visit as well. All participants will schedule the remainder of their visits and dietary 
recalls at the conclusion of the Baseline Visit. 
6.2.3 Baseline Visit (~Week -2) 
Participants are asked to not consume food or caffeine for 4 hours prior to the beginning of the 
visit. During the Baseline Visit (Duration: ~3 hours) participants will: 
 
1. Perform a CO breath assessment, answer combustible marijuana items, and complete a 
concomitant medication review. 
2. Provide daily smoking rate (timeline follow back [TLFB]). 
3. Have weight measured. 
4. Complete paper and pencil questionnaires: 
• 
Withdrawal Symptoms (MNWS) 
• 
Smoking Urges/Craving (QSU-B) 
• 
Depression Symptoms (CES-D) 
• 
Hedonic Capacity (SHAPS) 
• 
Positive & Negative Affect (PANAS) 
• 
Physical Activity (PAR) 
• 
Habitual Food Craving (FCQ-T) 
• 
Eating Behavior (DEBQ) 
• 
Eating Inventory-Disinhibition (EI-D)   
• 
Weight Concerns  

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5. Immediately prior to the laboratory tasks, participants will be asked to rate, “How hungry 
are you right now?” using a scale from 0 “not at all” to 10 “extremely.” 
6. Participants will be provided with a Boost® Nutritional Drink to consume prior to 
completing the laboratory tasks.  
7. Complete computerized laboratory tasks: 
• 
Food Cue-Induced Craving (FCQ-S) 
• 
Food Reward 
• 
Food Reinforcement (RRVF) 
 
8. Immediately after the laboratory tasks, participants will be asked to rate, “How hungry 
are you right now?” using a scale from 0 “not at all” to 10 “extremely.” 
 
9. Participants will complete a standardized 30-minute wait period. During the wait period, 
participants will complete the paper and pencil questionnaire: 
• 
Alternative Reinforcers (freq, enjoy) (PES) 
 
10. Complete Session 1 of assigned counseling condition (BAS+ or SC) and schedule the 
remainder of their study visits and 24-hour dietary recalls. Participants will receive a 
copy of their study calendar at this time. 
6.2.4 Pre-Quit Visit (~Week -1) 
During the Pre-Quit Visit (Duration: ~2 hours) participants will: 
 
1. Perform a CO breath assessment, answer combustible marijuana items, and complete a 
concomitant medication review. 
2. Provide daily smoking rate (timeline follow back [TLFB]). 
3. Have weight measured. 
4. Participants who required multiple blood pressure readings during the Intake Visit will 
complete an additional blood pressure reading to reconfirm eligibility to receive TN as 
scheduled (See Blood Pressure Procedures under Screening/Covariates). 
5. Complete paper and pencil questionnaires: 
• 
Side Effect Checklist (SEC) 
• 
Adverse Events Form (Open-Ended AEs) 
• 
Withdrawal Symptoms (MNWS) 
• 
Smoking Urges/Craving (QSU-B) 
• 
Positive & Negative Affect (PANAS) 
• 
Physical Activity (PAR) 
6. Complete Session 2 of assigned counseling protocol (BAS+ or SC) and receive TN per a 
standardized distribution schedule (see section 6.5.1: Treatment; Transdermal Nicotine). 
6.2.5 Target Quit Day Visit (Week 0) 
During the Target Quit Day Visit (Duration: ~1.5 hours) participants will: 
 
1. Perform a CO breath assessment, answer combustible marijuana items, and complete a 
concomitant medication review. 
2. Provide daily smoking rate (timeline follow back [TLFB]). 
3. Have weight measured. 
4. Complete paper and pencil questionnaires: 

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• 
Side Effect Checklist (SEC) 
• 
Adverse Events Form (Open-Ended AEs) 
• 
Withdrawal Symptoms (MNWS) 
• 
Smoking Urges/Craving (QSU-B) 
• 
Positive & Negative Affect (PANAS) 
• 
Physical Activity (PAR) 
5. Complete Session 3 of assigned counseling protocol (BAS+ or SC), as well as provide 
TN progress and adherence information. 
6.2.6 Mid-Treatment 1 Visit (Week 1) 
Participants are asked to not consume food or caffeine for 4 hours prior to the beginning of the 
visit. During the Mid-Treatment 1 Visit (Duration: ~3 hours) participants will: 
 
1. Perform a CO breath assessment, answer combustible marijuana items, and complete a 
concomitant medication review. 
2. Provide daily smoking rate (timeline follow back [TLFB]). 
3. Have weight measured. 
4. Complete paper and pencil questionnaires: 
• 
Side Effect Checklist (SEC) 
• 
Adverse Events Form (Open-Ended AEs) 
• 
Withdrawal Symptoms (MNWS) 
• 
Smoking Urges/Craving (QSU-B) 
• 
Positive & Negative Affect (PANAS) 
• 
Physical Activity (PAR) 
5. Immediately prior to the laboratory tasks, participants will be asked to rate, “How hungry 
are you right now?” using a scale from 0 “not at all” to 10 “extremely.” 
6. Participants will be provided with a Boost® Nutritional Drink to consume prior to 
completing the laboratory tasks.  
7. Complete computerized laboratory tasks: 
• 
Food Cue-Induced Craving (FCQ-S) 
• 
Food Reward 
• 
Food Reinforcement (RRVF) 
8. Immediately after the laboratory tasks, participants will be asked to rate, “How hungry 
are you right now?” using a scale from 0 “not at all” to 10 “extremely.” 
9. Participants will complete a standardized 30-minute wait period. During the wait period, 
participants will complete the paper and pencil questionnaire: 
• 
Alternative Reinforcers (freq, enjoy) (PES) 
10. Complete Session 4 of assigned counseling condition (BAS+ or SC), provide TN 
progress and adherence information, and receive TN per a standardized distribution 
schedule (see section 6.5.1: Treatment; Transdermal Nicotine). 
6.2.7 Mid-Treatment 2 Visit (Week 2) 
During the Mid-Treatment 2 Visit (Duration: ~1.5 hours) participants will: 
 
1. Perform a CO breath assessment, answer combustible marijuana items, and complete a 
concomitant medication review. 
2. Provide daily smoking rate (timeline follow back [TLFB]). 

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3. Have weight measured. 
4. Complete paper and pencil questionnaires: 
• 
Side Effect Checklist (SEC) 
• 
Adverse Events Form (Open-Ended AEs) 
• 
Withdrawal Symptoms (MNWS) 
• 
Smoking Urges/Craving (QSU-B) 
• 
Positive & Negative Affect (PANAS) 
• 
Physical Activity (PAR) 
• 
Alternative Reinforcers (freq, enjoy) (PES) 
5. Complete Session 5 of assigned counseling condition (BAS+ or SC), as well as provide 
TN progress and adherence information. 
6.2.8 Mid-Treatment 3 Visit (Week 4) 
Participants are asked to not consume food or caffeine for 4 hours prior to the beginning of the 
visit. During the Mid-Treatment 3 Visit (Duration: ~3 hours) participants will: 
 
1. Perform a CO breath assessment, answer combustible marijuana items, and complete a 
concomitant medication review. 
2. Provide daily smoking rate (timeline follow back [TLFB]). 
3. Have weight measured. 
4. Complete paper and pencil questionnaires: 
• 
Side Effect Checklist (SEC) 
• 
Adverse Events Form (Open-Ended AEs) 
• 
Withdrawal Symptoms (MNWS) 
• 
Smoking Urges/Craving (QSU-B) 
• 
Positive & Negative Affect (PANAS) 
• 
Physical Activity (PAR) 
• 
Habitual Food Craving (FCQ-T) 
• 
Eating Behavior (DEBQ) 
• 
Eating Inventory-Disinhibition (EI-D)   
5. Immediately prior to the laboratory tasks, participants will be asked to rate, “How hungry 
are you right now?” using a scale from 0 “not at all” to 10 “extremely.” 
6. Participants will be provided with a Boost® Nutritional Drink to consume prior to 
completing the laboratory tasks.  
7. Complete computerized laboratory tasks: 
• 
Food Cue-Induced Craving (FCQ-S) 
• 
Food Reward 
• 
Food Reinforcement (RRVF) 
8. Immediately after the laboratory tasks, participants will be asked to rate, “How hungry 
are you right now?” using a scale from 0 “not at all” to 10 “extremely.” 
9. Participants will complete a standardized 30-minute wait period. During the wait period, 
participants will complete the paper and pencil questionnaire: 
• 
Alternative Reinforcers (freq, enjoy) (PES) 
10. Complete Session 6 of assigned counseling condition (BAS+ or SC), provide TN 
progress and adherence information, receive TN per a standardized distribution 
schedule (see section 6.5.1: Treatment; Transdermal Nicotine), and confirm the 24-hour 
dietary recall (#2) schedule. 

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6.2.9 Mid-Treatment 4 Visit (Week 6) 
During the Mid-Treatment 4 Visit (Duration: ~1.5 hours) participants will: 
 
1. Perform a CO breath assessment, answer combustible marijuana items, and complete a 
concomitant medication review. 
2. Provide daily smoking rate (timeline follow back [TLFB]). 
3. Have weight measured. 
4. Complete paper and pencil questionnaires: 
• 
Side Effect Checklist (SEC) 
• 
Adverse Events Form (Open-Ended AEs) 
• 
Withdrawal Symptoms (MNWS) 
• 
Smoking Urges/Craving (QSU-B) 
• 
Positive & Negative Affect (PANAS) 
• 
Physical Activity (PAR) 
5. Complete Session 7 of assigned counseling condition (BAS+ or SC) and provide TN 
progress and adherence information. 
6.2.10 End of Treatment Visit (Week 8) 
The End of Treatment Visit will be scheduled after patch treatment has concluded.  Participants 
are asked to not consume food or caffeine for 4 hours prior to the beginning of the visit. During 
the End of Treatment Visit (Duration: ~3 hours) participants will: 
 
1. Perform a CO breath assessment or provide a urine sample for a cotinine assessment answer 
combustible marijuana items, and complete a concomitant medication review. 
2. Provide daily smoking rate (timeline follow back [TLFB]). 
3. Have weight measured. 
4. Complete paper and pencil questionnaires: 
• 
Side Effect Checklist (SEC) 
• 
Adverse Events Form (Open-Ended AEs) 
• 
Withdrawal Symptoms (MNWS) 
• 
Smoking Urges/Craving (QSU-B) 
• 
Positive & Negative Affect (PANAS) 
• 
Physical Activity (PAR) 
• 
Habitual Food Craving (FCQ-T) 
• 
Eating Behavior (DEBQ) 
• 
Eating Inventory-Disinhibition (EI-D)   
5. Immediately prior to the laboratory tasks, participants will be asked to rate, “How hungry 
are you right now?” using a scale from 0 “not at all” to 10 “extremely.” 
6. Participants will be provided with a Boost® Nutritional Drink to consume prior to 
completing the laboratory tasks.  
7. Complete computerized laboratory tasks: 
• 
Food Cue-Induced Craving (FCQ-S) 
• 
Food Reward 
• 
Food Reinforcement (RRVF) 
8. Immediately after the laboratory tasks, participants will be asked to rate, “How hungry 
are you right now?” using a scale from 0 “not at all” to 10 “extremely.” 

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9. Participants will complete a standardized 30-minute wait period. During the wait period, 
participants will complete the paper and pencil questionnaire: 
• 
Alternative Reinforcers (freq, enjoy) (PES) 
10. Complete Session 8 of assigned counseling condition (BAS+ or SC), provide TN 
progress and adherence information, and confirm the 24-hour dietary recall (#3) 
schedule. 
6.2.11 COVID-19 Quitting Experiences Survey  
Active enrolled participants who concluded their patch treatment and completed their EOT Visit 
on or after 3/30/2020 may be contacted to complete a survey intended to capture their 
experiences quitting smoking during the COVID-19 pandemic. Participants will be asked to 
provide verbal consent for this data collection when contacted, as well as, for any future contact 
needed to clarify any information collected during the survey. Participants will also be asked to 
provide verbal consent for the recording of the survey. If a participant does not consent to 
completing the survey or being recorded, the survey will not be administered and the call will be 
ended. The call will be recorded using a recording service, e.g. TapeACall. All recordings will be 
stored on our secure server, and only staff will have access to those files. Recording will be 
used to ensure participant responses were captured exactly when the data is reviewed. Staff will 
complete the survey via REDCap (i.e. verbally administering questions and recording 
responses), and no other personal information will be collected. Participants will complete the 
survey during the End of Treatment or Follow-Up 1 Visit when possible. 
 
The survey will include 24 questions recommended by the NIH for research pertaining to 
COVID-19: 11 questions related to smoking behavior and the pandemic formulated by the staff, 
and the PHQ-2 and GAD-2 measures for depression and anxiety symptoms (4 questions total). 
If a participant scores a 3 or higher on either the PHQ-2 or GAD-2 measure, they will be offered 
resources for coping strategies.  
6.2.12 Follow-Up Visits 1 and 2 (Week 12 and Week 26) 
During Follow-Up Visits 1 and 2 (Duration: ~30 minutes) participants will: 
 
1. Perform a CO breath assessment or provide a urine sample for a cotinine assessment, answer 
combustible marijuana items, and complete a concomitant medication review. 
2. Provide daily smoking rate (timeline follow back [TLFB]). 
3. Have weight measured. 
4. Complete paper and pencil questionnaires: 
• 
Adverse Events Form (Open-Ended AEs) 
• 
Physical Activity (PAR) 
 
5. If a participant reports not smoking (not even a puff of a cigarette) for at least the 7 days 
prior to the Follow-Up Visit without the aid of NRT, the participant will be asked to 
provide a 5ml saliva sample used to assess cotinine levels and verify abstinence from 
smoking. 
6. Confirm the 24-hour dietary recall (Week 12 [#4] and Week 26 [#5]) schedule. 
6.2.13 fMRI Scan Visits 1 & 2 (~Week -2 and ~Week 7-8) 
Participants who are both eligible and elect to participate in the neuroimaging sub-study will 
complete two neuroimaging sessions: Scan 1 will occur prior to the Baseline Visit (~week -2) 
and Scan 2 will occur during the final week of nicotine patch therapy (~week 7-8). Prior to each 
scan, participants will be instructed to fast overnight (beginning at ~10pm) until after the 

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completion of their fMRI scanning visit the following day. The fast period does not include a 
Boost® Nutritional Drink (Vanilla) that will be provided during the scanning visit to standardize 
prior food intake and remove deprivation to increase sensitivity to changes in food reward.  
Since participants are asked to fast overnight, all scanning sessions will be scheduled to occur 
in the morning. However, a scan may be completed in the afternoon at the discretion of the 
Principal Investigator due to extenuating circumstances. Additionally, participants will be 
instructed not to consume caffeine for 4 hours prior to the beginning of the visit in order 
standardize satiety.  Including the 1-hour fMRI scan, scanning visits are expected to last ~3 
hours in duration.  If a scanner hardware/software malfunction occurs and data is unable to be 
collected, an fMRI scan(s) may be rescheduled at the discretion of the Principal Investigator. 
 
At both scanning visits participants will: 
 
1. Complete a urine drug screen (at least 30ml [two tablespoons] of urine). The urine drug 
screen will assess the use of any study-prohibited medications/recreational drugs (See 
Key Exclusionary Criteria; Alcohol/Drugs). Participants who test positive for any study-
prohibited medications/recreational drugs will not be permitted to complete the 
neuroimaging sub-study and may be deemed ineligible for the main study at the 
discretion of the Principal Investigator.   
2. Self-administer a CLIA-waived urine pregnancy test (female participants only). 
Participants who believe that they may be pregnant are instructed to discontinue 
participation in both the neuroimaging sub-study and parent study at this time. 
 
3. Perform a BrAC assessment to control for alcohol consumption.  
• 
Participants with a BrAC greater than 0.010 will be ineligible to complete the 
neuroimaging sub-study (may remain in the parent study) unless the Principal 
Investigator permits the participant to reschedule the neuroimaging scan to 
another day. 
4. Perform a CO breath assessment, answer combustible marijuana items, and complete a 
concomitant medication review. 
5. Self-report smoking behavior over the past 24 hours to control for prior tobacco 
exposure and provide their daily smoking rate (timeline follow back [TLFB]).  
6. Have weight measured. 
• 
Participants weighing over 300 lbs will be ineligible to complete the neuroimaging 
sub-study. However, participants may remain enrolled in the main study. 
7. SCAN 2 ONLY: Provide TN progress and adherence information. 
 
8. SCAN 2 ONLY: Complete paper and pencil questionnaires: 
• 
Side Effect Checklist (SEC) 
• 
Adverse Events Form (Open-Ended AEs) 
 
9. Complete a magnet safety form. 
• 
Participants who do not meet the fMRI eligibility criteria will be deemed ineligible 
for the neuroimaging sub-study. Participants may still participate in the parent 
study per protocol.  
10. Complete a set of abbreviated practice tasks similar to those that will be administered 
during the fMRI scan, as well as an individualized calibration task to determine the 
amount of food (i.e. “Food Value Number”) that is equivalent to $0.25 in order to 
calculate the standard portion size of a participant’s preferred snack food (i.e. chips or 
M&Ms®) that may be earned on a given trial within the in-scanner Food 

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Reinforcement/Choice task. Participants will be expected to demonstrate an 
understanding of the tasks and the response device prior to the fMRI scan. 
11. Be provided with a Boost® Nutritional Drink and water. 
12. Be escorted to the imaging facility at either the Hospital of the University of Pennsylvania 
or the Stellar Chance building for the brain-scanning portion of the session. 
13. SCAN 1 ONLY: Participants will smoke one of their own cigarettes (~30 min. before 
initiating fMRI) in a designated smoking area outside of the building where the fMRI 
scanner is located in order to standardize the timing of cigarette exposure for all 
participants.  
14. SCAN 2 ONLY: Participants will be instructed to remove their TN patch prior to entering 
the MRI environment. Participants will be provided with a loose, sealed 7mg 
(NicoDerm® CQ® - Clear) patch to reapply after exiting the MRI environment. 
15. Undergo a 1-hour fMRI scan adhering to the procedures and Table 1 below: 
Scanning Protocol/Data Acquisition: MRI is performed in a 1-hour session, which, in our 
experience, participants tolerate easily without discomfort or excessive motion. Prior to entering 
the scanning area, an approved MRI Technician or MRI User will review the participant’s 
magnet safety form and will confirm that the participant has removed all metal and/or objects 
containing magnetic strips from their persons. Once the participant is approved to enter the 
scanning area, the participant will be placed supine in the scanner, wearing earplugs to muffle 
noise, and fitted with adjustable foam cushions to limit head motion. If a participant requires 
corrective lenses for vision, but does not have contact lenses, a set of plastic glasses that are 
approved for use in an MRI scanner will be provided to him/her. Participants will be provided 
with an emergency squeeze ball, so that they may interrupt the scan and/or be removed from 
the scanner if necessary. Head fixation will be assured through a foam-rubber device mounted 
on the headcoil.   
 
Image acquisition is performed on a 3T Siemens 
Tim-Trio scanner with a FDA approved head 
coil. A T1-weighted multi-echo magnetization-
prepared, 
rapid 
acquisition 
gradient 
echo 
(MPRAGE) structural image is acquired using 
standard parameters at 1mm resolution. This 
MPRAGE is used for functional image co-
registration and transformation into standard 
template space. Resting BOLD fMRI will be 
obtained followed by the three task paradigms.  
 
Task stimuli will be rear projected to the center 
of the visual field using a PowerLite® 7300 Video projector system (Epson American, Inc., Long 
Beach, CA) and viewed through a mirror mounted on the head coil.  Participants will use a fiber 
optic response pad (FORP™ Current Design, Inc., Philadelphia, PA) made of non-ferromagnetic 
components. This MR-compatible button-box is used to record task responses and reaction 
times. Pulse and respiration are recorded as an index of physiological arousal during the task 
and to statistically reduce the effects of physiological noise in the fMRI data.  
 
Resting State fMRI: Whole-brain functional MR images will be acquired while subjects rest with 
eyes closed over 39 axial, interleaving, 4-mm sections by means of a gradient-echo echo planar 
imaging sequence (150 volumes; echo time/repetition time, 27/2000 milliseconds; flip angle, 
80°; field of view, 220 x 220 mm; image matrix, 64x64). 
 
Task fMRI: BOLD images will be acquired using a whole-brain, single-shot gradient-echo (GE) 
echo-planar imaging (EPI) sequence with the following parameters: TR/TE=2000/30 ms, flip 
angle 90°, field of view (FOV)=192 mm, matrix = 96X96, isotropic voxel resolution 2.5 mm, slice 
TABLE 1: fMRI Session  
~Duration 
(mins.) 
Activity  
5 
Structural Scans (localizer, MPRAGE) 
10 
Resting State BOLD fMRI 
15 
Food Reinforcement/Choice a 
12 
Working Memory a,b 
10 
Food Cue Reactivity a 
2 
B0 Map *if time permits* 
Total Time in Scanner: ~54 minutes 
a fMRI tasks will be presented in a fixed order 
b Stimuli (Form A/B) will be counterbalanced within subject 

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thickness/gap=2.5/0mm, 38 slices axial-oblique parallel to AC-PC. In ongoing studies we find 
these parameters produce robust signal in ventral brain regions including ventral striatum and 
orbital/ventral prefrontal cortex with little distortion or signal loss. 
 
Food Cue Reactivity: The task will present (5 sec) 20 pictures of food rated (at Intake) as most 
appetizing and 20 pictures of food rated (at Intake) least appetizing, and 20 pictures of a water 
glass. Participants will be instructed to imagine tasting and eating the pictured food for as long 
as the food is presented. Order of presentation is randomized and the task consists of 60 
events separated by an inter-stimuli interval (fixation point) ranging from 2-11 sec (mean 5.5 
sec). As a secondary measure, food craving will be assessed prior to and after completion of 
the scan. The food craving assessment is the 3-item “desire” subscale of the reliable and valid 
state version of the Food Craving Questionnaire (FCQ-S). Total task time: ~10 minutes. 
 
Food Reinforcement/Choice: Participants choose between a standard low effort monetary 
reward and either (on separate trials) a food or monetary reward of higher value and effort. 
Each trial presents a choice between a standard reward (27 button clicks for $0.25) or 
exerting greater effort to earn a larger reward. On half of the trials, larger rewards will be $0.50 
(2 x standard value). In the remaining trials the larger reward will be double the calibrated 
snack portion (e.g., 20 M&Ms). Effort for more valuable rewards will vary from 27 to 775 
responses in 25 log10 steps. Pairs of visual stimuli depicting the two options appear for 4.5 
sec followed by a 3-14 sec inter-trial interval. Each pairing is presented twice making 50 trials 
for each class. Left/right position of stimuli is randomized, as is trial type (monetary vs. food; 
effort levels). To increase motivation to choose food and monetary reward, participants are 
told they will complete the work and receive the outcome of 4 randomly selected food and 
monetary (maximum $2.00) trials. Total task time: ~15 minutes.  
 
Working Memory: We will use a 12-minute visual N-back task validated for fMRI studies of 
smokers. A total of 20 fractals (target-foil ratio 1:3) are presented for each condition (i.e., 0-
back, 2-back, 3-back), and each condition (60 sec block) is repeated 3 times in pseudo-
random block design experiment. Each fractal is displayed for 500ms followed by 2500ms 
inter stimuli interval. Total task time: ~12 minutes. 
 
16. When all scans are completed, participants will be removed from the MRI scanner and 
be asked to complete a brief ~5-minute “work” task (i.e. clicking on a target a certain 
amount 
of 
times) 
based 
on 
their 
selections 
during 
the 
in-scanner 
Food 
Reinforcement/Choice task on a laptop computer. 
 
17. Participants will receive the appropriate reward(s) (food and/or monetary) per the post-
scan work task, as well as receive compensation for time and travel per the study 
compensation schedule. At the end of the session, participants will be escorted to the 
exit of the imaging facility where s/he will be free to leave.  
6.3 Microbiome Sub-Study 
Participants who are both eligible and elect to participate in the microbiome sub-study will be 
instructed to collect and return stool samples to the Center at Week -2 (Baseline Visit), Week 4 
(Mid-Tx 3 Visit), and Week 8 (End of Treatment Visit after completing TN treatment). 
Participants will be asked about their consumption of yogurt, probiotics, and prebiotics at the 
Baseline Visit, Mid-Tx 3 Visit, and End of Treatment Visit. Participants will be asked to 
answer a few questions regarding their antibiotic use over the past 6 months at the Baseline 
Visit as well.  
 
Participants will receive a stool sample collection kit and detailed instructions (written and 
verbal) about how to complete the collection of their stool sample at the in-Center visit prior to 
the visit when which they are scheduled to return their sample. Ideally, stool samples will be 

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collected and returned to the Center in person within 24 hours (up to ~36 hours is permissible) 
of the designated visit. If a participant is unable to attend a visit at which a stool sample 
collection kit is distributed, the stool sample collection kit may be mailed to the participant if 
deemed appropriate by the Principal Investigator. If a participant is unable to attend a visit at 
which a stool sample is scheduled to be returned or they are physically unable to provide a stool 
sample within 24-36 hours of their designated sample-return visit, the participant may return 
their stool sample to the Center on a date after the designated sample-return visit. The Principal 
Investigator will determine the window of time that a participant will be permitted to return their 
stool sample after the designated sample-return visit on a case-by-case basis.  
 
In addition to take-home collection instructions and Stool Sample Collection Form, participants 
will receive the following supplies in a stool sample collection kit: Stool collection bucket with a 
lid, a frame into which the bucket fits for collection, a large, sealable gallon bag, cold packs and 
a bag for ice, small styrofoam cooler, nitrile gloves, absorbent, and a shipping box. Participants 
will complete each stool sample collection at their residence. Participants will be instructed to 
place the stool collection bucket in the commode, which allows for separation of urine and 
feces, and keeps the feces separated from the toilet water. Participants will place a lid on the 
bucket (labeled with participant ID number and designated time point) and record the date and 
time of sample collection on the Stool Sample Collection Form. The sealed bucket will then be 
secured in the large bag with absorbent material. The bagged sample should then be placed in 
the cooler with several cold packs and/or bags of ice.  
 
If the participant is unable to return their stool sample to the Center in person, a cardboard 
shipping box may be included in the stool sample collection kit for shipping directly to the CHOP 
Microbiome Center or CIRNA. To prepare for shipping, the Styrofoam cooler is placed in the 
cardboard shipping box with a biohazard label for shipping by courier. The participant will then 
call the courier service for pick-up of the sample for overnight delivery to the CHOP Microbiome 
Center or CIRNA per a standardized procedure.    
 
Stool samples returned to the CIRNA will be immediately refrigerated and hand delivered within 
a cooler to the CHOP Microbiome Center by the research staff as soon as possible. Once the 
stool sample is aliquot for metagenomics analyses, the appropriate amount of sample will be 
delivered to the Penn Metabolomics Core for metabolomics analyses per a standardized 
procedure.  
6.3.1.1 Metagenomics  
Metagenomics will be used to examine changes in the composition of the gut microbiome. 
Shotgun libraries will be generated from 1 ng of DNA using the NexteraXT kit (Illumina, San 
Diego, CA). Libraries will be sequenced on the Illumina HiSeq using 2x125 bp chemistry in High 
Output mode. Extraction blanks and DNA free water will be included to empirically assess 
environmental and reagent contamination. Laboratory-generated mock communities consisting 
of DNA from Vibrio campbellii, Cryptococcus diffluens, and Lambda phage will be included as 
positive sequencing controls. Bioinformatics analysis will be carried out with the Sunbeam 
metagenomics 
analysis 
pipeline, 
which 
Dr. 
Bittinger 
and 
staff 
helped 
write 
(https://doi.org/10.1101/326363). Adaptor sequences will be removed from reads using 
Trimmomatic. Host DNA will be identified by alignment to the human genome (version hg38), 
and low-complexity sequences will be removed using the Komplexity tool, which is distributed 
with Sunbeam pipeline. Taxanomic classification will be performed using Kraken and a 
reference database of bacterial genomes available from NCBI. Sequence reads will be 
assembled into contigs using the ensemble method in MEGAHIT. The bioinformatics analysis 
will include taxonomic and gene function abundances for bacteria, fungi, and double stranded 

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DNA viruses. For classification of bacterial genes, we will utilize the KEGG reference database, 
for which the Center maintains an institutional license. 
6.3.1.2 Metabolomics 
Metabolomics will assess the downstream changes in neuroactive products of gut bacteria. 
Metabolites will be extracted from stool samples according to well-established, validated 
methods for tissue-based metabolomics and readied for untargeted LC/MS metabolomics. 
Reversed-phase C18 chromatography to retain and separate medium polarity to nonpolar 
metabolites will be performed on a Thermo Scientific Ultimate 3000 UHPLC using a Waters 
Acquity BEH C18 column (2.1 mm x 150 mm, 1.7 μm). HILIC chromatography to retain highly 
polar metabolites, not retained by reversed-phase C18 chromatography, will be performed on 
the Ultimate 3000 using a Waters Acquity BEH-NH2 column (2.1 mm x 150 mm, 1.7 μm). The 
Ultimate 3000 UHPLC will be coupled to a novel Thermo Fisher Scientific Orbitrap ID-X mass 
spectrometer scanned from 75-1000 Da at a resolution of 70,000. Compound Discoverer 
(Thermo Fisher Scientific, San Jose, CA) will be used to process the LC/MS metabolomics data 
to identify metabolites and determine statistical differences between study groups. 

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6.4 Table 2. Study Measures and Time Points 
Time Point  
(Scan 1 and 2 are completed as part of the fMRI/neuroimaging sub-study only)  
Intake Scan 
1 
BSL 
PQ 
TQD 
Mid-Tx 1 Mid-Tx 2 Mid-Tx 3 Mid-Tx 4 
Scan 
2 
EOT 
FU  
1 
2 
Counseling Session (BAS+ or SC) 
 
 
S1 
S2  
S3 
S4 
S5 
S6 
S7 
 
S8 
 
 
Week 
-3 
-2 
-2 
-1 
0 
1 
2 
4 
6 
~7-8 
8 
12   26 
TREATMENT 
 
 
 
 
 
 
BAS+ or SC 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Transdermal Nicotine (TN) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
SCREENING/COVARIATES 
 
Urine Drug Screen  
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
Urine Pregnancy Screen (if applicable) 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
Urine Cotinine 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Breath Alcohol (BrAC) 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Pressure  
(*only if multiple BP assessed at Intake) 
X 
 
 
X* 
 
 
 
 
 
 
 
 
 
Medical History Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Microbiome Medication Review (Microbiome Sub-Study Only)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
fMRI Medical Hx. Form (fMRI Sub-Study Only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Magnet Safety Form (fMRI Sub-Study Only) 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
Emergency Contact Form (fMRI Sub-Study Only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
ETOH History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking History/Nicotine Dependence (FTND) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cigarette Brand Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Program Referral Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Shipley Institute of Living Scale (SILS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hunger Scale  
(**administered before and after lab tasks) 
 
 
X** 
 
 
X** 
 
X** 
 
 
X** 
 
 
Physical Activity (PAR) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Habitual Food Craving (FCQ-T) 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Eating Behavior (DEBQ) 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Eating Inventory-Disinhibition (EI-D)   
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Positive & Negative Affect (PANAS) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Withdrawal Symptoms (MNWS) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Smoking Urges/Craving (QSU-B) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Hedonic Capacity (SHAPS) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Treatment Adherence (Counseling/TN) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Side Effects Checklist (SEC) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events Form (Open-Ended AEs)  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Carbon Monoxide (CO) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Combustible Marijuana Items 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Antibiotics Form (Microbiome Sub-Study Only) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Yogurt and Pro/Prebiotics Form  
(Microbiome Sub-Study Only) 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
MODERATORS  
 
Weight Concerns   
 
 
X 
 
 
 
 
 
 
 
 
 
 
Depression Symptoms (CES-D) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Gender  
X 
 
 
 
 
 
 
 
 
 
 
 
 
MECHANISMS  
 
Individualized Food (Pre-FCQ-S) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Preferred Snack Choice (Pre-RRVF) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Food Cue-Induced Craving (FCQ-S)  
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
Food Reward  
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
Food Reinforcement (RRVF) 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
Alternative Reinforcers (freq, enjoy) (PES) 
 
 
X 
 
 
X 
X 
X 
 
 
X 
 
 
MICROBIOME VARIABLES  
 
Stool Sample (Microbiome Sub-Study Only) 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
OUTCOMES 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Food Intake (24-Hour Dietary Recalls) 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
Smoking Rate Timeline Follow Back (TLFB) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking Cessation (CO) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking Cessation (Saliva Cotinine) 
 
 
 
 
 
 
 
 
 
 
 
X 
X 

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fMRI Tasks (fMRI Sub-Study Only) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
6.5 Description of Study Measures 
6.5.1 Treatment  
Standard Smoking Cessation Counseling (SC): The initial session (week -2, Baseline [pre-
quit]) begins with a review of smoking and quitting history, reasons for smoking and quitting, 
triggers for smoking, obtaining social support for quitting, and self-monitoring of smoking. The 
2nd session (week -1, Pre-Quit) will focus on the management of smoking triggers, slip 
recovery and relapse prevention. In preparation for the TQD (following week) the counselor will 
discuss the role of TN in withdrawal symptom management, directions on how to use TN, and 
the schedule (e.g., 4 weeks 21mg, 2 weeks 14mg, 2 weeks 7mg; (NicoDerm® CQ® - Clear). 
The 3rd session (week 0, TQD) will focus on the quit day experiences given that the participant 
will have been instructed to quit the morning of this session. The benefits of quitting will be 
emphasized along with evaluating and reinforcing progress with cessation, managing triggers, 
and relapse prevention. Adherence to nicotine patch use recommendations will be emphasized. 
Sessions 4-8 (weeks 1, 2, 4, 6 and 8 post-TQD) will include evaluating and reinforcing 
progress with cessation, reviewing the management of triggers to smoke, relapse prevention, 
and problem solving difficulties and challenges such as slips. Overeating and weight gain are 
common concerns reported during smoking cessation treatment.  Per convention, SC will 
address these concerns through standard recommendations to consume low-calorie snack 
foods, drink water, eat nutritious meals, and exercise (e.g., NCI’s Clearing the Air). SC will not 
include skills to shape the use of these suggestions. 
Behavioral Activation Intervention (BAS+): SC is incorporated into BAS+ in an additive design to 
cover best practice guidelines for smoking cessation. The goal of the BAS+ is to maintain a 
level of overall reward after cessation by structuring and enhancing opportunities for 
reinforcement to: (1) ensure that not smoking is as reinforcing as smoking; and (2) prevent an 
over-reliance on food as a substitute reinforcer for smoking so that PCWG does not precipitate 
smoking relapse. The unique treatment components of BAS+ include facilitating the 
identification and engagement in a variety of rewarding activities (other than eating and not 
associated with smoking) and maximizing the enjoyment derived from these rewarding 
activities.  As such, this intervention should benefit all smokers trying to quit, not just those 
participants who feel that preventing PCWG is meaningful.      
In the initial session (week -2, Baseline), the counselor will discuss why smokers easily 
substitute snacking for cigarettes after smoking cessation, and the consequences for weight 
gain and continued abstinence. The treatment rationale for promoting smoking cessation and 
preventing PCWG will focus on structuring a variety of reinforcing activities to promote a more 
rewarding nonsmoking lifestyle; one that has many rewarding options besides food. By 
replacing the pleasure previously derived from smoking, the participant will miss cigarettes less, 
rely less on calorie-dense snacks, gain less weight, and be less likely to return to smoking. The 
counselor will introduce daily activity monitoring and the identification of values and goals in 
several life domains (e.g., family and intimate relationships, employment/career, hobbies, 
recreation, spirituality). The daily activity monitor promotes awareness of time spent in important 
and or enjoyable activities and their association with smoking.  The identification of values and 
life goals will be used to identify rewarding activities consistent with helping one live according 
to his or her values.  Participants will be assisted in identifying rewarding activities (i.e., 
alternative reinforcers, not linked to smoking) in important life domains through a life activities 
checklist.   
In the second session (week -1, Pre-Quit), the goals and experiences with daily activity 
monitoring will be reviewed, noting the time spent in important and/or enjoyable activities. Using 
the life values and goals self-identified in the 1st session, participants will set daily goals for 
selecting and engaging in these activities (e.g., reinforcer sampling) to begin to increase 
alternative reinforcers prior to quitting smoking. Through an activity hierarchy (easiest to most 

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difficult to achieve), the counselor will ensure that the planned activities are realistic, available 
and accessible. Participants will self-select activities to ensure that they engage in activities that 
they feel are rewarding. Participants will keep track of their daily progress with the daily activity 
monitoring form.  Participants will rate the enjoyment/importance of the self-selected activities 
and note if any of the activities increased craving or were not enjoyable. Smoking is a daily 
reinforcer and this task will facilitate thinking about alternative reinforcers to smoking and 
snacking that are linked to their goals and values. Participants will be counseled to use caution 
(or forego) and employ smoking cessation strategies when engaging in activities (i.e., friends 
who smoke, alcohol use), that increase the risk of smoking.  
Given that nicotine may increase the pleasure derived from available reinforcers, BAS+ will 
include a component to build skills to enhance the pleasure derived from reinforcers. These 
types of “savoring” skills are effective at promoting long-term increases in positive emotions and 
life enjoyment. At the end of each day, while rating the enjoyment level of planned activities or 
experiences, participants will mentally re-visit three things that made these activities enjoyable. 
These behavioral skills also serve to enhance the relative value of smoke-free and snack-free 
activities. 
In addition to quit day events, the third session (week 0, TQD) will focus on daily activity 
monitoring, engagement and planning.  Based on successful engagement in selected activities, 
new activities will be added for monitoring in with the goal of progressively adding more 
challenging activities.  Reward enhancement goals and experiences also will be reviewed. The 
rationale and importance of alternative reinforcers for quitting smoking and minimizing weight 
gain will be emphasized. Based on experience, the participant will tailor their planned daily 
activities to link remaining abstinent and gaining less weight to the broader context of their 
values and goals.   
Sessions 4-8 (weeks 1, 2, 4, 6 and 8 post-TQD). Key components will be discussed including 
identifying and engaging in rewarding activities, and enhancing the reward derived from the 
activities. The sessions will focus on reviewing successes and problem-solving difficulties, such 
as whether slips/relapse to smoking or over-snacking coincided with absent alternative 
reinforcers or reinforcers not consistent with remaining abstinent. Relapse will be considered 
within the context of available alternative reinforcers and the participant’s specific values and life 
goals. Individuals who relapse will be directed to set another quit date and to re-evaluate their 
selection of alternative reinforcers. Some activities may not be as rewarding as originally 
thought or they may be associated with smoking or snacking.  Additionally, participants will be 
encouraged to revisit overall values and goals if difficulties arise.  The rationale for these core 
behavior activation practices will be reiterated from the standpoint of remaining abstinent, 
lessening PCWG and achieving value-driven life goals. 
Transdermal Nicotine (TN): All participants who report smoking 10 or more cigarettes a day will 
receive the 21mg dose for the first 4 weeks, 14mg for the subsequent 2 weeks, and 7mg for the 
final 2 weeks. Participants who report smoking 5-9 cigarettes a day will receive the 14mg dose 
for 6 weeks and the 7mg dose for the final 2 weeks. TN treatment will commence week 0 (TQD) 
and conclude week 8 (EOT). Any severe adverse reactions or significant side effects of TN will 
be medically evaluated by the Study Physician as per this protocol. TN use by individuals 
experiencing notable side effects will be monitored, adjusted, or discontinued as needed. If the 
21mg patch proves too strong for some participants, and they begin to experience signs of 
nicotine overdose, the 14mg and/or the 7mg patch will be provided instead (all other study 
procedures will remain standard). The appropriate amount of nicotine patches (NicoDerm® 
CQ® - Clear) will be distributed to participants at week -1 (PQ), week 1 (Mid-Tx.1), and week 4 
(Mid-Tx. 3) according to a standardized patch distribution schedule. Regardless of whether a 
participant lapses or relapses, patch treatment will only be distributed for a total of 8 weeks. If a 
participant is unable to attend an in-person visit or does not have enough patches to continue 
with their treatment schedule, additional supplies of nicotine patches may be mailed (authorized 
parcel service) or picked up by the participant if approved by the Principal Investigator. If TN is 
mailed, the participant must be available to sign for the delivery and receive the TN patches 

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personally. Participants who discontinue TN due to a medical event may continue with the study 
sans TN. 
6.5.2 Screening/Covariates 
Urine Drug Screen: A urine sample (~20-30ml) will be collected at the Intake Visit and both 
neuroimaging scans (neuroimaging sub-study only) to conduct a urine drug screen. The urine 
drug screen indicates whether the subject has recently taken any of the following recreational 
drugs 
or 
medications: 
THC, 
cocaine, 
opiates, 
amphetamines, 
methamphetamines, 
phencyclidine (PCP), ecstasy (MDMA), barbiturates, benzodiazepines, methadone, tricyclic 
antidepressants, and/or oxycodone. Participants with a positive urine drug screen for any 
substance listed above other than THC or tricyclic antidepressants at the Intake visit will be 
deemed ineligible. A urine sample that doesn’t register a temperature reading of at least 90 
degrees Fahrenheit will not be considered a valid sample. In an effort to remain CLIA-compliant, 
results from urine drug screen will not be shared with participants. Participants will be informed 
that the testing is for research purposes only and that they will be informed of their eligibility 
status, but not of the specific testing results. In order to document inclusion/exclusion criteria for 
regulatory purposes, results of the urine drug screens (test cup) will be retained in research 
charts and in an electronic research record within our local data management system (Access). 
These results are not and will not be entered into a participant’s electronic medical record.   
 
Participants who test positive for any study-prohibited medications/recreational drugs at either 
neuroimaging scan (neuroimaging sub-study only) will not be permitted to complete the 
neuroimaging sub-study and may be deemed ineligible for the main study at the discretion of 
the Principal Investigator. 
 
Urine Cotinine Test: While the University of Pennsylvania continues to limit the number of 
personnel allowed in research spaces and requires all researchers and research participants to 
wear a mask, at the Intake Visit, the End of Treatment (EOT), and Follow-Up 1 and 2 Visits, a 
urine sample of (~20-30 mL) will be collected to conduct a urine cotinine screen. The urine 
cotinine screen indicates the presence of cotinine in the urine, which is a product of nicotine 
metabolism with a sensitivity of 100 ng/mL. Participants will be informed of their eligibility status 
at Intake, but not the specific testing results. The Urine Cotinine Test will be used to confirm 
their spoking behavior at the subsequent EOT and Follow-Up 1 and 2 visits. This measure will 
be used to confirm a participant’s smoking status until the Principle Investigator believes it is 
safe per federal and University guidelines for the participants and staff to resume CO readings 
to confirm smoking status. In order to document inclusion/exclusion criteria and smoking 
behavior data for analytic and regulatory purposes, results from the urine cotinine screen will be 
retained in research charts and in an electronic research record within our local data 
management system (Access). These results are not and will not be entered into a participant’s 
electronic medical record.  
 
Urine Pregnancy Test: At the Intake Visit and both neuroimaging scans (neuroimaging sub-
study only), female participants will be supplied with a simple, CLIA-waived hCG pregnancy test 
strip and a urine sample cup (participants may use the urine drug screen cup if desired). 
Participants will then be instructed to self-administer the pregnancy test and be told that if they 
are (or believe they may be) pregnant they should not participate in the research study. The 
participants will inform the study staff if they are able to continue participation after they have 
reviewed the results of the pregnancy test.  Participants will be informed that there is no penalty 
for discontinuing participation at this point in the visit and that they will still receive travel 
reimbursement for the visit.  
  

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Breath Alcohol Concentration (BrAC): ): If the PI deems it is safe for the participant and 
research staff, based upon federal and University COVID-19 guidance, participants who 
complete an in-person IRB Approved Consent and HIPAA form will complete a BrAC 
assessment at the Intake Visit and both neuroimaging scans (neuroimaging sub-study only). 
Participants will be made aware of the BrAC assessment prior to all applicable visits and asked 
to avoid alcohol and alcohol-based products (e.g. mouthwash, breath spray, etc.) the evening 
and morning before the Intake Visit and both neuroimaging scans (neuroimaging sub-study 
only). The BrAC monitor is a handheld device that uses a disposable mouthpiece and reports 
the concentration of alcohol in exhaled breath. Any reading greater than 0.000 indicates alcohol 
consumption within the last 14 hours. Participants with a BrAC greater than 0.000 at the Intake 
Visit will be deemed ineligible. Participants with a BrAC greater than 0.010 at either 
neuroimaging scan will be ineligible to complete the neuroimaging sub-study (may remain in the 
main study) unless the Principal Investigator permits the participant to reschedule the 
neuroimaging scan to another day. Participants testing positive for breath alcohol with a reading 
equal to or greater than .08 (the legal driving limit in Pennsylvania) or who are visibly impaired 
will be instructed not to drive themselves home after the visit. If a participant needs to use a 
phone to call for a safe ride home, an office telephone will be made available to the participant. 
 
Height: Research staff will collect and document participant height utilizing a mounted 
stadiometer at the Intake Visit. 
 

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Blood Pressure Procedures:  
 
Intake Visit. Participants presenting with elevated blood pressure (SBP greater than 159 
mmHg and/or DBP greater than 99 mmHg) at the Intake Visit will have a second blood 
pressure reading taken after a 10-minute rest period in which the participants will be 
instructed to sit comfortably. If, after the second reading: 
• A participant presents with a SBP reading less than 160 mmHg and a DBP less 
than 100 mmHg, s/he will be ELIGIBLE for the study. 
• A participant presents with a SBP reading greater than 159 mmHg and/or DBP 
greater than 99 mmHg, s/he will be INELIGIBLE for the study. 
• A participant presents with a SBP reading greater than 190 mmHg and/or DBP 
greater than 110 mmHg, s/he will be deemed INELIGIBLE for the study and 
instructed to seek immediate medical attention (e.g. Emergency Room or Walk-in 
Clinic). 
 
After the first or second blood pressure reading, if a participant presents with a SBP 
between 151-159 mmHg and/or DBP between 91-99 mmHg, the research staff will inform 
the participant that they may have mild, Stage I, hypertension and advise they consult with a 
physician. The participant will remain ELIGIBLE for the study.  
 
Pre-Quit Visit. Participants who required a second blood pressure at the Intake Visit (i.e. the 
first measurement was a SBP greater than 159 mmHg and/or a DBP greater than 99 mmHg) 
will have their blood pressure reassessed at Pre-Quit. If a participant presents with elevated 
blood pressure (SBP greater than 159 mmHg and/or DBP greater than 99 mmHg), staff will 
take an additional blood pressure reading after a 10-minute rest period in which the 
participant will be instructed to sit comfortably. If, after the second reading: 
• 
A participant presents with a SBP reading less than 160 mmHg and a DBP less 
than 100 mmHg, s/he will be ELIGIBLE to receive TN patches as scheduled. 
• 
A participant presents with a SBP greater than 159 mmHg and/or DBP greater than 
99 mmHg, the participant will be required to obtain written permission (a formal 
letter will be provided by the study team) from their physician in order to receive TN 
patches. If TN patches are not distributed at the Pre-Quit Visit for this reason, the 
participant may still participate in the study and receive counseling only. The 
participant may receive TN patches after the receipt of an approved letter signed 
by the participant’s physician. 
• A participant presents with a SBP greater than 190 mmHg and/or DBP greater than 
110 mmHg, s/he will be instructed to seek immediate medical attention (e.g. 
Emergency Room or Walk-in Clinic). The participant may still participate in the 
study and continue and receive counseling, but they will not have the option to 
receive TN patches. 
 
After the first or second blood pressure reading, if a participant presents with a SBP 
between 151-159 mmHg and/or DBP between 91-99 mmHg, the research staff will inform 
the participant that they may have mild, Stage I, hypertension and advise they consult with a 
physician. The participant will remain eligible for the study and receive TN patches as 
scheduled. 
 
Missed Pre-Quit Visit. For participants requiring a second blood pressure at the Intake Visit 
(i.e. first measurement was SBP greater than 159 mmHg and/or DBP greater than 99 
mmHg) who miss their scheduled Pre-Quit Visit, a blood pressure measurement will occur at 
the next in-person visit the participant attends. Blood pressure will be collected in 
accordance with the procedures (Pre-Quit Visit) listed above. TN patches will not be 
distributed until the participant presents a blood pressure reading within the established 
eligibility range (post Intake).  
 

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Hypotension. If a participant presents with a SBP less than 90 mmHg at either the Intake 
Visit or Pre-Quit Visit, blood pressure should be retaken after a 10-minute rest period. If after 
the second reading the participant still presents with a SBP less than 90 mmHg, the Study 
Physician will be consulted to determine study eligibility and/or if TN patches should be 
distributed. 
 
Medical History Form: A medical history form (led by the research staff) will be completed to 
review for applicable contraindications previously listed under Key Inclusion/Exclusion Criteria at 
the Intake Visit.  
 
Microbiome Medication Review: Participants who elect to participate in the microbiome sub-
study and met the initial microbiome sub-study eligibility criteria at phone screen will be asked 
about their use of medications that would be considered contraindicated for participation. Those 
reporting the use of an exclusionary medication will be deemed ineligible to participate in the 
microbiome sub-study. 
 
fMRI Medical History Form: Participants who are eligible to potentially complete the 
neuroimaging sub-study and met the initial fMRI eligibility criteria at phone screen will be asked 
to complete a separate fMRI medical history form to review for applicable contraindications 
previously listed under Key Inclusion/Exclusion Criteria.  
 
Magnet Safety Form:  Participants participating in the neuroimaging sub-study will complete a 
standard magnet safety form provided by the Department of Radiology at the Hospital of the 
University of Pennsylvania at the Intake visit and before entering the scanner at each fMRI 
scan. The magnet safety form assesses a history of specific prosthesis, surgical implants, and a 
variety of other MRI contraindications. 
 
Emergency Contact Form: Participants participating in the neuroimaging sub-study form will 
provide emergency contact information in the event of an emergency at the fMRI scanner.  
 
Demographics, Smoking History, Cigarette Brand, and Nicotine Dependence (FTND): Standard 
questionnaires will be administered at the Intake Visit to collect the following data: 
demographics, age at smoking initiation, current smoking rate, previous quit attempts, and own 
cigarette brand information (Cigarette Brand Form). The Fagerstrom Test for Nicotine 
Dependence (FTND) will also be administered. The FTND is a 6-item, self-report measure of 
nicotine dependence derived from the Fagerstrom Tolerance Questionnaire. The FTND scale 
has satisfactory internal consistency (Cronbach's alpha = .64) and high test-retest reliability 
(r =.88). 
 
ETOH History: An ETOH history questionnaire will be administered at the Intake Visit and will 
assess alcohol consumption over the past 7 days. 
 
Program Referral Form: Participants who are in contact with current or past study participants 
may share information exclusive to their assigned counseling condition (BAS+/SC). To avoid this 
situation and protect blind integrity, participants will be asked to complete a Program Referral 
Form at the Intake Visit in which they will identify if they know someone currently enrolled or 
someone who has previously completed the trial. Those acquainted with current or previous 
participants may be randomized to the same counseling condition (BAS+/SC) at the Principal 
Investigator’s discretion. 
 
Shipley Institute of Living Scale (SILS): All participants will complete the SILS via REDCap prior 
to coming into the center to complete the remainder of their Intake Visit unless it is deemed safe 

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for the participants and the staff to spend larger durations of time in the center under federal and 
University COVID-19 safety guideliens.The SILS is a self-administered test designed to assess 
general intellectual functioning in adults and adolescents and to aid in identifying cognitive 
impairments. The scale consists of two subtests, a 40-item vocabulary test and a 20-item test of 
abstract thinking. The total administration time is 20 minutes (10 minutes per subtest). The 
REDCap Exam will score the test according to the SILS instructions and WAIS-R conversion. 
The SILS correlates with the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Estimated IQ 
Test; those participants earning less than an estimated WAIS-R IQ of 75 will be ineligible. The 
SILS is considered a highly reliable assessment tool with good total score internal consistency 
(Cronbach’s alpha= .92).  
 
Hunger Scale: Immediately prior to and after completion of computerized laboratory tasks, 
participants will be asked to rate, “How hungry are you right now?” using a scale from 0 “not at 
all” to 10 “extremely.” 
 
Physical Activity (PAR): Physical activity will be assessed with the 7-day Physical Activity Recall 
(PAR). The PAR has excellent test-retest reliability (r=0.81) and validity (r = 0.72 heart rate 
monitor). It is a widely used measure of habitual activity. The PAR provides data on frequency, 
intensity, duration, and kilocalories expended. 
 
Habitual Food Cravings (FCQ-T):  Habitual food cravings will be assessed with the trait version 
of the Food Craving Questionnaire. This valid and reliable 39-item measure asks participants to 
indicate on 6-point scale the frequency of food craving (never to always). 
 
Eating Behavior (DEBQ): The Dutch Eating Behavior Questionnaire will assess restrained 
eating (10 items, tendency to restrict food intake), external eating (10 items, tendency to eat in 
response to food related cues) and emotional eating (13 items, tendency to eat in response to 
emotions). These scales are associated with food craving and response to food cues. 
Participants indicate on a Likert-style scale how often each item is applicable to them (0= not 
relevant; 1 = never to 5=very often). 
 
Eating Inventory-Disinhibition (EI-D): Disinhibition will be measured with a subscale (16 items) 
of the Eating Inventory that is thought to reflect responsivity to environmental food cues, and 
internal cues, and linked to food reinforcement and weight change.   
Positive and Negative Affect (PANAS): The Positive and Negative Affect Schedule (1-week 
frame of reference), a 20-item Likert-format self-report questionnaire, will be used to measure 
positive mood and negative mood. The two subscales have 10 items each, are internally 
consistent in both nonpsychiatric and psychiatric samples (α = .79 to 91), and exhibit good 
convergent and discriminant validity.  
Withdrawal Symptoms (MNWS): The Minnesota Nicotine Withdrawal Scale - Revised version 
(MNWS-R) will measure withdrawal symptoms (n=15) associated with quitting smoking. 
Participants will rate the intensity of their symptoms on the following scale: 0 = none, 1 = slight, 2 
= mild, 3 = moderate, 4 = severe and a summary score will be calculated. The MNWS with a 1-
week frame of reference will be utilized throughout the trial. 
Smoking Urges/Craving (QSU-B): The well-validated and reliable 10-item brief Questionnaire of 
Smoking Urges will assess craving for cigarettes. The QSU-B utilizes a “right now” frame of 
reference. 
Hedonic Capacity (SHAPS): Hedonic capacity will be measured with the 14-item Snaith-
Hamilton Pleasure Scale (SHAPS). Participants will rate the degree of enjoyment they would get 
from hypothetical activities typically experienced as enjoyable. The SHAPS loads strongly on 

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measures of anhedonia (r = .92), is internally consistent ( = .87), stable over time, and has 
adequate convergent and discriminant validity in clinical and nonclinical populations.  
 
Treatment Adherence: Treatment adherence is defined as attending 6 of 8 counseling sessions 
and using 6 or more patches on average per week. TN adherence will be assessed and 
recorded at every in-person visit over the treatment period. 
 
Side Effects Checklist (SEC): Participants will complete a SEC at all in-person visits after the 
Baseline Visit. The SEC will assess the severity of side effects that may be TN related and 
experienced by participants in the study (See section 7.1: Potential Study Risks; Transdermal 
Nicotine). These reports will be formally documented as anticipated (expected) AEs whether or 
not the event(s) is ultimately deemed related or not related to the use of TN in this study. The 
reporting period for each assessment will inquire about any side effects experienced since the last 
in-person visit. Items will be rated by participants utilizing the following severity scale: 0 
(None=No Concerns), 1 (Mild=Side effect does not interfere with usual daily activities), 2 
(Moderate= Side effect does interfere with some activities), and 3 (Severe=No normal activities 
are possible).  See section 8.2.1: AE Collection Methods for further details. 
 
Adverse Events Form (Open-Ended AEs): Participants will be asked an open-ended question 
about any symptom or medical event that may be related to their study participation not included 
on the SEC form at all in-person visits after the Baseline Visit. These events will documented as 
unanticipated (unexpected) AEs unless they are otherwise outlined in the protocol and/or 
consent form (i.e. related to withdrawal, assessments, etc.). The reporting period for each 
assessment will inquire about any event(s) or symptom(s) experienced since the last in-person 
visit.  If a participant reports a symptom or medical event, they will be asked to rate the severity of 
the event utilizing the following severity scale: 0 (None=No Concerns), 1 (Mild=Issue does not 
interfere with usual daily activities), 2 (Moderate=Issue does interfere with some activities), and 
3 (Severe=No normal activities are possible). See section 8.2.1: AE Collection Methods for 
further details. 
 
Carbon Monoxide (CO): If the PI deems it is safe for the participant and research staff, based 
upon federal and University COVID-19 guidance, CO will be measured at the Intake Visit and 
all subsequent in-person visits to confirm smoking status. The CO monitor is a handheld device 
that uses a disposable mouthpiece, reports CO in parts per million (ppm), and takes about 3-5 
minutes to administer. In order to remain eligible and confirm smoking status at the Intake Visit, 
a participant must present with a CO greater than or equal to 5 ppm.  
 
Combustible Marijuana Items: Participants will be asked if they smoked combustible marijuana in 
the past 24 hours. If yes, the participant will be asked how many hours ago they last used. 
Information collected on combustible marijuana may be considered a confounding variable 
during data analysis in relation to CO level. 
 
Concomitant Medications: At the Intake Visit, participants will be asked to list all medications 
(prescription or non-prescription) and NRTs currently taken and/or recently discontinued (within 
the past 14 days) as a baseline collection. All information will be collected on a Concomitant 
Medication Log that will be maintained within the participant’s study chart. At every subsequent 
in-person visit, participants will be asked if they have taken any additional medications 
(prescription or non-prescription), NRTs, and/or changed the dosage or stopped taking any 
previously reported medications since their last in-person visit. Participants who report taking 
contraindicated medication(s) over the course of the study period may only remain eligible if the 
Study Physician and/or Principal Investigator determine that the contraindicated medication(s) 
did not impact the study design, data quality, and/or participant safety and welfare.  

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Antibiotics Form: Participants who are participating in the microbiome sub-study will be asked 
about their antibiotic use over the past six months at the Baseline Visit. 
 
Yogurt and Pro/Prebiotic Form: Participants who are participating in the microbiome sub-study 
will be asked about their consumption of yogurt and pro/prebiotics use over the past four weeks 
at the Baseline Visit (wk-2), Mid-Tx. 3 Visit (wk4), and End of Treatment Visit (wk8). 
6.5.3 Moderators 
Weight Concerns: Weight concerns associated with quitting smoking will be measured with a 
reliable (α=.87) and valid 6–item scale. Responses to the 6 items range from 1 (not at all) to 10 
(very much). Scores are the average of responses to all items. 
 
Depression Symptoms (CES-D): The Center for Epidemiologic Studies Depression Scale is a 
20-item Likert-style scale used to assess depressive symptomatology. This scale has high 
internal consistency (r=.85-.90) and has been shown to correlate with clinical ratings of the 
severity of depression. In our previous research, CES-D scores have correlated significantly 
with self-medication smoking and nicotine dependence.  
 
Gender: Gender (self-identification) will be assessed via self-report during the initial telephone 
screen and reconfirmed in-person at the Intake Visit.   
6.5.4 Mechanisms 
Individualized Food (Pre-FCQ-S): In preparation for the food cue-induced craving task, 
participants will rate how appetizing they find pictures of food (e.g., cupcakes, fruits, vegetables) 
at the Intake Visit. Foods rated least appetizing (n=20) and foods rated most appetizing (n=20) 
will be selected to create personalized food cue stimuli. 
 
Preferred Snack Choice (Pre-RRVF):  Participants will select either the salty (Lay’s® Classic 
potato chips) or sweet (M&M's®) snack food as the snack to “work for” when completing the 
RRVF task over the remainder of the study. 
 
Food Cue-Induced Craving (FCQ-S): Food cue-induced craving will be assessed using a 
personalized food cue exposure paradigm, whereby pictures of foods rated least appetizing (L, 
n=20), most appetizing (M, n=20), and a picture of a glass of water (W, n=20) will be presented 
to participants seated at a computer screen. Participants will be instructed to imagine tasting 
and eating the pictured food for as long as the image is presented. The images will be 
presented in six blocks. Each block consists of image presentation (10 images, 8 sec duration) 
and craving assessment. The M, L, and W food cues will be presented in one of two sequences 
(i.e., MWLMWL or LWMLWM) counterbalanced across participants. Before the task and after 
each block, participants will complete the state version of the Food Craving Questionnaire, 
Desire Subscale (FCQ-S). The 3 items (desire to eat, craving, urge to eat) will be tailored to ask 
about the M, L, and W images on a 5-point scale (strongly disagree to strongly agree). 
Personalized cues can maximize craving induction and produce greater increases in subjective 
craving and objective indices of cue reactivity than standard cues. Reactivity to palatable food 
images is associated with body mass and weight gain. The Food Cue-Induced Craving task will 
be administered at the Baseline (Week -2), Mid.-Tx 1 (Week 1), Mid.-Tx 3 (Week 4), and End of 
Treatment (Week 8) Visits. 
 
Food Reward: Food reward will be assessed by exposing participants to 16 computer-based 
images of common snack foods spanning caloric content and macronutrient composition 
(low/high fat sweet, low/high fat savory). After each 5-second snack food exposure, participants 

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will provide ratings of how much they like the food and how pleasant it would be to eat this food 
right now.  Ratings will be made on visual analog scales anchored by 0 (not at all) to 100 
(extremely). The food reward task will be administered at the Baseline (Week -2), Mid.-Tx 1 
(Week 1), Mid.-Tx 3 (Week 4), and End of Treatment (Week 8) Visits. 
 
Food Reinforcement (RRVF): The Relative Reinforcing Value of Food will be assessed via a 
validated behavioral choice task, permitting the evaluation of the preference for food over other 
alternatives.  Participants will be asked to move a computer mouse to hit targets on one of two 
sides of a split-screen monitor, to earn points toward either food or money. Participants selected 
the snack food (salty or sweet) that they wanted to consume for the assessment at the Intake 
Visit. Using a concurrent schedule, participants will be told that they can switch from working on 
one side of the screen to the other as often as they wish. Adapted from previous research, 
participants will be instructed to move the computer mouse to have the cursor hit the targets 
(either a $ or food). Consistent with relative reinforcement paradigms, the reinforcement 
schedule in the money-earning screen will remain constant at a fixed ratio FR-25 (25 targets 
achieved to earn a point) while the reinforcement schedule for food will increase (require more 
effort) with a progressive ratio schedule of PR-25x over 10 trials, such that 25, 50, 75, 100, 125, 
150, 175, 200, 225, and 250 targets will have to be achieved to earn a point. The computer task 
will be performed until a participant completes 10 trials and accumulates a total of 10 points 
from which they will earn either $0.10 for each point (i.e., up to $1.00 paid at the end of the task) 
or a standardized amount (grams) of their chosen snack food for each point. Food earned is 
consumed at the end of the task to prevent satiation from influencing responding in subsequent 
trials. Participants will then begin a 30-minute wait period to standardize session duration and 
ensure that responding is based on reinforcer preference. At the discretion of the research staff, 
participants who become frustrated with the length of the RRVF task may bypass the 30-minute 
wait period. Per convention, the RRVF outcome is defined by a breakpoint (maximum amount of 
responding) for food vs money across the trials.  The Relative Reinforcing Value of Food 
behavioral choice task will be administered at the Baseline (Week -2), Mid.-Tx 1 (Week 1), Mid.-
Tx 3 (Week 4), and End of Treatment (Week 8) Visits. 
 
Alternative Reinforcers (freq, enjoy) (PES): Alternative reinforcers will be measured by the 
adapted Pleasant Events Schedule, designed to assess reinforcers that occur in the natural 
environment. The 78 items are rated once in terms of frequency (0 = none to 2 = often) and 
once in terms of enjoyability (0 = none to 2 = very) over a specified number of days, yielding a 
frequency score, an enjoyability or subjective reward score, and the cross product is the 
reinforcement from the activity. This measure differentiates among smoking and treatment-
seeking status, is sensitive to changes in reinforcers across smoking cessation treatment, and 
has been used to assess reinforcers in substance abusers. Alternative reinforcers (PES) will be 
measured at the Baseline (Week -2), Mid.-Tx 1 (Week 1), Mid.-Tx 2 (Week 2), Mid.-Tx 3 (Week 
4), and End of Treatment (Week 8) Visits. 
6.5.5 Microbiome Variables 
Participants who are participating in the microbiome sub-study will be instructed to provide stool 
samples for metagenomic and metabolomic analysis on Week -2 (Baseline Visit), Week 4 
(Mid-Tx 3 Visit), and Week 8 (End of Treatment Visit after completing TN treatment).  
Changes in gut microbiome composition, as determined by metagenomics, will be derived by 
comparing the relative abundance of bacteria from baseline to weeks 4 and 8. Changes in 
neuroactive metabolites, as determined by metabolomics, will be derived by comparing levels 
from baseline to weeks 4 and 8. Although we have hypotheses involving specific metabolites, 
we chose an untargeted metabolomics approach to enable the identification of other biomarkers 
of importance. 

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6.5.6 Outcomes 
Weight: Weight (primary outcome) will be measured by a physician’s scale (pounds) at the 
beginning of every in-person visit. Participants will be wearing light clothing without shoes. Pre-
cessation weight will be computed as the average of weights at the Intake and Baseline Visits 
prior to any change in smoking behavior. Weight change from Baseline to the 26-week follow-up 
will serve as a primary weight outcome variable. 
Food Intake (24-Hour Dietary Recalls): Food intake (secondary outcome) will be assessed via 3 
telephone-administered, 24-hour dietary recalls during the week after (or near) the Baseline, 
Mid-Treatment 3 (week 4), End of Treatment (week 8) and the 12-week and 26-week follow-up 
visits (n=15). A trained member of the research staff will use a multi-pass method with an 
interactive computerized software program, the ASA24® (Automated Self-Administered 24-hour 
Recall), to determine total kcal/day (outcome variable). The ASA24® was created by 
investigators at the NCI. Three recalls are considered optimal for assessing dietary intake, 
especially when weekend and weekdays are assessed, as we propose to do when possible.  If 
participants are unable to complete a scheduled recall over the telephone or are onsite for a 
scheduled visit, participants may be asked to complete a 24-hour dietary recall with the 
research staff in-Center. Comparable accuracy can be achieved when administered in-person 
and over the telephone. Food recalls are widely used, reliable and valid, assessing kcals/day 
within 10% of actual dietary intake measured under laboratory observation and by doubly 
labeled water.  
Changes in food intake (kcals) from baseline to week 12 will serve as an outcome for the 
microbiome sub-study. 
 
Smoking Cessation (CO, Urine Cotinine,and Saliva Cotinine): Smoking abstinence (primary 
outcome) will be assessed and biochemically verified at EOT (week 8), at 12 and 26 weeks after 
the target quit date. The primary smoking outcome variable will be 7-day point prevalence 
abstinence (no smoking, not even a puff, for at least 7 days prior to the assessment) 
biochemically verified by CO < 5 ppm or Urine Cotinine assessment at a sensitivity of 100 
ng/mL at EOT (week 8) and Follow-Up 1 and 2 visits (Week 12 and Week 26).  Smoking status 
will also be biochemically confirmed by saliva cotinine < 15ng/ml at the 12- and 26-week follow-
up. 
 
Smoking Cessation will be assessed and biochemically verified at EOT (week 8) and at 12-
weeks post TQD as a primary outcome for the microbiome sub-study. A reliable and valid 
timeline follow-back method is used to assess daily smoking (presence and rate). The smoking 
outcome variable is 7-day point prevalence abstinence biochemically verified by CO < 5 ppm  
or Urine Cotinine assessment at a sensitivity of 100 ng/mL at EOT (week 8) and Follow-Up 1 
and 2 visits (Week 12 and Week 26).  Smoking status will also be biochemically confirmed by 
saliva cotinine < 15ng/ml at the 12- and 26-week follow-up. 
 
Smoking Rate Timeline Follow Back (TLFB): A reliable and valid timeline follow-back method 
will be used to assess daily smoking (presence and rate) at every visit post Intake. 
 
fMRI Tasks *Neuroimaging Sub-Study Only: See section 6.2.12: fMRI Scanning Visits for the 
complete descriptions of the in-scanner tasks.  
 
Food Cue-Induced Craving. The key outcome for this variable is BOLD signal change for 
most appetizing foods (versus water, and versus least appetizing foods as an active 
control). Primary regions of interest for the BOLD fMRI analysis are insula, caudate, OFC 
and ACC. As a secondary measure, food craving will be assessed prior to and after 
completion of the scan. The food craving assessment is the 3-item “desire” subscale of the 
reliable and valid state version of the Food Craving Questionnaire (FCQ-S).  

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Relative Reinforcing Value of Food (via Food Reward Reinforcement/Choice task). The 
primary behavioral outcome will be the amount of additional effort subjects are willing to 
expend in order to obtain food. The primary regions of interest for the BOLD fMRI analysis 
are VS and vmPFC. Within these regions, the food choices (all 50 trials where food is an 
option) vs. fixation will be the primary contrast. Selection of this primary contrast will ensure 
the same stimuli will be analyzed across participants and conditions and maximize statistical 
power for detecting food-related activation.  
 
Working Memory N-Back Task. Based on our prior work, the primary performance measure 
will be correct reaction time, and the secondary measure will be number correct; the primary 
regions of interest for the BOLD analysis will be DLPFC and medial/frontal cingulate gyrus. 
6.6 Tissue Specimens  
Saliva: If a participant reports not smoking (not even a puff of a cigarette) for at least the 7 days 
prior to the 12-week and 26-week Follow-up Visits without the aid of NRT, the participant will be 
asked to provide a 5ml saliva sample used to assess cotinine levels and biochemically verify 7- 
day point prevalence abstinence.  
 
Urine: A urine sample will be required at the Intake Visit, EOT Visit, Follow-Up 1 and 2 Visits,  
and both fMRI Scan Visits (neuroimaging sub-study only) for drug (~20-30ml),pregnancy , and 
cotinine screenings . These samples will be disposed of following the conclusion of the study 
visit.  
 
Stool (microbiome sub-study only):  Stool samples will be provided by participants at Week -2 
(Baseline Visit), Week 4 (Mid-Tx 3 Visit), and Week 8 (End of Treatment Visit. See the 
Microbiome Sub-Study procedures for additional detail.  
6.7 Sample Size Determination- Parent (Main) Study 
For Aim 1 we hypothesize that BAS+ vs. SC will have higher smoking abstinence rates and less 
PCWG at the 26-week follow-up (primary outcomes). Power calculations were all approximated 
as t-tests or z-tests, and conducted using PASS Software (Power and Sample Size, NCSS 
Software, Kaysville, UT), Bonferroni corrected for two primary outcomes (p=.025). Proportions 
of abstinent and smoking subjects will be compared using the log of the odds-ratio, which has a 
known variance. Informed by smoking cessation counseling plus TN research, we anticipate 
that the 6-month abstinence rate will be 13% in the SC (control) group and 25% in the BAS+ 
group (consistent with a persistent effect of BAS+ after the discontinuation of TN). A sample of 
213 per group provides 82% power to detect this 12% difference in quit rates at 6 months.  This 
represents a clinically meaningful effect and corresponds to a small effect size (=.15). For 
PCWG, we will include all participants in the analysis, while testing a smoking status x treatment 
interaction.  Informed by epidemiological and clinical studies of PCWG, we will have 80% power 
to detect a 6 pound (2.72 kg) difference in PCWG between BAS+ and SC, using the interaction 
term.  We expect BAS+ vs. SC will have less post-cessation food intake (secondary outcome) at 
the 26-week follow-up. We have 80% power to detect a 320 kcal/day difference between the 
two groups (p = .05). In light of these considerations (i.e., 213 subjects per arm; total 426) and 
an attrition estimate of 15% across accrual, we will recruit a total of 245 subjects to each arm for 
a total of 490 subjects (~500). 
For Aim 2, we hypothesize that BAS+ vs. SC, will increase alternative reinforcers, and reduce 
food reward, the RRVF, and food cue-induced craving. These changes, in turn, will predict less 
food intake and PCWG, and greater smoking abstinence at the 26-week follow-up. Using 
structural equation modeling, we will test the treatment effect on the slope of the mediators 
versus time, with pre-quit values representing the intercepts. We will examine the proportion of 

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treatment effect explained, and test with a delta method generated z-score (Type I error of .05). 
There are four proposed mediating pathways between treatment and outcome, so our Type I 
error will be corrected to 0.0125.  For smoking abstinence, a sample of 426 gives us 80% power 
to detect small effects (=.32) for changes in the proposed mediators, where serial observations 
are uncorrelated within subject. This also applies to individual path strength. Even a modest 
within-subject correlation (=0.3) provides 80% power to detect a small treatment effect 
(=0.20). For PCWG, smoking status will be treated as a time-varying covariate, where changes 
in weight are represented as a slope factor (based on observed repeated measures of weight). 
With a sample of 426, we will have power to detect a small effect ( < 0.20), even without 
adjustment for within-subject correlation.   
As an exploratory aim, we will test whether females, or participants with greater pre-treatment 
depression symptoms, or weight concerns, are more likely to experience PCWG and more likely 
to benefit from BAS+ vs. SC.  We will test an interaction effect predicting that the effects of the 
BAS+ will be more pronounced for females, and for those who have greater depression 
symptoms, or weight concerns. For smoking abstinence, with a 6-month quit rate difference of 
12% (25% BAS+ vs. 13% SC), we approximated power by simulation using a z-test based on 
the ratio of odds ratio (ORR). If this effect, for example, is completely derived from a larger 
effect of BAS+ among females (no effect in males), then we will have 80% power to detect an 
interaction with 213 subjects per treatment arm. This corresponds to an odds ratio of ~4.0 for a 
BAS+ effect in females and an odds ratio of 1.0 in males. All tests will be performed at a p < .05 
significance level.  We approximated the same interaction for PCWG using the z-score.  
Restricting the sample to abstinent participants (54 BAS+, 28 SC) with continuous moderators 
dichotomized at the median, a standard deviation of 3.5 kg, and a standard error of 1.63 for the 
interaction, we will have 80% power to detect an interaction difference of 4.7 kg (10.4 lbs.).   
6.8 Sample Size Determination - Neuroimaging Sub-Study  
We plan to test hypotheses at a global 5% Type I error (alpha) for each family of hypotheses, 
and have chosen a completed sample (N=60) that will achieve at least 80% power using 2-
sided tests. Our analysis of power was based on “effect size” (standardized difference). Effect 
sizes were calculated from our own preliminary data, from published data summaries, and from 
published estimates of effects (e.g., t statistics, coefficients, p-values) using validated summary 
methods. We have several hypotheses and more than one outcome measure for some (e.g., 
different brain regions). We will control error in a family-wise manner, adjusting alpha 
(Bonferroni Aims 1 and 2, Hochberg step-up procedure for Aim 3) for the number of tests within 
each hypothesis family. Bonferroni corrections will also be adjusted for the correlations among 
multiple outcomes. 
 
Aim 1 includes 2 hypotheses (H1a&b) regarding treatment effects on neural responses 
including 5 ROIs responding to food-related tasks. We test at p<0.02 because of the high 
correlation among ROIs within subjects (rho=0.54). Estimates of effect size from our center data 
(d=0.36) indicate that we have 80% power to detect the effects. Aim 1 also tests hypothesis H1c 
for cessation effects. At the Bonferroni corrected threshold of p=0.0167, we have 80% power to 
detect small to medium effect sizes (d=0.37). 
 
Aim 2 (H2a&b) essentially tests for mediation. The hypothesis that cessation increases food 
intake will be tested at 0.05, with power for effect sizes ~d=0.32 [9, 58]. For Aim 2b (ROIs 
predicting food intake), we expect a weaker correlation than H1a (rho=0.4), and our adjusted 
threshold for significance is p<0.01. Expected effect sizes are approximately 0.5, and we expect 
96% power to detect the effects. 
 
Aim 3 begins with the model in Aim 2b above, and tests interacting effects of working memory-
related BOLD signal and food reinforcement (or food cue reactivity) on food intake. We will 
reduce the complexity of this analysis by using difference scores (pre minus post) to model a 2-

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way interaction between working memory and food reinforcement on food intake. We will only 
test for brain ROIs found to be sensitive to treatment in Aim 1, the number of tests for interaction 
is uncertain. We anticipate that these effects will be positively correlated and will use the 
Hochberg step-up procedure, which is robust to correlations among outcomes in the range we 
expect. For purposes of power calculation, we assumed a correlation of 0.5, which resulted in a 
corrected p-value of 0.02 for 5 tests. Keeping the independent variables continuous, we can 
detect an interaction term (one-sample per subject, standardized) of d=0.36 with 80% power. 
Literature estimates for similar interactions were 0.65, 0.66, and 0.35. The lowest estimate gives 
77% power, and the average (0.55) yields 98% power. 
6.9 Sample Size Determination - Microbiome Sub-Study  
Hypotheses will be tested at a global 5% Type 1 error rate (alpha) for each family of 
hypotheses, and we have chosen a completed sample (N=60) that will achieve at least 80% 
power using 2-sided tests. Our analysis of power is based on “effect size” (standard difference). 
We will control error in a family-wise manner, adjusting alpha using the Hochberg step up 
method for the number of tests within each hypothesis family. For Aim 1, we examined power 
using a preliminary longitudinal MANOVA to test for overall significance, and then examined the 
individual terms by bacteria or metabolite. If we have 12 to 18 taxa in our panel, we have 80% 
power for the overall test if two taxa make a 0.35-SD shift in abundance in response to smoking 
cessation. This assumes no within-subject correlation. Imposing a within subject correlation and 
using the jackknife variance estimate (clustered by subject) increases power. For follow-up 
testing, we will detect individual effects provided that at least one effect size exceeds ~ 1.3. 
 
Aim 2 examines whether the changes in the gut microbiome are associated with food intake 
and smoking abstinence at week 12. As with Aim 1, we will begin with the omnibus test using 
the multivariate pairwise distance measure (within subject) as a predictor. For the smoking 
outcome, we have 80% power to detect an odds ratio of 2.0, reflecting approximately a 20% 
difference resulting from a 1-SD change in pre-post distance. We also have 80% power to 
detect a correlation of 0.38, reflecting a 400 Kcal change in food intake. Aim 3 begins with the 
model in Aim 2, above and explores interacting effects of treatment (BAS+ vs SC) on the 
relationship between gut microbiome changes, food intake and smoking abstinence. We will test 
an interaction effect predicting that the effects of gut microbiome changes (pre-post distance) on 
food intake and smoking abstinence will favor BAS+ versus SC. We have 80% power to detect 
a difference of 0.68 in the correlation of pre-post distance with food intake (0.68 versus 0), and a 
ratio of odds ratios (ORR) of 3.15, corresponding to a 25 to 30% greater change in abstinence 
for the BAS+ subjects. 
6.10 Statistical Methods - Parent (Main) Study 
Prior to the analyses, we will: (a) screen the data for data-entry errors, (b) check for outliers, and 
(c) assess the extent and type of missing data, and select the most appropriate method for 
dealing with the missing data (e.g., multiple imputation, all available data).  We will create all 
summary scores needed for analysis, and check that distributional assumptions are met. We will 
assess for participation biases, attrition differences and treatment adherence (controlled for in 
primary analyses) across treatment arms.  Main effects and moderated effects analyses will be 
conducted using Stata software (StataCorp, College Station, Texas) and mediation analyses will 
be evaluated using Mplus software 7.2.  
Aim 1 will evaluate smoking abstinence (point-prevalence, binary outcome) and PCWG (kg 
weight gain, continuous outcome) in the context of a longitudinal model with categorical and 
continuous predictor variables. We will use generalized linear models fitted with random effects 
using Generalized Estimating Equations. We will specify the logistic model for the binary 
abstinence outcome, and Gaussian weight gain outcome.  Models will include treatment 
assignment, time point, adherence measures, and covariates related to the outcome in 

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preliminary analyses. Comparisons are all between-subjects. We will test for interaction 
between treatment and time point using the Wald Chi-square, and estimate a common odds-
ratio across time points if they show no evidence of differing across time. The primary 
hypothesis will be tested using the z-score corresponding to treatment assignment at EOT, and 
at 12- and 26-weeks post quit, with the primary test of hypothesis 1a at 26-weeks post-TQD. 
Consistent with ITT analyses, we will measure smoking cessation and weight gain in the full 
sample at the 26-week follow-up, evaluating a smoking status (days x rate) by treatment 
interaction for the PCWG analysis (H.1.b.). The exploratory aim will evaluate variables that 
modify the effect of treatment on smoking cessation and PCWG. We will enter interaction terms 
(e.g., treatment x depression) to the models generated for Aim 1. The interactions will be 
retained if the z-score is significant (p<0.05). We will focus first on EOT, then the 12-week and 
26-week follow-up time points, and finally the combined effect across time point. 
Aim 2 will involve assessing the direct effect of treatment on smoking cessation and PCWG, 
and the indirect or mediated effects of treatment on these outcomes through the hypothesized 
sequential mediating mechanisms using structural equation modeling. Mediation exists when a 
relationship between treatment and smoking cessation or PCWG is accounted for in full, or in 
part, by one or a set of intervening variables (e.g., alternative reinforcers, food cue-induced 
craving, food reward, RRVF). Longitudinal change in the mediators will be represented with a 
slope factor (based on observed repeated measures of each mediator). We will assess the 
mediation strength (absent to complete) by estimating the effect proportion mediated 
(βindirect/βtotal), and determine the significance of effects with Delta method standard errors, with 
bootstrapped standard errors for validation. We will employ a weighted least squares estimation 
technique with robust standard errors, and a mean and variance adjusted chi-square test for the 
estimation of model parameters. Multiple indicators of model performance will be used, 
including the 2 test, Comparative Fit Index (< .95), Weighted (<.90) and Standardized Root 
Mean Square Residual (<.80), Root Mean Squared Error of Approximation (< .05), and an 
examination of standardized model residuals. Bayesian Information Criterion and Scaled Unit 
Information Prior BIC will be used to compare different models.  
6.11 Statistical Methods - Neuroimaging Sub-Study  
fMRI preprocessing will use standard algorithms in FSL (FMRIB’s Software Library, 
www.fmrib.ox.ac.uk/fsl) including distortion correction, slice-time correction, motion correction, 
spatial smoothing, high-pass filtering (120s) and co-registration to the structural MRI. Quality 
assessment (QA) procedures will examine global and ROI based temporal signal-to-noise ratio 
(tSNR), absolute and relative motion, and signal spike count. Following preprocessing, subject-
level BOLD timeseries analysis is carried out using the general linear model (GLM) as 
implemented in FSL, with a canonical double-gamma hemodynamic response function (HRF) 
for convolution, and linear contrasts to estimate task-specific BOLD responses for each 
individual session. To enhance sensitivity and reliability, including motion regressors in the 
model will reduce potential motion artifact. For group-level Image analysis, Subject-level 
statistical maps will be transformed into a common anatomic space (Montreal Neurological 
Institute, MNI) for group-level analysis. A priori region of interest (ROI) analyses will focus on 
specific regions for each task. For the n-back, primary ROIs will be MF/CG, and bilateral 
DLPFC. For the cue and reinforcement tasks, primary ROIs will be VS and ventromedial PFC; 
secondary ROIs will include MF/CG, amygdala, OFC, and insula. Percent signal change and 
activation extent within these ROIs will be used for statistical tests of key hypotheses. In 
addition, we will use voxel-wise random effects analysis in FSL to test for the effects outside of 
predicted regions. These voxelwise analyses will be conservatively corrected using Z>3.09 and 
cluster probability (family-wise error) p<0.001 
 
Hypothesis Testing. Percent signal change data will be exported for hypothesis testing using 
Stata (StataCorp, Texas).  
 

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Aim 1: Identify effects of BAS+ (vs SC) treatment on food related neural activity and behavior: 
These comparisons are all between subject, and will be analyzed using mixed models 
regression (xtmixed, StataCorp, Texas). The model predictors will include a binary indicator for 
group (BAS+ vs. SC). The hypothesis will be tested using the z-score corresponding to the main 
effect of group. Covariates can be included in the model to control error (sex, BMI, nicotine 
dependence, age, weight concerns), although we do not expect to make large gains for adding 
subject-level controlling variables in a mixed model. 
 
Aim 2: Evaluate the relative contribution of these neural processes to post-cessation caloric 
intake: Our outcome variable is average daily calories based on food recalls. The first 
comparison (pre vs. post-treatment) is within-subject, and will be analyzed using mixed models 
regression with subject specific random effects. As before, we include a binary predictor for 
condition, a categorical indicator for serial day, and we will test using the z-score corresponding 
to condition. For testing candidate mediators, we will again model calories using mixed models, 
entering variables as time-varying (condition varying) predictors, along with subject specific 
random effects. Finally, we will build the larger model, looking for confounding that represents 
potential mediation. For this purpose, we will use regression-based multi-equation path models. 
Path Analysis partitions a directly measured bivariate relationship, for example, between 
abstinence and calories ingested, into direct and indirect causal paths, to tease apart the 
important components mediating the response. We will deem that mediation has occurred when 
a relationship between abstinence and food intake accounted in full, or in part, by one or more 
of the intervening variables (BOLD signal change or subjective responses in cessation vs. 
smoking). We will assess the strength of the indirect effects through confidence intervals, 
evaluate the proportion mediated (i.e., partial or complete mediation), and determine 
significance with Delta method standard errors. To assess the level of mediation for a pathway, 
we will estimate the ratio of the indirect effect to the total effect (i.e., effect proportion mediated 
βindirect/βtotal). 
 
Aim 3: Test whether cessation-induced working memory deficits moderate the relationship 
between neural responses to food cues and reinforcement and food intake: This implies a 3-way 
interaction for a repeated measures analysis (e.g. cessation condition by food reinforcement by 
working memory on food intake). We will reduce the complexity and eliminate the repeated 
measures by conducting the analysis using difference scores (pre vs post), and will use multiple 
linear regression to analyze the differences in food intake. We will model the brain responses to 
cue reactivity and to food reinforcement separately. The models will contain a term for the 
difference in BOLD signal, and we will introduce a candidate moderator. 
6.12 Statistical Methods - Microbiome Sub-Study  
For Aim 1, H1a, the abundance of bacterial taxa will be analyzed at a community level using 
pairwise distance between samples, and visualized with Principal Coordinates Analysis. That 
pairwise distance will be the basis for the omnibus tests in all three aims. Prior to the testing of 
individual taxa, we will conduct a longitudinal MANOVA (Multivariate ANOVA) based on the 
profile of relative abundances of the gut taxa of interest. P-values from multiple testing 
procedures will be corrected to control for a specified false discovery rate using the Hochberg 
method. For H1b, we will repeat the omnibus MANOVA test as in H1a using the absolute levels 
of metabolites, and follow with tests on individual metabolites should the overall test prove 
significant. Smoking behavior (smoking rate) will be included in the statistical models for Aim 1 
as a covariate, because not all participants will have maintained smoking abstinence from TQD 
through EOT. Aim 2 will evaluate the impact of post-cessation changes (pre-post changes) in 
the gut microbiome on dietary intake (kcals, continuous outcome) and smoking cessation (point-
prevalence, binary outcome). We will use generalized linear models fitted using Generalized 
Estimating Equations. We will specify the logistic model for the binary abstinence outcome, and 

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Gaussian dietary intake outcome. We will begin the analysis with the effect of the omnibus 
measure (pre-post distance). Should that prove significant, we will continue on to specific taxa 
and metabolites. Aim 3 will explore whether treatment modifies the effect of gut microbiome 
changes on dietary intake and smoking cessation. We will enter interaction terms (e.g., 
treatment x microbiome changes) to the models generated for Aim 2. The interactions will be 
retained if the z-score is significant (p<0.05). 
7 Risks / Benefits 
7.1 Potential Study Risks 
The potential risks to participants, their likelihood and seriousness, and strategies to mitigate 
risks are described below. Participants can choose, as an alternative, to not enroll in this study. 
Overall, there is minimal risk for serious adverse reactions as a consequence of enrolling in this 
study. Adverse reactions/AEs will be collected, assessed, and reported as per the study 
protocol (see section 8: Safety and Adverse Events), federal law, and University of 
Pennsylvania regulations.  
 
Transdermal Nicotine (TN): Some individuals who use TN patches experience mild skin irritation 
at the patch site, such as itching, burning, and tingling, which subsides in a few hours.  Mild to 
moderate skin redness, rash, or swelling may also occur. Additionally, participants will be 
instructed to inform the research staff if they experience an irregular heartbeat or palpations. 
Sleep disturbances and vivid dreams may occur, but these sleep-related issues can be resolved 
by removing the TN patch before going to bed and reapplying a new TN patch in the morning. 
Other side effects such as, nausea, vomiting, weakness, dizziness, and rapid heartbeat occur 
rarely and may be related to nicotine overdose. Nicotine overdose is most often caused by 
continuing to smoke while using the patch. If these reactions occur, and the participant is 
currently smoking and using the patch (i.e., the participant has relapsed/lapsed but still is 
wearing the patch), participants will be counseled to reestablish a target quit day and gradually 
reduce their smoking rate. Participants will not be instructed to discontinue their patches if they 
have a smoking lapse unless a serious adverse event or experience severe/intolerable side 
effects. If a participant experiences symptoms of an allergic reaction, such as difficulty breathing 
or notable rash, they will be instructed to cease use of TN and consult with the research staff 
and Study Physician immediately.  
 
Other nicotine patch risks can include risks to children and pets if TN patches are not stored or 
disposed of properly. Unused and used patches have enough nicotine to poison children and 
pets. Participants will be instructed to keep patches out of the reach of children and pets. 
Participants will be instructed to fold the sticky ends together when disposing of used patches. 
Participants will be informed that if a child or pet swallows a nicotine patch, they seek 
professional help or contact a Poison Control Center immediately. 
 
The overall risk of adverse responses to TN will be minimized by only admitting subjects to the 
study if they do not have preexisting conditions that significantly increase the risk for adverse 
responses (e.g., heart disease, uncontrolled high blood pressure, allergy to adhesives, poorly 
controlled diabetes, etc.) per the product labeling. In addition, no TN will be distributed to a 
participant without the documented approval (via email) of the Study Physician post Intake. The 
research staff, in conjunction with the Study Physician and Principal Investigator, will monitor for 
anticipated side effects of TN per the SEC form and other AE assessment measures (see 
section 8.2.1: AE Collection Methods) at every in-person visit over the treatment period. 
Participants will be provided with an information sheet describing the proper use of TN, the 
possible adverse reactions of TN, and the methods for minimizing the possibility of adverse 
reactions. Participants will be specifically instructed to contact the study staff or the Study 

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Physician if they 1) experience severe or persistent skin reactions (e.g., skin redness, itching, or 
swelling) caused by the patch that last more than 4 days, or a generalized skin reaction (e.g., 
hives or rash); 2) notable irregular heartbeat or palpitations (e.g. notable hard or fast beats); 3) 
persistent nausea, vomiting, dizziness, weakness, or rapid heartbeat (symptoms of nicotine 
overdose); or 4) symptoms of an allergic reaction such as difficulty breathing or notable rash. 
Participants should not stop using the patch without discussing their symptoms with the Study 
Physician and study staff unless they experience severe or intolerable side effects. The Study 
Physician is knowledgeable of side effects related to TN treatment and is qualified to manage 
possible side effects. Any severe adverse reactions or significant side effects of TN as identified 
in section 8.2: Safety and Adverse Events will be medically evaluated by the Study Physician.  
 
Reproductive Risks: Because TN safety for an unborn baby is unknown, participants will be told 
that they should not become pregnant while in this study. Women in the study should not 
breast-feed a baby. If a woman is of childbearing potential, she must agree to use an adequate 
form of contraception or abstain from sexual intercourse for the duration and for at least one 
month after the end of the trial. If a woman is pregnant or breast-feeding, she should not 
participate in this study. If she becomes pregnant during the study, she will be asked to notify 
staff immediately and will be removed from the study. Women will be asked to self-administer a 
pregnancy test during the Intake Visit (prior to the TN treatment period).  
 
Withdrawal Syndrome: Many individuals who quit smoking exhibit a pattern of symptoms related 
to withdrawal from tobacco use. These symptoms include: anger, irritability, frustration, 
anxiousness or nervousness, depressed mood or sadness, cravings for nicotine, difficulty 
concentrating, appetite change and weight gain, insomnia or other sleep problems, 
restlessness, impatience, constipation, dizziness, coughing, nightmares, nausea, sore throat, 
headache, muscular pain, or fatigue. Eliminating the risk for these would not be possible, 
although in most cases these events are short-lived and have low intensity, lasting for 1-2 
weeks. The study personnel will be trained to recognize these symptoms and educate the 
participants about them (e.g., duration and methods for reducing them). 
 
Food Allergies: Participants will be provided with nutritional shakes and potato chips or milk 
chocolate and as part of their participation in this research trial. The risk of a participant 
experiencing an allergic reaction to any of the ingredients in these commercially available food 
products will be mitigated by prospectively excluding those with the applicable food allergies. In 
addition, the research staff will reconfirm that the participant doesn’t have any of the applicable 
food allergies prior to distribution of the aforementioned food products at the Baseline Visit. 
 
Psychological Distress: Participants may experience emotional distress during smoking 
cessation counseling and assessments from discussing feelings and attitudes about smoking or 
from learning about the risks from smoking. These events happen very rarely and in almost all 
cases are short-lived and of low intensity, lasting for 1-2 weeks. Study personnel will be alerted 
to expect this from a small number of subjects and will be trained to make referrals for mental 
health services as needed. Personnel will be trained to query for adverse emotional reactions 
during counseling and assessments and will be trained to deal with such reactions and to 
provide additional referrals if needed.  
 
Urine and Saliva Sample Collection: Participants may experience mild discomfort from providing 
urine or saliva samples. All samples will be collected by trained member of the research staff.   
 
Email Communications: In this research study participants may prefer to receive appointment 
reminders via email or submit questions related participation via email.  Email is not a secure 
means of communication. Email messages travel across the Internet passing through multiple 

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computers before reaching their final destination.  It is not possible to know whether an email a 
participant sends will be viewed along the way.  Additionally, if sent messages are not deleted, 
an email provider may have an archive of everything that is sent. If someone gets access to an 
email account (for example, a participant’s family member), they could see archived messages.  
There are many other ways in which emails are not secure—these are only selected examples. 
To manage this risk the informed consent form will include specific language to educate 
research participants on the privacy risks involved in email communications. Participants will 
also be explicitly instructed to only use email communications for routine matters and never for 
personal or confidential messages or questions. 
 
fMRI: The known MRI-related risks associated with this study are minimal.  All sequences and 
RF coils will be approved by the Center for Magnetic Resonance Imaging and Spectroscopy 
(CAMRIS) prior to utilization.  Because of the strong magnetic field, people with pacemakers, 
certain metallic implants, or metal in the eye cannot participate in this study. These exclusions 
will be reviewed carefully with the study staff prior to scanning. Although the Nicoderm® CQ® 
package insert states that patches should be removed before undergoing any MRI procedures – 
“for the opaque Nicoderm® CQ® patch only,” we will err on the side of caution and instruct 
participants in the neuroimaging sub-study to remove their 7mg Nicoderm® CQ® - Clear patch 
before entering the MRI environment during their Scan 2 Visit only (no patch worn during the 
pre-treatment scan). Participants will be provided with a loose, sealed 7mg (NicoDerm® CQ® - 
Clear) patch to reapply after exiting the MRI environment.  
 
The greatest risk with MRI is a metallic object flying through the air toward the magnet and 
hitting the participant.  To reduce this risk we require that all people involved with the study 
remove all metal from their clothing and all metal objects from their pockets. No metal objects 
are allowed in the magnet room at any time.  In addition, once the participant is in the magnet, 
the door to the room will be closed so that no one inadvertently walks into the magnetic field. 
Although there are no known risks of MRI on pregnant women or a fetus, there is a possibility of 
yet undiscovered pregnancy related risks. Since there is no direct benefit from participating in 
this protocol for a pregnant woman, women of child bearing potential will be supplied with a 
simple, CLIA-waived urine pregnancy screen to self-administer at each scan visit, and will be 
told that pregnant women may not participate in the study.  They will then be instructed to 
administer the pregnancy test independently and will inform study staff if they would like to 
continue participation after they have administered the pregnancy screen. Participants will be 
informed that there is no penalty for discontinuing participation at this point in the visit and that 
they will still receive travel reimbursement for the visit.  
 
There is no known health risk associated with exposure to magnetic fields during an MRI. There 
are minimal risks from the loud noise associated with the MRI scanner and from the discomfort 
of lying on a hard surface. Participants will be provided with protective earplugs as necessary 
and every attempt will be made to ensure comfort with blankets, etc. during the scan. 
 
The levels of energy used to make magnetic resonance measurements are far less than are 
used in a single X-ray, and many patients have been safely studied using magnetic resonance 
techniques.  However, some people become uncomfortable or claustrophobic while inside the 
magnet. If participants become uncomfortable, they may withdraw immediately from the fMRI 
portion of the study. During some of the MRI scans, participants have occasionally reported 
“tingling” or “twitching” sensations in their arms or legs, especially when their hands are clasped 
together.  To prevent this, all participants will be instructed to keep arms and legs apart.  
 
The imaging component of this study is part of a research protocol, and is not intended to 
provide a comprehensive clinical fMRI examination of the brain. In the event that a significant 

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brain abnormality is observed while processing subject brain images for the research study, the 
images will be reviewed by the radiologist affiliated with this protocol in conjunction with the 
Study Physician. There will be no charge to the subject for this examination of their images.  A 
report will be filed in the subject’s chart at the Center. The subject will be contacted and Center 
staff will arrange for the radiologist’s report and structural images to be sent to the subject 
and/or their physician.  Subjects will also be offered a consult with the Study Physician and/or 
radiologist if appropriate. These possible finding(s) may or may not be significant and may lead 
to anxiety about the subject’s condition and to further work-up by the subject’s physician. 
 
Risks associated with stool samples (microbiome sub-study only): 
Collecting stool may contain germs that spread disease. Participants will be reminded to 
carefully wash their hands and use the provided gloves to avoid spreading infection. Some 
people may feel uncomfortable or embarrassed using the stool sample collection kit. There 
should be no pain while collecting the stool sample. However, if a participant is constipated, 
straining to pass stool may be painful. We will discuss this risk with the participant during the 
informed consent presentation to ensure that the individual subject is comfortable with the 
process. 
  
Risks associated with genetic testing (microbiome sub-study only): 
This research includes genetic testing. We will sequence all the genomes present in each stool 
sample (both human and microbial) via a technique called shotgun metagenomics. Part of the 
analysis process involves assembling the microbial reads into contigs. We do not assemble 
contigs from the human data. Even without a name or other identifiers, a participant’s genetic 
information is unique to them. The researchers believe the chance that someone will identify a 
participant is very small, but the risk may change in the future as people come up with new 
ways of tracing information. We will not complete genetic testing of inherited traits for research 
purposes. 
 
Confidentiality and Loss of Privacy: See section 9.7.1 and 9.7.2 for methods in which 
Confidentiality and Subject Privacy/Protected Health Information will be secured and 
maintained. 
7.2 Potential Study Benefits 
Participants who enroll in this trial will benefit from the knowledge that they are contributing in an 
important way to potentially furthering scientific knowledge concerning ways to improve 
treatment for smokers, and prevent PCWG. Weight gain can precipitate smoking relapse and 
contribute to other health issues. All eligible smokers will receive TN and behavioral counseling 
and may quit smoking and learn skills to stay quit as a result of participating. 
7.3 Risk/Benefit Assessment 
There is minimal risk for serious adverse events by enrolling in this research study. The 
treatments and procedures used in this study have been shown to be relatively safe. Numerous 
clinical trials have demonstrated the safety and efficacy of transdermal nicotine and behavioral 
counseling for nicotine dependence. Research staff will monitor subjects closely during their 
participation. Thus, the risk to benefit ratio for this project is perceived to be low and justifies its 
implementation. 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others: 
Any incident, experience, or outcome that meets all of the following criteria:  

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• Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
Adverse Event: 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study (regardless if TN related). Intercurrent illnesses or 
injuries should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event: 
Adverse events are classified as serious or non-serious.  A serious adverse event (SAE) is 
any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, 
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period: 
The study period during which AEs/SAEs will be reported is from the initiation of any study 
procedures until the end of the study.  Any event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in the study after the final time 
point will be assessed and reported as appropriate.   
 
Preexisting Condition: 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
Post-study Adverse Event: 

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All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.   
 
Hospitalization, Prolonged Hospitalization or Surgery: 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as a SAE unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an AE if the condition meets the criteria for an 
AE.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition. Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
8.2 Collection and Recording of Adverse Events 
8.2.1 AE Collection Methods 
 
All AEs and SAEs occurring during the study period will be captured through the methods 
described below: 
1. SEC: Participants will complete an SEC at all in-person visits during the treatment period 
(including Pre-Quit as a baseline measure) after the Baseline Visit. The SEC will assess 
the severity of side effects that may be TN related and experienced by participants in the 
study (See section 7.1: Potential Study Risks; Transdermal Nicotine). These reports will 
be formally documented as anticipated (expected) AEs whether or not the event(s) is 
ultimately deemed related or not related to the use of TN in this study. The reporting period 
for each assessment will inquire about any side effects experienced since the last in-
person visit. Items will be rated by participants utilizing the following severity scale: 0 
(None=No Concerns), 1 (Mild=Side effect does not interfere with usual daily activities), 2 
(Moderate= Side effect does interfere with some activities), and 3 (Severe=No normal 
activities are possible). Any side effect rated severe or moderate will require additional 
follow up per the internal reporting procedures outlined below in section 8.2.2. Mild skin 
redness, skin rash, skin swelling, irregular heartbeat, or heart palpitations also 
require additional follow up per the internal reporting procedures outlined below in section 
8.2.2. Other side effects reported as mild, but not identified above, do not require 
additional follow up from the research staff or communication with the Project Manager, 
Study Physician, and Principal Investigator. However, these mild reports are maintained 
within the data management system and are available via aggregate report.  
2. Open-Ended AE Form: Participants will be asked an open-ended question about any 
symptom or medical event that may be related to their study participation not included on 
the SEC form at all in-person visits after the Baseline Visit. These events will be 

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sponsor 
documented as unanticipated (unexpected) AEs unless they are otherwise outlined in the 
protocol or consent (i.e. related to withdrawal, assessments, etc.). The reporting period for 
each assessment will inquire about any event(s) or symptom(s) experienced since the last 
in-person visit.  If a participant reports a symptom or medical event, they will be asked to 
rate the severity of the event utilizing the following severity scale: 0 (None=No Concerns), 
1 (Mild=Issue does not interfere with usual daily activities), 2 (Moderate=Issue does 
interfere with some activities), and 3 (Severe=No normal activities are possible). Any 
report on the Open-Ended AE Form will require additional follow up per the AE 
documentation and internal reporting procedures outlined below in section 8.2.2.  
3. Spontaneous Assessment: Once enrolled, participants will be instructed to inform the 
research team about any notable symptom or medical event/concern throughout their 
participation in the study. A participant may also request the Study Physician be 
consulted about any reported medical event or concern of any severity at any time 
throughout their participation. At the Pre-Quit Visit (Week -1), participants will receive an 
emergency medical card (EMC) with the Study Physician’s direct contact information 
should a medical issue or concern that they believe may be related to the study 
procedures require immediate attention.  
An “AE Note” template will be available to the research staff to collect supporting AE 
information and will function as the source document. However, research staff may 
collect AE information on any source document available to them and transfer the 
relevant information to a formal AE Note at a later time. Any notable AE reported 
spontaneously will require additional follow up per the AE documentation and internal 
reporting procedures outlined below in section 8.2.2. 
8.2.2 AE/SAE Documentation and Internal Reporting Procedures 
 
AE/SAE Documentation: As noted above in section 8.2.1, research staff are trained to collect 
follow-up information about any severe, moderate, or select mild side effects reported on the 
SEC Form, any medical event(s) reported on the Open-Ended AE Form, or any notable 
spontaneously reported medical event or concern.  At a minimum, follow-up information will 
include AE/SAE onset/resolution, description of event/course, severity, action taken, outcome, 
and possible relation to TN treatment (if applicable). 
 
Information surrounding AEs and SAEs will be initially recorded on the appropriate source 
document such as the SEC Form, Open-Ended AE Form, an “AE Note” or SAE Form, and/or 
any document in which the AE/SAE information was originally recorded. All applicable AEs and 
SAEs will then be documented on a cumulative AE and SAE log maintained within the 
regulatory binder.   
 
Completed documentation of applicable AEs will include the following information: 
• 
Protocol Title and IRB# 
• 
Subject Identifier  
• 
Event Title 
• 
Date Site Notified  
• 
Event Start Date and Time  
• 
Event Stop Date and Time 
• 
Description of Event/Course (including sequelae) 
• 
Severity: 
o None = No concerns 
o Mild = Side effect or issue does not interfere with usual daily activities 

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o Moderate = Side effect or issue interferes with some activities 
o Severe = No normal activities are possible 
• 
Relatedness to the study procedures (PI and/or Study Physician): 
o Unrelated = Definitely not related   
o Unlikely = Doubtfully related 
o Possibly = May be related  
o Probably = Likely related 
o Definitely = Related 
• 
Expectedness per protocol and/or consent  
o Expected/Anticipated 
o Unexpected/Unanticipated 
• 
Action(s) taken (if appropriate) 
• 
Outcome (if appropriate) 
 
Documentation of SAEs will include the following information on a standardized SAE Form: 
• 
Protocol name and number 
• 
Subject identifiers 
• 
Demographic data 
• 
TN Lot number, expiration date, and other descriptive information  (if appropriate) 
• 
Date Site Notified  
• 
Date and time of SAE onset 
• 
Date and time of SAE resolution, if available 
• 
Course/Description of Event (including sequelae) 
• 
Action Taken 
• 
Outcome 
• 
Follow-up plan 
• 
Serious Status (What makes the event an SAE) 
• 
Severity of the event 
o None = No concerns 
o Mild = Side effect or issue does not interfere with usual daily activities 
o Moderate = Side effect or issue interferes with some activities 
o Severe = No normal activities are possible 
• 
Relatedness to the study procedures (PI and/or Study Physician): 
o Unrelated = Definitely not related   
o Unlikely = Doubtfully related 
o Possibly = May be related  
o Probably = Likely related 
o Definitely = Related 
• 
Clinical assessment of subject conducted at time of SAE (if appropriate) 
• 
Results of any laboratory tests and/or diagnostic procedures (if appropriate) 
• 
Autopsy findings (if appropriate) 
• 
Concomitant medications and therapies  (excluding treatment of event) 
• 
Relevant Medical History (if appropriate) 
 
Internal Reporting Procedures:  All relevant follow-up information outlined above (see AE/SAE 
documentation) concerning applicable AEs, including all information regarding the occurrence of 
concurrent smoking and TN (if applicable) and previously reported event(s) and/or side effects, 
will be reported to the Study Coordinator (or other senior personnel), Principal Investigator, and 

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Study Physician to determine a course of action (e.g. continue to monitor, reduce medication 
dose, stop medication), relatedness (causality) to the study, and expectedness (if not already 
established). This consult will be documented via email. The clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not (or unlikely) to be the cause.  
 
SAEs that are still ongoing at the end of the study period must be followed up to determine the 
final outcome unless it has been determined that the study treatment or participation is not the 
cause. Any SAE that occurs after the study period and is considered to be possibly related to 
the study treatment or study participation should be recorded and reported immediately per this 
protocol. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems  
The reporting requirements of applicable SAEs and/or Unanticipated Problems including 
reportable AEs (see section 8.1 for definitions) to external entities are detailed in the following 
sub-sections:   
8.3.1 Investigator reporting: notifying NCI and FDA 
In adherence with NCI reporting requirements and GCP standards regardless of IND status, the 
procedures for reporting SAEs (detailed below) suspected/associated with TN to the FDA are as 
follows: 
1. An SAE that is drug-related (reasonable possibility or related) and unexpected will be 
reported to the FDA within 15 calendar days of discovery of event. 
2. An SAE that is drug-related (reasonable possibility or related), unexpected, and life-
threatening or fatal will be reported to the FDA within 7 calendar days of discovery of the 
event. 
3. The FDA will be notified of applicable SAE reports via the MedWatch form/system (FDA 
Form 3500). 
 
The NCI program officer assigned to this trial will be notified of any actions taken by IRB with 
regard to data safety monitoring.  
8.3.2 Investigator reporting: notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are Penn 
faculty, affiliated with a Penn research site, or otherwise responsible for safety reporting to the 
Penn IRB. The University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those 
events related to study participation that are unforeseen and indicate that participants or others 
are at increased risk of harm.  The Penn IRB will not acknowledge safety reports or bulk 
adverse event submissions that do not meet the criteria outlined below. The Penn IRB requires 
researchers to submit reports of the following problems within 10 working days from the time the 
investigator becomes aware of the event: 
• Any AE (regardless of whether the event is serious or non-serious, on-site or off-site) that 
occurs any time during or after the research study, which in the opinion of the Principal 
Investigator and Study Physician is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved informed consent 
document and other relevant sources of information, such as product labeling and 
package inserts.) 
AND 

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Related to the research procedures (According to the Penn IRB standard operating 
procedures [SOPs], an event is “related to the research procedures” if the event is 
deemed probably or definitely related to the procedures.”) 
 
Reporting Process: 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
Penn IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including 
Reportable Adverse Events” or as a written report of the event (including a description of the 
event with information regarding its fulfillment of the above criteria, follow-up/resolution and 
need for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 
 
Reporting Deaths (more rapid reporting requirements): 
Deaths that occur during the course of a research study and that are:  
• 
Unexpected; AND  
• 
Related to the research study; AND  
• 
When other participants are believed to be at an increased risk of harm 
 
Must be reported to the IRB within 3 days from the time the investigator becomes aware of the 
death.  
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
• Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
• Any adverse event that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to assure 
protection of human subjects. 
• Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more 
frequent than initially expected. 
– A paper is published from another study that shows that an arm of your research 
study is of no therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant. 
• Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain 
on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 

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• Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants 
at increased risk, or affects the rights or welfare of subjects. 
8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator and Study Physician to oversee the safety of 
the study. This safety monitoring will include careful assessment and appropriate reporting of 
AEs/SAEs as noted above, as well as adherence to the study data and safety monitoring plan 
outlined in sections 8 and 10.   
9 Data Management 
The CIRNA Data Management Team has developed a data management system (DMS) that 
will facilitate the operational facets of this study, including determination of entry eligibility, 
production of lists of subjects for telephone contacts for scheduling, and data entry. The DMS 
uses the relational database product Microsoft Access as the primary software platform for data 
entry and validation, storage, retrieval, modification, and security. The DMS ensures data 
integrity through range and validity checks during the data entry process. Daily backups are 
performed to protect data against accidental destruction or corruption. 
9.1 Data Management System Development  
The CIRNA Data Manager will work closely with the trial investigators to develop an 
understanding of the data collection, storage, and quality assessment needs for the trial. This 
includes the design and development of the trial data collection forms and any additional 
administrative CRFs, to ensure that standardized, uniform data collection and data management 
procedures are implemented and sustained throughout the trial. The data collection forms will 
serve as templates for designing the data entry screens. The Data Manager will work closely 
with trial investigators and senior personnel to design, develop, and test an appropriate 
database structure to support the requirements of the DMS and to promote data security and 
integrity. Electronic audit trails of changes to database contents are incorporated into the design 
and will capture and record those changes automatically. In addition to the trial database where 
actual results will be maintained, a development database will be created. The development 
database is a working environment that facilitates the development, testing, troubleshooting, 
enhancement, and training for the DMS without adversely affecting the integrity of the collected 
project data. 
 
Prior to deployment and use by the research staff, the database and DMS will be subjected to 
extensive functional testing. This testing is conducted according to a written test plan and is 
intended to verify the proper functioning of all components of the DMS. Any components that do 
not function as they were intended will be identified and evaluated by the development team to 
determine appropriate corrective action. Testing will also include an evaluation by user 
representatives for adherence to the requirements established by the intended users for the 
DMS. Successful completion of these user acceptance tests will mark the end of development 
and predicate the deployment of the DMS for use in storing and managing active trial data. Any 
modifications made to the DMS will be conducted in accordance with change control 
procedures. 
9.2 Data Security  
All research data for the trial will be stored in an electronic Access database that is managed by 
the Data Manger. The database will be hosted on a secure computing server and will be 
restricted to only those individuals who are authorized to work on the trial. Individual user 
accounts with passwords will be used to restrict access to the database. Specific privilege 
assignments within the database will also be employed to limit the types of functions that 
authorized users can perform to those functions that are appropriate for their role in the trial. 

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Additional measures to prevent unauthorized external access to the database environment will 
be employed using network firewall technologies. The Data Manager will maintain the database 
in an appropriate manner for the retention period required by regulation. Database 
administration includes user account maintenance, database security, performance monitoring, 
and database change management. 
 
Storage and archiving for imaging data will be stored on The Center for Functional 
Neuroimaging (CfN) secure computer cluster. 
9.3 Data Processing  
The data entry screens will resemble the data collection forms as closely as possible to allow 
visual referencing during data entry. This data entry module will be configured for single data 
entry. Participant data will be collected by research staff, recorded on study-specific CRFs, and 
scanned in or entered directly into the appropriate DMS module. Data entry checks will be 
included in the entry screen designs where appropriate to limit the opportunity for erroneous 
entries due to mistyping. Such data entry checks would include value range comparisons, valid 
data type checks, required value checks, and/or skip pattern enforcement. Following telephone 
eligibility screening, research staff will perform subject registration. Following the Intake Visit, 
research staff will randomize eligible subjects. The randomization module will allow the research 
staff to randomize subjects into one of the two trial arms. At the randomization attempt, the DMS 
will check the eligibility data to confirm that randomization is valid. A randomization assignment 
will then be provided.  
9.4 Data Quality Assurance        
A data quality module will be developed to assess data entered into the database in relation to a 
set of rules that describe expectations for those data items. This set of data validation rules will 
be defined by the data manager, working closely with trial investigators, to identify data items 
that may have been collected incorrectly or entered into the database inaccurately. The module 
will run automatically to inspect all newly entered or modified data. The research staff will review 
the results of the data validation and take any required corrective action for invalid data. Queries 
will be recorded and tracked in the data quality module. Corrections identified for individual data 
items will be managed by the research staff. All changes made will be recorded in an electronic 
audit trail and documented using change control procedures. 
 
Monitoring of trial progress will be accomplished, in part, through the use of standard reports. 
The Data Manager will program a set of standard enrollment, tracking, quality review, and safety 
monitoring reports. Data audits will occur after the first few participants are enrolled and 
periodically during the trial to detect errors in data entry. Eligible participants will have 100% of 
their source document information compared with the data entered in the database. Any errors 
will be investigated, resolved, and a plan will be implemented to prevent further errors should 
concerning patterns emerge. 
9.5 Subject and Specimen Tracking  
The Data Manager will develop a module to assist research staff in recruitment and retention 
tracking for trial subjects. This module will accept and store contact information for potential 
subjects and will include data items to indicate the completion status of significant events. The 
tracking module will include information about contact and visit schedules to assist in preparing 
communications to potential subjects and trial participants concerning scheduled events. The 
module will also allow for incentive-related inventory management. When obtaining saliva 
specimens, the research staff will complete a specimen registration CRF and scan/enter the 
data into the DMS. A unique specimen identifier will be assigned and recorded on the CRF. 
Labeled specimens and applicable information will be transferred to the lab for analysis as 
required for analysis.  
 

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Stool specimens (microbiome sub-study) delivered to the CHOP Microbiome Center and the 
Penn Metabolomics Core will be labeled by study ID only. Samples will be processed, analyzed, 
stored, and logged at the CHOP Microbiome Center and Penn Metabolomics Core. Additionally, 
stool sample tracking and collection information (i.e., sample status, date returned, date 
transported, etc.) will be tracked via the study DMS.   
9.6 Retaining Data and Biospecimens for Future Research Use 
Permission will be sought from participants that elect to enroll in microbiome sub-study to retain 
their information and stool samples for possible use in future research. Providing permission is 
optional and the participant’s choice will be documented and maintained on both the combined 
Informed Consent and HIPAA Form and the study DMS. Participants will not directly benefit 
from future research with their information and stool samples, but they will be informed that the 
information and stool samples that they provide could be useful to future researchers by 
improving the understanding of health and disease, improving health care, making safer or more 
effective medical therapies, and developing new scientific knowledge. There are no plans to 
inform participants about any of the specific research that will be done. Further, we will not 
provide participants with any results from these future studies. It is possible that participants 
may have chosen not to participate in these future research studies, had they been approached.  
 
Although participant data and stool samples collected in this study will be labeled and stored 
with a study identification number only, there is a possibility that a study identification number 
and personal identifiers could be linked. See the Data Handling and Record Keeping section for 
methods and descriptions about how Confidentiality and Participant Privacy/Protected Health 
Information will be secured and maintained. 
 
Participants may change their mind and withdraw their permission for the future use of their 
information and stool samples at any time by contacting the Principal Investigator and informing 
them that they no longer want their information and stool samples to be retained for use in 
future research. Although most uses of biospecimens or information do not lead to commercial 
products or to profit for anyone, participants will be informed that it is possible that their stool 
samples may be used for commercial profit and that there are no plans to tell them, or to pay 
them, or to give any compensation to their family. Additionally, participants will be informed that 
individual research results obtained as part of future research will not be shared with them.  
 
Participants’ information and stool samples will be stored for future research purposes only. 
Participants’ information and stool samples may be retained and used for future research for an 
indefinite amount of time. Future researchers may receive information that could identify 
participants. This can be done without seeking participants’ consent in the future, as permitted 
by law. The future use of participant information and samples only applies to the information and 
stool samples collected during this study. 
9.7 Data Handling and Record Keeping 
9.7.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. Note in 
the event that a subject revokes authorization to collect or use PHI, the investigator, by 

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regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  
 
Confidentially of study data will be maintained in the following manner: 
• 
Paper-based records will be kept in a secure location and only be accessible to 
personnel involved in the study. 
• 
Computer-based files will only be made available to personnel involved in the study 
through the use of access privileges and passwords. 
• 
Prior to access to any study-related information, personnel will be required to review and 
sign statements agreeing to protect the security and confidentiality of identifiable 
information. 
• 
Whenever feasible, identifiers will be removed from study-related information. 
• 
Precautions are in place to ensure the data is secure by using passwords and 
encryption, because the research involves web-based surveys. 
• 
Audio recordings will be reviewed by the Principal Investigator for training purposes and 
then deleted to eliminate audible identification of subjects. 
 
Since self-report and biological data will be collected and stored as part of this study, it is 
possible that subject privacy or confidentiality can be threatened. To address this concern, the 
data management system has set up several safeguards to prevent unauthorized access to 
participant data. In the subject map table, an automatically generated index number is assigned 
to a subject’s study identification number. A linked subject identification table is created to store 
subject name, address, and telephone contact information. This table uses the automatically 
generated index number rather than the study identification number. The master subject map 
and subject identification information are maintained in separate locations. Using this method, 
no identifying subject information is directly linked to bio-samples or results. Any publication of 
data will not identify participants by name or with an identifier that could be used to reveal 
identity. 
 
All biological samples will be labeled with study ID only.  All subject data that can be linked to 
the study ID will be stored in the secure data management system, which has limited, 
password-required access. The aforementioned precautions and procedures will be applied to 
protecting subject privacy and the protected health information detailed in Section 9.7.2 below. 
9.7.2 Subject Privacy/Protected Health Information 
The following protected health information (PHI) may be collected as part of this study: 
1. Name 
2. Street address, city, county, zip code 
3. All elements of dates (except year) for dates directly related to an individual and all ages 
over 89 
4. Date of birth 
5. Social Security Number 
6. Telephone number, email address 
7. Any other unique identifying number, characteristic, or code  
8. Results from all questionnaires, tests, and procedures  
 
Potential participants will be contacted over the phone after responding to recruitment efforts or 
having agreed to be contacted for future studies. Only individuals who have responded to 
recruitment efforts or who have agreed to be contacted regarding research studies at our Center 
will be contacted. If an individual cannot be reached immediately, staff members will identify 
themselves only as calling from the University of Pennsylvania; no mention will be made of the 
inquiry regarding study participation. Participants will undergo an initial telephone screening 
where preliminary eligibility for the research study will be determined. Only if a participant is 

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initially eligible, will they be asked to attend an in-person Intake Visit to confirm eligibility. All 
data collected over the phone and during in-person visits will be collected by research staff that 
have completed the CITI-Protection of Human Subjects Research Training as well as HIPAA 
Compliance Training. Once enrolled, information will never be recorded with identifiers other 
than study ID. A separate list of names with ID numbers will be accessible only by authorized 
personnel. All records will be kept in locked filing cabinets to maintain confidentiality. All 
analyses will be conducted on de-identified data.  
 
Data will be accessible only to the Study Investigators, Study Physician and Study Radiologist, 
study staff, applicable Center staff, UPenn IRB, Office of Clinical Research, CAMRIS, 
authorized UPENN and CHOP staff (e.g. accounting and billing matters, provide treatment, 
oversee MRI scans [MRI Technicians], stool analysis, etc.), PennCHOP Microbiome Program 
(CHOP Microbiome Center), Penn Metabolomics Core, National Cancer Institute, and the FDA.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This website will not include information that can identify a subject directly. At most, 
the website will include a summary of the results. Subjects may search this website at any time. 
10 Data and Safety Monitoring 
10.1 Research Roles 
During the course of the study, data and safety monitoring will be performed on an ongoing 
basis by the Principal Investigator, Study Physician, research staff, and the IRB. The research 
staff are responsible for collecting and recording all clinical data. This includes ensuring that all 
source documents exist for the data on the case report forms (CRFs), ensuring all fields are 
completed appropriately, and all error corrections are done according to GCPs. Any 
inconsistencies/deviations will be documented and addressed as appropriate. The research 
staff will perform regular chart reviews to verify data integrity. The Study Coordinator (or senior 
personnel) and Principal Investigator will maintain the study regulatory binder/essential 
documents per GCP. The Study Physician will be available to review medical issues related to 
participation for each participant on an ongoing basis as outlined in this protocol. Research staff 
will meet and communicate on a regular basis to reconcile data queries and safety concerns. 
The IRB will review the trial on an on-going basis per institutional and federal regulations until 
the study is formally closed-out.   
 
CAMRIS will be responsible for the regulatory oversight of all MRI related activities within this 
protocol including initial review and approval of the neuroimaging sub-study.  
10.2 Staff Training 
Staff training will consist of an initial explanation and review of the protocol, informed consent 
form, CRFs and laboratory tasks, sample collection protocols, data management system, 
adverse event collection and reporting, and all study-specific SOPs. In addition, during a 
standardized training period, the duties of each staff member will be clearly outlined and all 
applicable regulations will be reviewed. The Principal Investigator, Dr. Audrain-McGovern, will 
oversee the behavioral activation intervention and smoking cessation counseling training, as 
well as the transdermal nicotine procedures. Training interactions will be documented in a 
training log, which will be maintained within the regulatory binder. Senior personnel will 
supervise junior staff and provide re-training as needed.   
 
Dr. Loughead and senior staff will oversee the development of protocols for activities pertaining 
to the neuroimaging sub-study and training of staff in these protocols. Dr. Loughead and/or the 
Project Manager will also be responsible for the development of procedures pertaining to all 

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neuroimaging study visits and implementing and monitoring ongoing staff training procedures 
accordingly.  
 
All personnel working on this project will complete required training in the protection of human 
subjects and the protection of personal identifiable information (i.e. HIPAA) before interacting 
with study data or research participants.  All human subject and privacy protections certifications 
will be maintained in the regulatory binder. 
10.3 Monitoring Activities 
10.3.1 AE/SAE Monitoring  
Monitoring and management of AEs/SAEs will be conducted in real-time by the Principal 
Investigator, Study Physician, and the research team at regular time points as per the methods 
and procedures detailed in section 8: Safety and Adverse Events. 
10.3.2 Initial Assessment (Intake) Monitoring  
The study staff will conduct a manual review of source documents and CRFs for all subjects 
determined to be eligible at telephone screen and again prior to the Intake Visit. Eligibility data 
will be reviewed in real-time at the Intake Visit by the research staff. In addition, The Study 
Coordinator (or senior personnel) will verify that all data have been collected and, when 
applicable, meet the eligibility criteria on a “Final Eligibility Checklist.” The Final Eligibility 
Checklist will be signed and dated by the Study Coordinator (or senior personnel) to formally 
document review. In addition to confirming eligibility, a brief, internal report describing the 
findings will be compiled and distributed to study staff (if applicable). If the Study Coordinator (or 
senior personnel) notes a pattern of improper data collection or deviations, additional trainings 
will occur. 
 
After the Intake Visit, but prior to TN distribution at Pre-Quit, the Study Coordinator (or senior 
personnel) will inform the Study Physician that applicable participants have met all the eligibility 
criteria (i.e. did not present with any exclusions) including blood pressure, medical history, and 
concomitant medications via email for formal approval to dispense TN. The Study Physician’s 
approval via email will be maintained in the participant’s study chart, as well as on file in an 
electronic format. The Study Physician will be available to respond to any additional eligibility 
queries as well. 
10.3.3 Protocol Monitoring  
Protocol monitoring includes a survey of those activities that are associated with protocol 
adherence such as identifying, reporting, and rectifying protocols deviations, reviewing for 
violations of inclusion/exclusion criteria, and ensuring the adherence to study-specific SOPs, 
GCP, and other federal and institutional regulations. Protocol monitoring will be performed on an 
ongoing basis through the following methods: 
1. Checklists will be utilized at all time points to ensure all data is collected per protocol and 
procedures are followed as appropriate. 
2. A Final Eligibility Checklist will be completed after the Intake Visit for all participants who 
enroll (i.e. sign consent) in the study. The Final Eligibility Checklist will serve as final 
confirmation of eligibility status prior to seeking approval for TN distribution from the Study 
Physician.  Additionally, a neuroimaging sub-study Final Eligibility Checklist will be 
completed in order to confirm sub-study eligibility for those participants who met initial sub-
study eligibility at Phone Screen and elected to participate in the sub-study at Intake. 
3. An internal chart review procedure will be completed for ~25% of randomly selected 
eligible subjects. The chart review procedure is a thorough review of all source 
documentation to ensure the integrity of the data, all study paperwork is present, all fields 
are completed per GCP, and all study-specific SOPs have been followed appropriately.  

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10.3.4 Database Auditing  
As outlined in section 9: Data Management, the study DMS will be equipped with internal 
validation checks to ensure data is entered within reasonable ranges. Error messages will be 
displayed in real-time if data appears inaccurate. Staff will have to respond to these error 
messages before data can be saved. In addition, The Study Coordinator (or senior personnel) 
will perform regular milestone quality assurance checks. 
10.3.5 Data Security 
As outlined in section 9: Data Management, study data will be secured through controlled user 
access and accessible to authorized personnel only.  Source documents will be secured in 
locked filing cabinets.  
10.4 Frequency of Data and Safety Monitoring  
Data will be reviewed internally on a regular basis. Specifically: 
 
1. At data capture, the research staff will review data for completeness and integrity. 
2. At data entry, the DMS will include multiple internal validity checks which will prompt the 
staff if an entry was made that is out of range or in an unacceptable format. 
3. Eligibility data will be reviewed in real-time at the Intake Visit. In addition, the Study 
Coordinator (or senior personnel) will review and verify that all data have been collected 
and, when applicable, meets the eligibility criteria on a “Final Eligibility Checklist.”  
4. Between the Intake Visit and TN distribution (Pre-Quit), the Study Physician will receive 
confirmation from the Study Coordinator (or senior personnel) that a participant has met 
all the eligibility criteria via email. Any additional eligibility queries will be addressed at 
this time as well. No TN will be distributed without documented approval of the Study 
Physician via email. 
5. On a regular basis, the project staff will review data through an internal chart review 
procedure supported by the DMS.  A random subset of eligible participants (~25%) will 
be reviewed. 
6. All CRFs for eligible subjects are 100% source-data verified through an internal data 
management system (Data Entry/Quality Assurance) on an ongoing basis.   
7. The study statistician will review data prior to analysis to ensure integrity and validity. 
 
10.5 Auditing and Inspecting 
The Principal Investigator will permit study-related monitoring, audits, and inspections by the 
EC/IRB, the sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data, etc.).  The Principal Investigator will ensure 
the capability for inspections of applicable study-related facilities. Participation as an investigator 
in this study implies acceptance of potential inspection by government regulatory authorities and 
applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 

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the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.   
11.1 Informed Consent 
A fully trained staff member will obtain informed consent using the combined consent and 
HIPAA form approved by the IRB (UPENN).  The consent process will take place prior to the 
initiation of any study procedures. If the PI deems it is safe for the participant and research 
staff, based upon federal and University COVID-19 guidance, then the consent process will 
occur in person at the CIRNA and will involve a discussion of the study requirements and 
procedures. The combined consent and HIPAA form will be read verbatim to participants. 
Participants will have an opportunity to ask any questions and/or express concerns. To limit the 
number of people at the research center and the duration of Intake visits for the safety of the 
research staff and participants, the combined consent and HIPAA form will be completed 
virtually via REDCap. Participants will be required to reach the entire consent in order to 
participate in the research study. Participants will have the opportunity to indicate if they have 
any questions and a trained research staff member will contact them to complete a consent 
discussion via the telephone. Their questions and answers will be recorded. Participants can 
elect not to participate and may withdraw at any time without penalty. Participants will receive a 
copy of the combined consent and HIPAA form for their records. In addition, participants will be 
given the Principal Investigator’s and Study Physician’s contact information (located on pg.1 of 
the consent) should they wish to speak to the Investigator or Study Physician during the course 
of the study regarding their consent or the study procedures.  The consent process will take 
place in English, there will be no waiting period, no coercion to participate, and all participants 
will be considered competent to provide informed consent (i.e., they will be asked if they 
understand what they are consenting for). The consent form must be signed and dated by the 
participant and the investigator-designated research professional obtaining the consent. The 
original signed combined consent and HIPAA form will be centrally stored in regulatory binders 
(consent). 
12 RESOURCES NECESSARY FOR HUMAN RESEARCH 
PROTECTION 
12.1 Research Staff  
The following research staff will be directly involved with the implementation and execution of 
the current study:   
• 
Janet Audrain-McGovern, Ph.D., Principal Investigator  
• 
Frank Leone, M.D., Study Physician 
• 
E. Paul Wileyto, Ph.D., Collaborating Investigator and Biostatistician 
• 
Rebecca Ashare, Ph.D., Collaborating Investigator 
• 
Kenneth Perkins, Ph.D., Collaborating Investigator (University of Pittsburgh) 
• 
James Loughead, Ph.D., Neuroimaging Sub-Study Collaborating Investigator 
• 
Kyle Bittinger, Ph.D., Microbiome Sub-Study Collaborating Investigator 
• 
Christopher Petucci, Ph.D., Microbiome Sub-Study Collaborating Investigator 
• 
John Detre, M.D., Radiologist 
• 
Susan Ware, Database Developer/Manager 
• 
Paul Sanborn, Research Staff   
• 
Alexa Mazur, Research Staff 
• 
Stephen Pianin, Research Staff  
• 
Wen Cao, Research Staff 
• 
Shannon Testa, Research Staff 

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• 
Jazmin Ricks, Research Staff 
• 
Kiera Zehner, Research Staff 
12.2 Study Facilities 
This project will be conducted at and through the CIRNA. The CIRNA has successfully 
conducted similar protocols and has well-developed procedures for staff training, data collection 
and storage, and study completion. The facilities available for this project include a large and 
small conference room, individual consulting rooms with computer/internet access, storage 
rooms, office space for study personnel, and data management facilities. In addition, CIRNA 
houses two freezers for sample storage.  A -80°C freezer is used for long-term sample storage, 
while a -30°C freezer is utilized for daily access of current sample boxes. These freezers 
contain temperature and power monitoring sensors which are connected to a Sensaphone 
alarm system that will contact specific biospecimen staff in the event of an emergency.  
 
If participants require referral for psychological services, information about such programs at 
3535 Market Street and/or the Philadelphia area will be provided; we have a form with specific 
information about such programs already in use in other CIRNA studies. 
 
The Center for Functional Neuroimaging (CfN) provides infrastructure support for functional 
neuroimaging and is comprised of investigators and staff with a broad range of experience 
including regulatory affairs pertaining to neuroimaging, MRI methods development, MRI physics 
and pulse programming, instrumentation, experimental design, computing and image analysis 
procedures. The center provides support for technical aspects of neuroimaging using MRI, 
including experimental design, data acquisition, and image analysis, and interfaces with several 
other complementary programs in brain, behavior and imaging. The CfN currently has a 
computing cluster of over 600 computing cores at 3.1 GHz on a 10GbE network linked to public 
terminals by a high speed network along with 100TB of RAID storage and tape backup. This 
cluster runs Matlab, IDL, AFNI, and a variety of customized software environments. The CfN is 
supported by an NINDS P30 Center Core. The CfN also manages access to neuroscience MRI 
scanning on research dedicated systems to be used in this trial: A 3 Tesla Siemens Trio whole-
body MRI system located in the Hospital of the University of Pennsylvania and a Siemens 
Prisma 3 Tesla whole-body MRI with a 64-channel head/neck array located in the basement of 
the Stellar Chance Building. 
13 Study Finances 
13.1 Funding Source – Parent (Main) Study 
This study is financed through a grant from the U.S. National Cancer Institute. 
13.2 Funding Source – Neuroimaging Sub-Study 
The neuroimaging sub-study is financed through a supplement grant from the U.S. National 
Cancer Institute. 
13.3 Funding Source – Microbiome Sub-Study 
The microbiome sub-study is financed through a supplement grant from the U.S. National 
Cancer Institute. 
13.4 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 

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reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study. All University of Pennsylvania investigators will follow the University 
conflict of interest policy. 
13.5 Subject Compensation 
Participants will be compensated in cash at each in-person visit they attend. When the 
neuroimaging sub-study is actively recruiting, participants enrolled in the sub-study may receive 
up to $730.00 including travel reimbursement for successfully completing all study requirements 
in their entirety as per the Study Compensation table (Table 3) below. When the microbiome 
sub-study is actively recruiting, participants enrolled in the sub-study may receive up to $590.00 
including travel reimbursement for successfully completing all study requirements in their 
entirety as per the Study Compensation table (Table 3) below. When neither the neuroimaging 
sub-study nor microbiome sub-study are recruiting, participants enrolled in the main study may 
receive up to $490.00 for successfully completing all study requirements in their entirety. No 
dietary recall compensation will be provided if a participant fails to complete any of the three 24-
hour dietary recalls at each of the five assigned time points. Compensation that is earned for 
completing the 24-hour dietary recall assessments will be distributed in-person or via check 
(mailed) at the participant’s discretion.  Participants can earn up to an additional $4.00 during 
the completion of the RRVF task (up to $1.00 per task attempt). Moreover, participants enrolled 
in the neuroimaging sub-study may receive up to an additional $4.00 based upon choices made 
while completing the in-scanner Food Reinforcement Task (up to $2.00 for each Scan Visit).  
 
Participants who are found ineligible for any reason during the Intake Visit or prior to entering 
the MRI scanner during Scan Visits (neuroimaging sub-study) will only receive travel 
reimbursement ($5.00). No study compensation will be distributed to participants who complete 
visit activities over the telephone. Participants will be asked to complete a W-9 tax form at the 
conclusion of the Intake Visit because the University of Pennsylvania is required to report to the 
Internal Revenue Service (IRS) any cumulative payments for participation in research studies at 
the University of Pennsylvania that exceed a total of $600.00 in a calendar year.  A W-9 will aid 
the Center in tracking and reporting those who participate in multiple projects at the Center and 
accrue over $600.00 in a calendar year. 

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Table 3. Study Compensation 
Study Time Point/ 
Activity 
Compensation Completion 
Bonus 
Travel 
Reimbursement 
Total 
Intake 
$20.00 
N/A 
$5.00 
$25.00 
fMRI Scan 11 
$90.00 
$5.00 
$95.00 
Baseline (Wk -2) Stool Sample 2 
$25.00 
 
 
$25.00 
Baseline 
$20.00 
 
$5.00 
$25.00 
24-Hour Dietary Recalls (3) 4 
$30.00 
 
N/A 
$30.00 
Pre-Quit 
$20.00 
$5.00 
$25.00 
Target Quit Day 
$20.00 
$5.00 
$25.00 
Mid-Treatment #1 
$20.00 
$5.00 
$25.00 
Mid-Treatment #2 
$20.00 
$5.00 
$25.00 
Mid-Treatment #3 (Wk 4) Stool Sample 2  
$25.00 
 
 
$25.00 
Mid-Treatment #3 
$20.00 
 
$5.00 
$25.00 
24-Hour Dietary Recalls (3) 4 
$30.00 
 
N/A 
$30.00 
Mid-Treatment #4 
$20.00 
$5.00  
$25.00 
fMRI Scan 2 1 
$90.00 
$50.00 5  
$5.00 
$145.00 
End of Treatment (Wk 8) Stool Sample 2 
$25.00 
$25.00 3 
N/A 
$50.00 
End of Treatment 
$35.00 
N/A 
$5.00 
$40.00 
24-Hour Dietary Recalls (3) 4 
$30.00 
 
N/A 
$30.00 
Follow-Up #1 
$45.00 
$5.00 
$50.00 
24-Hour Dietary Recalls (3) 4 
$30.00 
N/A 
$30.00 
Follow-Up #2 
$45.00 
$5.00 
$50.00 
24-Hour Dietary Recalls (3) 4 
$30.00 
N/A 
$30.00 
TOTALS 
Main + fMRI Sub-Study 
Up to $730 6, 7 
Main + Microbiome Sub-Study 
Up to $590 7 
Main Study 
Up to $490 7 
1 Only applicable to fMRI eligible participants who elect to participate in the neuroimaging sub-study (when actively accruing).  
2 Only applicable to participants who are both eligible and elect to participate in the microbiome sub-study (when actively accruing).  
3 Participants who return all three stool samples per study instructions are eligible to receive a $25.00 bonus. 
4 Participants must complete all three 24-hour dietary recall assessments to receive compensation ($30.00) at each assigned time 
point. 
5 Eligible participants who elect to participate in the neuroimaging sub-study (when actively accruing) and complete both fMRI scans 
will receive a fifty-dollar completion bonus distributed via check in the mail in addition to the $95 in cash received after completing 
Scan 2. 
6 Total does NOT include the in-scanner Food Reward Reinforcement/Choice Task (up to an additional $2.00 for each Scan Visit).  
7 Total does NOT include payment that may be earned during the RRVF task (up to an additional $4.00).  
14 References 
See the NCI parent, neuroimaging supplement, and microbiome supplement grant proposals for 
references.