Understanding the Role of Cognitive Dysfunction in the Treatment of Nicotine Dependence Among HIV-infected Smokers
Conditions: Smoking Cessation
Sponsor: University of Pennsylvania

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Application for Review of Human Research: IRB Protocol Summary 
Biomedical Research   
Section II 
 
Version 23: June 7, 2021 
IRB#: 824860 
 
 
Principal Investigator:  Rebecca Ashare, Ph.D. 
 
 
 
Co-Investigators & Study Physicians:  
Ian Frank, M.D. 
 
 
 
 
 
Frank Leone, M.D. 
 
 
 
 
 
Rajat Deo, M.D.  
 
Co-Investigators:  
Robert Schnoll, Ph.D. 
David Metzger, Ph.D. 
E. Paul Wileyto, Ph.D. 
 
 
 
 
 
 
 
 
 
 
PROTOCOL TITLE 
1.  Full Title 
Understanding the Role of Cognitive Dysfunction in the Treatment of Nicotine Dependence  
 
2.  Brief Title 
Cognition and Smoking Relapse  
 
BRIEF DESCRIPTION 
This study tests whether withdrawal-related cognitive deficits increase smoking relapse among HIV-infected (HIV+) vs. 
HIV-uninfected smokers (HIV-). Adult smokers (N=300; 150 HIV+, 150 HIV-) will complete 2 sessions to assess cognition 
(24h abstinence vs. smoking-as-usual; order counterbalanced; weeks 0-2). Subjects will then receive smoking cessation 
counseling and open label transdermal nicotine (weeks 3-12). Outcomes are: 1) cognition; and 2) abstinence rates at the 
end-of-treatment. 
 
STUDY SPONSORSHIP 
1.  Funding Sponsor 
National Institutes of Health 
 
2.  Primary Sponsor 
Rebecca Ashare, Ph.D. 
 
ClinicalTrials.gov IDENTIFIER 
NCT03169101 
 
PROTOCOL ABSTRACT 
Medical advances in the treatment of HIV/AIDS have improved the life expectancy of HIV-infected individuals. 
Unfortunately, HIV-infected individuals are three times more likely to use tobacco than those in the general population, 
but little is known about the mechanisms that underlie these high smoking rates. This will be the first study to test whether 
the neurocognitive impairments associated with HIV-1 infection may be exacerbated during nicotine withdrawal and 
increase the probability of smoking relapse among HIV-infected smokers (HIV+), compared to HIV-uninfected smokers 

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(HIV-). To this end, adult treatment-seeking smokers (N=300; 150 HIV+ and 150 HIV-) will complete this 12-week study, 
which is divided into two phases: a pre-quit laboratory phase (weeks 0-2) and a treatment phase (weeks 3-12). Subjects 
will complete two laboratory sessions during the pre-quit phase: once following 24 hours of mandatory smoking 
abstinence and once while smoking-as-usual (order counterbalanced). A comprehensive cognitive task battery assessing 
memory, attention, and executive function will be administered during each laboratory session. During the treatment 
phase, all subjects will receive standard smoking cessation treatment, including counseling (weeks 3-8) and open-label 
transdermal nicotine (TN) patches (weeks 4-12). The primary outcomes are: 1) cognitive performance following 24-hours 
smoking abstinence (vs. smoking-as-usual) during the pre-quit phase; and 2) 7-day point-prevalence, biochemically-
confirmed abstinence rates at the end-of-treatment (EOT) for the treatment phase. 
 
OBJECTIVES – Main Study 
1.  Overall Objectives 
Aim 1: To test whether HIV+ smokers experience greater abstinence-induced cognitive deficits versus HIV- smokers. 
Compared to HIV- smokers, HIV+ smokers will exhibit greater deficits in verbal and working memory during abstinence (vs. 
smoking-as-usual). 
Aim 2: To test whether HIV+ smokers have a lower probability of quitting following standard treatment compared to 
HIV- smokers. HIV+ smokers will have lower abstinence rates at EOT (vs. HIV- smokers). 
Aim 3: To test whether the association between HIV status and smoking relapse is mediated by abstinence effects on 
cognitive deficits. Abstinence-induced cognitive deficits will predict relapse at EOT and will account for (mediate) 
differences in abstinence rates between HIV+ and HIV- smokers.  
Exploratory Aim: We will evaluate multiple cognitive domains (e.g., verbal memory, executive function, and response 
inhibition) to explore whether these domains uniquely predict relapse in HIV+ smokers. We will also explore potential 
moderators (e.g., nicotine metabolite ratio [a biomarker for rate of nicotine metabolism], nicotine dependence). 
 
Rhythm Monitoring Sub-Study Aim(s) 
Sub-study Aim 1: To evaluate the burden of atrial fibrillation and other arrhythmias among HIV-infected smokers 
compared with smokers without HIV infection.     
Sub-study Aim 2: To assess the association between arrhythmia burden and neurocognitive performance and whether 
this relationship varies by HIV status. 
Sub-study Aim 3: To examine the relationship between arrhythmia burden and measures of depression and whether 
this relationship varies by HIV status. 
 
BACKGROUND – Main Study 
HAART and Increased Life Expectancy among HIV-Infected Individuals. The widespread use of highly active antiretroviral 
therapy (HAART) has greatly improved survival rates for those diagnosed with HIV/AIDS (Brugnaro et al., 2015; Deeken et 
al., 2012; Palella et al., 2006). Mortality rates among HIV-infected individuals have declined from 7 deaths per 100 person-
years in 1996 to 0.21 deaths per 100 person-years in 2010 (Palella et al., 2006). Despite this decrease in HIV-related 
mortality, rates of new HIV infections have remained constant, increasing the number of people living with HIV/AIDS four 
fold (2011; Hall et al., 2008; Palella et al., 1998). Although HAART enhances life expectancy and quality of life, HIV-infected 
individuals are increasingly vulnerable to non-AIDS-related diseases including cardiovascular disease and lung cancer 
(Palella et al., 2006; Rubinstein et al., 2014; Vaccher et al., 2014). Thus, addressing modifiable risk factors for disease 
mortality among HIV-infected individuals, including tobacco use, has become a critical priority (Nahvi and Cooperman, 
2009; Pacek and Cioe, 2015). 
Smoking Prevalence and Relapse Rates among HIV-Infected Individuals. The rate of smoking in the general population 
has decreased from >50% in 1965 to 18% today (Agaku et al., 2014). However, clinical populations of smokers, including 
individuals with cancer (Schnoll et al., 2003), cardiovascular disease (Rigotti et al., 2006), or major depression (Grant et 
al., 2004) continue to have elevated smoking rates. The persistence of smoking in certain groups of smokers, including 
HIV-infected individuals, may be partly due to the fact that they have been uniformly excluded from smoking cessation 
research (Nahvi and Cooperman, 2009; Niaura et al., 2000). Indeed, smoking rates among HIV-infected individuals are 50-
74% - about three times higher than in the general population (Burkhalter et al., 2005; Collins et al., 2001; Crothers et al., 
2005; Feldman et al., 2006; Webb et al., 2007). Importantly, despite the fact that the majority of HIV-infected smokers 

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report an interest in quitting smoking, evidence suggests that standard smoking cessation treatments have not been very 
effective (Pacek and Cioe, 2015). Even with transdermal nicotine (TN) – the most widely used over-the-counter treatment 
for nicotine dependence (Jonk et al., 2005; Pierce and Gilpin, 2002) – only 10-15% of HIV-infected smokers successfully 
quit smoking (Ferketich et al., 2013; Humfleet et al., 2013; Matthews et al., 2013) compared to 30% in the general 
population (Silagy et al., 2004). Thus, there is a clear need to identify mechanisms that underlie smoking behavior among 
HIV-infected individuals to guide development of population-specific smoking cessation treatments to help more HIV-
infected individuals quit smoking.  
Health Consequences of Smoking Specific to HIV-Infected Individuals. Recent epidemiological evidence suggests that 
HIV-infected smokers lose more life-years due to tobacco use than to HIV infection (Helleberg et al., 2013). Tobacco use 
increases the risk of developing cardiovascular and pulmonary diseases and cancer and can negate the beneficial effects 
of HAART among HIV-infected individuals (Feldman et al., 2006; Humfleet et al., 2009). Compared to HIV-infected non-
smokers, smokers on HAART are less likely to achieve a viral or immunologic response and have a greater chance of 
developing a viral or immunologic failure (Feldman et al., 2006; Marshall et al., 2009). The risk of developing non-AIDS-
defining cancers, including lung cancer, is two to three-fold higher among HIV-infected individuals compared to the 
general population (Brugnaro et al., 2015). Moreover, smoking among HIV-infected individuals can exacerbate HIV-related 
symptoms (e.g., respiratory problems, pulmonary pneumonia), worsen overall quality of life (Crothers et al., 2005; Cui et 
al., 2010; Turner et al., 2001; Webb et al., 2007), and increase the likelihood of death (Pines et al., 2011). Another 
consequence of smoking on HIV pathogenesis is that it can accelerate the incidence and progression of HIV-associated 
neurocognitive disorders (HANDs) (Purohit et al., 2013; Purohit et al., 2011).  
HIV-Associated Neurocognitive Disorders (HANDs) Impair Quality of Life. HANDs are classified into three 
categories: HIV-associated dementia (HAD), HIV-associated mild neurocognitive disorder (MND), and HIV-associated 
asymptomatic neurocognitive impairment (ANI) (Antinori et al., 2007; Robertson and Yosief, 2014). These deficits have 
been attributed to chronic neuroinflammation as a result of HIV-1 infection (Ballester et al., 2012; del Palacio et al., 2012) 
and the consequent neuronal damage and degradation via neurobiological mechanisms including neurotoxins that 
damage synaptic transmission of neurotransmitters [32,46]. Since the advent of HAART, the incidence of HAD – the most 
severe form of HAND – has substantially decreased from approximately 16% to more recent estimates of 5% (Heaton et 
al., 2010; Heaton et al., 2011). Nevertheless, milder forms of neurocognitive impairment persist, despite HAART. Indeed, 
39%-69% of HIV-infected individuals exhibit deficits in multiple cognitive domains including memory, attention, processing 
speed, verbal fluency, and executive function (Devlin et al., 2012; Heaton et al., 2011). Importantly, these mild cognitive 
deficits are associated with functional disabilities including unemployment, difficulty driving, and poor adherence to 
HAART (Doyle et al., 2013; Schouten et al., 2011; Thames et al., 2013).  
HIV-Associated Neurocognitive Disorders may be Exacerbated by Smoking. Abundant evidence suggests that, in 
the general population, chronic smoking increases the risk of neurocognitive dysfunction and increases levels of global 
cognitive impairment (Durazzo et al., 2012; Paul et al., 2006; Weiser et al., 2010). Similarly, HIV-infected smokers exhibit 
clinically significant deficits in learning, memory, and global cognitive function relative to HIV-infected non-smokers 
(Bryant et al., 2013; Durazzo et al., 2007). Although the mechanism by which smoking contributes to increased risk of 
HANDs is unknown, several theories have been proposed. For instance, in vitro evidence suggests that nicotine and HIV 
work together to alter synaptic plasticity and neuronal cells (Atluri et al., 2014). Chronic nicotine exposure may also 
compromise the integrity of the blood-brain barrier and increase the likelihood of exposure to HIV-infected monocytes 
and/or tobacco constituents, which, in turn, enhances the risk for neurodegeneration (Manda et al., 2010). Thus, in order 
to better understand why HIV-infected individuals have more difficulty quitting smoking, it will be essential to understand 
the relationship among HIV infection, smoking, and cognitive function. 
Smoking and Cognition: Deficits Produced during Abstinence and the Relationship to Relapse. The nicotine withdrawal 
syndrome is complex as the time course and nature of symptoms vary across smokers (Hughes, 2007b; Shiffman et al., 
2006). In addition to the physiological and psychological symptoms of nicotine withdrawal, cognitive impairment is 
common, reported by nearly 50% of smokers (Hughes, 2007c). These abstinence-induced cognitive impairments peak 
during the first few days after a quit attempt (Hendricks et al., 2006; Hughes, 2007c; Shiffman et al., 2006) and can be 
measured objectively in animals and humans. Data across species support the reversal of these effects following 
administration of nicotine or medications efficacious for smoking cessation (Davis et al., 2005; Patterson et al., 2009; 
Portugal and Gould, 2007). Interestingly, the domains of cognitive function impaired during abstinence are qualitatively 
similar to those observed in HANDs (Antinori et al., 2007; McArthur et al., 2010; Robertson and Yosief, 2014; Woods et 
al., 2004) and include attention (Myers et al., 2005), working memory (Jacobsen et al., 2005; Mendrek et al., 2006), and 
response inhibition (Ashare and Hawk, 2012; Harrison et al., 2009). The clinical relevance of abstinence-induced cognitive 
deficits is supported by the high prevalence in treatment seeking smokers (Covey et al., 2008; Hughes, 2007b; Rukstalis et 

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al., 2005) and the predictive validity for smoking relapse (Culhane et al., 2008; Krishnan-Sarin et al., 2007b; Patterson et 
al., 2010; Powell et al., 2004). Indeed, abstinence-induced cognitive impairment predicts relapse to smoking, perhaps in 
an effort to alleviate these symptoms and restore functioning to pre-cessation levels (Culhane et al., 2008; Kassel et al., 
2007; Krishnan-Sarin et al., 2007a; Patterson et al., 2010). Evidence supporting the importance of higher order cognitive 
control in maintaining goal-directed behavior (Hare et al., 2009; Kouneiher et al., 2009) may provide a theoretical 
framework for explaining why cognitive deficits may be associated with relapse. Indeed, cognitive deficits are gaining 
attention as a core dependence phenotype and a target for treatment development efforts (Ashare and Schmidt, 2014; 
Lerman et al., 2007; McClernon et al., 2015; Sofuoglu, 2010). Therefore, the neurocognitive impairments associated with 
HIV-1 infection and those observed during smoking abstinence may act synergistically to produce greater abstinence-
induced cognitive impairments among HIV-infected smokers compared to HIV-uninfected smokers, making quitting 
smoking particularly difficult for HIV-infected smokers. 
Cognitive Deficits may Underlie Smoking Persistence among HIV-Infected Individuals. Convergent evidence suggests that 
the combination of cognitive deficits associated with HIV-1 infection and cognitive deficits that occur during smoking 
abstinence may create a dual challenge for HIV-infected smokers during a quit attempt. Specifically, the cognitive deficits 
observed in HIV-infected individuals may be exacerbated during early nicotine withdrawal, relative to HIV-uninfected 
individuals (Aim 1). Indeed, smokers with comorbid disorders associated with deficits in cognition, such as depression and 
schizophrenia, may be more likely to experience abstinence-induced cognitive deficits (Ashare et al., 2014; George et al., 
2002; Sacco et al., 2005). We theorize that the presence of HANDs coupled with a further decrease in cognitive function 
during abstinence promotes persistence of smoking. We propose that, following standard treatment, HIV-infected 
smokers will have more difficulty maintaining abstinence compared to HIV- smokers (Aim 2) and this difference will be 
explained (mediated) by abstinence-induced cognitive deficits (Aim 3). It is also possible that HIV-infected smokers 
experience abstinence-induced deficits in specific cognitive domains that are not observed in HIV-uninfected smokers 
(Exploratory Aim). For example, HANDs is associated with deficits in verbal memory (Devlin et al., 2012; Heaton et al., 
2011), but verbal memory is not always impaired during smoking abstinence (Dawkins et al., 2007; Powell et al., 2002). 
Therefore, we will explore whether specific cognitive domains (e.g., verbal memory) are particularly important in 
explaining the relationship between HIV status and relapse, relative to other cognitive domains (e.g., executive function). 
The proposed study is uniquely positioned to identify a primary mechanism that may underlie smoking persistence among 
HIV-infected individuals with the goal of developing treatment approaches that target cognitive function. 
 
BACKGROUND - Rhythm Monitoring Sub-study  
People living with HIV (PLWH) are at a higher risk for developing cardiovascular disease including arrhythmic disorders 
such as atrial fibrillation (AF) (Hsu et al., 2013). Common HIV-related comorbidities are also associated with greater risk of 
AF including tobacco use (Heeringa et al., 2008) and hypertension. In pooled analyses of over 30,000 patients without a 
history of stroke, atrial fibrillation was associated with a 40% increased risk of cognitive impairment (Kalantarian et al., 
2013). Importantly, modifiable risk factors such as quitting smoking may reduce the incidence of AF (Chamberlain et al., 
2011). This sub-study aims to provide a better understanding of a) the burden of AF and other clinical arrhythmias such 
as sinus bradycardia, premature ventricular contractions, and non-sustained ventricular tachycardia in HIV-infected 
smokers compared with uninfected smokers and b) the impact of arrhythmia burden on cognitive and psychiatric 
measures in HIV infected individuals compared with uninfected persons.   
 
BACKGROUND – Recruitment & Retention Pilot Study 
Nearly one in three clinical trials closes prematurely due to under-enrollment. Reports of clinical trials consistently state 
that initial approaches to recruitment are rarely successful, take longer and are more costly than planned, and the pool of 
participants is overestimated. Unfortunately, many studies implement recruitment strategies without taking a systematic 
approach to identifying the most efficient and cost-effective approaches to enrolling subjects. With the increasing ubiquity 
of cell phones, text messaging (SMS) interventions have the potential to increase reach and reduce costs. In the United 
States, it is estimated that 85 to 91% of adults (18 and over) own a mobile phone, and these rates are observed across 
low- and high-income individuals. SMS interventions for improving adherence to antiretroviral treatment in people living 
with HIV as well as smoking cessation have demonstrated efficacy. However, few studies have explicitly examined 
strategies to optimize the use of SMS to enhance clinical trial enrollment. Behavioral economic strategies, including 

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information provision and incentives, may represent useful approaches to overcoming barriers to clinical research and 
ultimately advancing science. Information provision includes utilizing descriptive and injunctive norms, personalization, 
and reciprocity. Framing messages to shape social norms regarding research participation may increase engagement. For 
example, in addition to “personal medical benefit”, patients cite “contributing to research that could help other people” 
and “giving something back in return” as the most important reasons to participate in clinical research. Another common 
strategy for improving recruitment and retention is to offer incentives, including monetary payments or other rewards 
that target motivation. For instance, contingency management (CM), where tangible reinforcement is provided in close 
temporal proximity to a participant performing a target behavior (e.g., on-time attendance) is highly efficacious in 
engendering target behaviors. Although information provision and incentives are effective strategies for behavior change, 
they may target different aspects of motivation: intrinsic (i.e., the behavior itself is purposive) vs. extrinsic motivation (i.e., 
the prospect of gaining the incentive motivates the behavior), respectively. Although numerous studies comparing 
intrinsic vs extrinsic strategies to enhance motivation have yielded inconsistent results, a recent meta-analysis suggested 
intrinsic and extrinsic factors may act synergistically. Thus, we propose to employ information provision and incentive 
strategies independently and in combination to evaluate the optimal approach for recruiting and retaining subjects in 
clinical research studies. 
 
OBJECTIVES - Recruitment & Retention Pilot Study 
Aim 1: To evaluate the effects of information provision and incentives, alone and in combination, on study enrollment 
rates. 
Hypothesis: Behavioral economic interventions will (Information provision & contingency management) will produce higher 
rates of enrollment compared to standard recruitment. 
 
CHARACTERISTICS OF THE STUDY POPULATION 
1. Target Population 
Three hundred (150 HIV+ and 150 HIV-) adult male and female smokers 18 years of age or older who smoke at least 5 
cigarettes per day and are interested in quitting smoking will complete the study. HIV-infected smokers will have been 
diagnosed with HIV/AIDS (identified through the UPENN CFAR Clinical Core, UPHS PennChart reviews and community-
based HIV/AIDS organizations and events; see specific criteria below) and HIV-uninfected smokers will have no diagnosis 
of HIV, confirmed either via blood test (see recruitment strategy below) or self-report. Participants in the HIV+ and HIV- 
groups will be matched according to key demographic and smoking characteristics (see Accrual below). 
 
At PENN, a previous nicotine patch trial recruited a sample comprised of 45% women and 16% racial/ethnic minorities 
(Schnoll et al., 2010b). A separate PENN smoking cessation trial that used targeted efforts to recruit minority smokers had 
a sample comprised of 55% women and 52% racial/ethnic minorities (Schnoll et al., 2011). The UPENN CFAR Clinical Core 
population is 78% African American and 4% Hispanic American. 
 
2.  Accrual 
For this trial, we project that we will screen about 1200 smokers over 63 months (allowing six months to complete follow-
up). Based on our varenicline trial with HIV-infected smokers (IRB Protocol #815435) and the present inclusion/exclusion 
criteria, we expect about one-third of these smokers to be eligible for the trial (n = approximately 415). To be conservative, 
given the possible health problems evident in this population of smokers, we will project less than 25% of participants will 
withdraw from the trial and more than 75% of subjects will complete follow-ups to have 300 complete the study. As is 
advised in smoking cessation trials (Hughes et al., 2003), intent-to-treat will be used for primary analyses, with missing 
outcome data coded as smokers.  
 
Accrual - Cardio Monitoring Sub-study  
Eligible participants enrolled in the parent study will have the opportunity to participate in the cardio monitoring sub-
study.  We estimate that in order to achieve a sample of 50 smokers (25 HIV+ and 25 HIV-) with usable data, we will need 
to enroll 60 participants into the sub-study. Recruitment for the cardio monitoring sub-study ended as of March 2020.    

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3.  Key Inclusion Criteria 
Eligible subjects will be males and females: 
1. 18 years of age or older who self-report smoking at least 5 cigarettes (menthol and non-menthol) per day, on 
average. 
2. HIV status 
a) HIV-infected smokers: diagnosed with HIV infection and exhibiting viral load of less than or equal to 
1000 copies/mL and CD4+ counts of greater than or equal to 200 cells/mm3 within 12 months prior to 
enrollment. 
b) HIV-uninfected smokers: negative HIV status will be confirmed by an on-site rapid HIV blood test.   
3. Able to use transdermal nicotine (TN) safely, based on a medical evaluation. 
4. Residing in the geographic area for at least 4 months. 
5. Women of childbearing potential (based on medical history) must consent to use a medically accepted method 
of birth control (e.g., condoms and spermicide, oral contraceptive, Depo-Provera injection, contraceptive patch, 
tubal ligation) or abstain from sexual intercourse during the time they are in the study and using transdermal 
nicotine. 
6. If current or past diagnosis of bipolar disorder, eligible if:  
a. No psychotic features 
b. MADRS: total score less than 8 (past 4 weeks), suicidal item score less than 1 (past 4 weeks) 
c. Y-MRS: total score less than 8 (past 4 weeks), irritability, speech content, disruptive or aggressive behavior 
items score less than 3 (past 4 weeks) 
d. No psychiatric hospitalization or Emergency Room visits for psychiatric issues in the past 6 months  
e. No aggressive or violent acts or behavior in the past 6 months 
7. Able to communicate fluently in English. 
8. Capable of giving written informed consent, which includes compliance with the requirements and restrictions 
listed in the combined consent/HIPAA form. 
 
4.  Key Exclusion Criteria 
Subjects who present with and/or self-report the following criteria will not be eligible to participate in the study.   
Smoking Behavior 
1. Current enrollment or plans to enroll in another smoking cessation program in the next 4 months. 
2. Regular (daily) use of electronic cigarettes, chewing tobacco, snuff, snus, cigars, cigarillos, or pipes. 
3. Current use or plans to use nicotine substitutes (gum, patch, lozenge, e-cigarette) or smoking cessation treatments 
in the next 4 months. 
 
Alcohol/Drug Exclusion Criteria 
1. Current untreated and unstable diagnosis of substance dependence (eligible if past use and if receiving 
treatment and stable for at least 30 days). Current untreated and unstable diagnosis of substance abuse requires 
Study Physician approval. 
2. A positive urine drug screen for cocaine, methamphetamines, PCP, barbiturates, ecstasy (MDMA) at Intake (see 
Measures and Table 1 for details). At Lab 1 and Lab 2, positive urine drug screens will be reviewed on a case-by-
case basis. The PI will determine if the participant will be excluded or allowed to reschedule the visit, at which 
time they must provide a negative drug screen to continue with the study. Participants believed to have a false-
positive result on the drug screen may continue in the study, with investigator approval. 
 
Medication Exclusion Criteria 
Current use or recent discontinuation (within last 14 days) of the following medications:  
1. Other smoking cessation medications (e.g. Zyban, Wellbutrin, Wellbutrin SR, Chantix) 
a. Note: Once participants are found eligible for the study, they are instructed to only use the NRT provided 
to them by the study staff.  If a subject reports using a non-study smoking cessation medication (including 

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other forms of NRT), the study physician and PI will evaluate the situation and determine if it is safe for the 
subject to continue participation. 
2. Anti-psychotic medications (if used to treat psychotic symptoms. Other uses may be eligible pending physician 
approval). 
3. Daily use of opiate-containing medications for chronic pain (Duragesic/fentanyl patches, Percocet, Oxycontin). 
Smokers who report taking opiate-containing medications on an “as-needed” basis will be instructed to refrain 
from use until their study participation is over and that they will be tested to ensure they have complied with this 
requirement. 
4. Asthma medications/corticosteroids (require physician approval) 
5. Anti-depressants (require physician approval) 
 
Medical Exclusion Criteria 
1. Females who self-report current pregnancy, planning a pregnancy during the study, or currently 
breastfeeding/lactating. 
2. Current diagnosis of unstable and untreated major depression, as determined by self-report & MINI (eligible if 
stable for at least 30 days). 
3. Current or past diagnosis of psychotic disorder, as determined by self-report or MINI. 
4. History of heart disease, stroke or MI, unstable angina, or tachycardia (if stable, requires Study Physician 
approval). 
5. Uncontrolled hypertension (SBP greater than 160 or DBP greater than 100) present at Intake. 
a. Note: If a participant presents with blood pressure greater than 160/100 at sessions occurring on Week 3 
(Pre-Quit) or at any other point during the treatment period, they will not be provided with/able to 
continue on TN unless the study physician grants approval. 
6. Previous allergic reaction to TN. 
7. History of diabetes (requires Study Physician approval) 
8. History of seizures (requires Study Physician approval) 
9. History of stomach ulcers (requires Study Physician approval) 
 
Suicide History Exclusion Criteria 
1. Suicide risk as indicated by at least one of the following on the Columbia Suicide Severity Rating Scale (the PI 
&/or PM will be consulted to assess safety and determine eligibility in cases close to the eligibility cutoffs): 
a. Current suicidal ideation (within 30 days of enrollment) 
b. Two or more lifetime suicide attempts 
c.    Any suicide attempt within 2 years of enrollment 
        
General Exclusion Criteria 
1. Any medical condition or concomitant medication that could compromise subject safety or treatment, as 
determined by the Principal Investigator and/or Study Physician. 
2. Color blindness. 
3. Any impairment (physical and/or neurological) including visual or other impairment preventing cognitive task 
performance. 
4. Inability to provide informed consent or complete any of the study tasks as determined by the Principal 
Investigator and/or Study Physician. 
 
Rhythm Monitoring Sub-Study Exclusion Criteria. 
1. Skin sensitivity to monitoring devices (potential subjects will be screened prior to enrollment) 
 
 
 

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5.  Vulnerable Populations  
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study.  
 
6.  Populations vulnerable to undue influence or coercion 
Educationally or economically disadvantaged persons are included but not solely targeted for recruitment.  Cognitively 
impaired persons are not included in the current study.  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 study 
will be independent of the subject’s work or school activities.  
 
7.  Subject Recruitment  
Participants will be recruited from the Infectious Disease practices at the Hospital of the UPENN, Presbyterian Hospital, 
and Pennsylvania Hospital. Dr. Frank will oversee the integration of this study into the clinics, ensuring access to 
participants, collection of medical data (through UPHS PennChart medical record reviews and laboratory result requests), 
and access to private consulting rooms for screening at the CFAR clinics. These practices see over 500 patients monthly 
and more than 200 new patients each year.  
 
After obtaining the necessary training and clinic clearances to access PennChart for participating UPHS clinics, Research 
Assistants (RAs) will review the electronic medical records to identify potential subjects on a weekly basis (each site has 
patient smoking status indicated on the record). Individual medical records will be evaluated for eligibility based on the 
inclusion and exclusion criteria for this study. Daily clinic schedules will be ascertained and RAs will approach patients prior 
to or after consultation or treatment at the clinic. In addition to in-clinic recruitment, RAs will contact potentially eligible 
patients (after EMR review) by telephone based on their clinic provider’s specified research contact preference. Providers 
may choose one of the following contact options: 1) all patients identified as initially eligible may be contacted 2) all 
patient records identified as initially eligible will be sent to the provider via PennChart for review and approval prior to 
contact 3) all patient records identified as initially eligible may be sent to the provider, who assumes full responsibility and 
discretion regarding the research contact (no contact may be made by the research staff). Those patients deemed eligible 
for contact will be contacted by telephone. RAs will introduce the research study and the collaboration between the 
researchers, infectious disease clinic, and the patient’s provider. After assessing the patient’s interest, HIV status, and 
smoking status, the patient will then be provided with additional study information and an opportunity to assess his/her 
intake eligibility based on a screening questionnaire. 
 
If our accrual rate is lower than anticipated based on our feasibility data, Dr. Metzger and the CFAR CAB will use their 
connections, or we will attempt to make contact, with community-based organizations that provide services to people 
living with HIV and/or provide HIV testing services in the greater Delaware and Lehigh Valley regions to promote the trial 
and enhance accrual rates, through whichever means they use to carry out recruitment, including but not limited to 
social media, flyers etc. The CFAR CAB, comprised of people with HIV/AIDS or professionals in the treatment of 
substance use among those with HIV, has numerous linkages to community-based organizations that can be used to 
enhance participant recruitment should that be necessary. The Bradbury-Sullivan Center in Allentown, PA will also serve 
as a recruitment site, as well as visit site, to reduce the burden on subjects who live in that area. We will also advertise 
the study using poster, newspaper, and internet-based advertisements (this includes in-app advertising, Craigslist, and 
Twitter). Information about the study will be available on the CIRNA and iConnect websites. In addition, research staff 
will attend HIV/AIDS community events and community clinic intake hours to provide information about the study, 
distribute recruitment materials, and collect participant contact information via a secure, web-based data collection 
service. Additionally, we will place recruitment data requests with electronic research data warehouses such as Penn 
Data Store and Pennomics to obtain lists of pre-consented potential participants. ResearchMatch, a national health 
volunteer registry that was created by several academic institutions and supported by the U.S. National Institutes of 
Health as part of the Clinical Translational Science Award (CTSA) program, will also be utilized. ResearchMatch has a 
large population of volunteers who have consented to be contacted by researchers about health studies for which they 
may be eligible.  

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RAs and UPHS medical personnel will screen patients from UPENN and community-based HIV/AIDS clinics to identify 
potentially eligible and interested participants by phone or in person. Participants recruited through other methods will 
also be screened by phone or in person. Participants who are eligible and interested in the study will complete the Intake 
session tasks (Week 0) with research staff. The participant will review and sign an informed consent and HIPAA form, 
complete eligibility and baseline assessments, and be scheduled for a Week 1. The participant’s eligibility will be confirmed 
by Drs. Leone and Ashare. 
 
To ensure a high level of retention and adherence in this trial we will: 1) educate subjects about the benefits of protocol 
compliance; 2) schedule in-person sessions at convenient times (e.g., evenings); 3) use a TN adherence component in the 
counseling protocol (Gariti et al., 2009; Schnoll et al., 2008), and 4) as is standard practice in smoking cessation trials 
(Schnoll et al., 2010b; Niaura et al., 2005), provide modest financial compensation for session completion and 
transportation costs. 
 
Referral Bonus Program 
Participants who achieve their final booster session (Week 8) will be given the opportunity to receive a small bonus for 
referring others to the program. If the person who is referred completes the initial eligibility phone screen, regardless of 
outcome, the study participant will be awarded $20 per referral, for a maximum of 3 referrals ($60). This has been 
successfully implemented in IRB protocols #828125 and #824504. 
 
STUDY DESIGN 
1.  Phase 
n/a. 
 
2. Design 
Main Study. This study will use a prospective observational matched-design to test whether HIV+ smokers (vs. HIV- 
smokers) are more likely to experience cognitive deficits during nicotine withdrawal and whether these deficits are 
predictive of smoking relapse. As shown in Figure 1, adult treatment-seeking smokers (N=300; 150 HIV+ and 150 HIV-) 
will complete this 12-week study, which is divided into two phases: a pre-quit laboratory phase (weeks 0-2) and a 
treatment phase (weeks 3-12). Subjects will complete two laboratory sessions during the pre-quit phase: once following 
24 hours of mandatory smoking abstinence and once while smoking-as-usual (order counter-balanced; abstinence 
biochemically confirmed). A cognitive task battery assessing working memory, sustained attention, and response 
inhibition will be administered during each session. During the treatment phase, subjects will receive standard smoking 
cessation treatment, including six sessions of brief individual counseling (weeks 3-8) and eight weeks of open-label 
transdermal nicotine (TN) patch 
treatment (weeks 4-12) [34]. The 
primary outcomes will be: 1) cognitive 
performance (e.g., verbal and working 
memory) following 24-hours smoking 
abstinence (vs. smoking-as-usual) 
during the pre-quit phase, and 2) 7-day 
point-prevalence, biochemically 
confirmed abstinence rates at end-of-
treatment (EOT) for the treatment 
phase. Since randomization is not 
possible in this study, we will rely on 
inclusion criteria and matching to 
reduce the potential for confounding. 
More specifically, participants will be 
Figure 1. Study Time Points and Assessments 
Treatment Phase
Pre-Quit Lab Phase
Open label TN
Lab 1a
Study  Weeks
0b
8*
12
Follow-up 
Assessmentsc
EOT
* Counseling session
a Session order (24-h abstinent vs. smoking as usual) randomized between-subjects
7*
3*
4*
5*
6*
1
2
Cognitive Task 
Battery
Intake
Lab 2a
TQD
Smoking Rate, CO, 
Adherence, Counseling

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matched on age, race, education, and smoking rate.  
 
Rhythm Monitoring Sub-Study. This sub-study will explore differences in arrhythmia burden between HIV+ and HIV- 
smokers and will also look at the relationship between arrhythmic burden and cognitive function. Fifty smokers (25 HIV+ 
and 25 HIV-) will be asked to wear a non-invasive rhythm monitoring device for two 2-week periods during the course of 
the study: for two weeks prior to smoking cessation treatment (weeks 2-4) and then two weeks near the end of 
treatment (weeks 8-10). 
 
Recruitment & Retention Pilot. This pilot study will utilize a randomized controlled trial design to evaluate two 
components of behavioral economic strategies to improve recruitment and retention. To be eligible for the pilot study 
participants must meet all eligibility criteria for one of the four participating studies (828958, 824061, 824860, 828125), 
have a phone capable of receiving SMS messages, and consent to receive SMS messages. ~576 participants will be enrolled 
across the four participating research studies. All subjects will receive standard text messages and will be randomized to 
one of four groups (blocked within each study to ensure balanced groups): (1) Standard recruitment (SR): subjects will 
receive text messages ~2 days prior to their Intake visit with relevant information about the time, date, and location of 
the visit as well as contact information for study staff (“You have a study visit on [Date] at [Time]. Visit comp is $10. Reply 
Y to confirm. See http://j.mp/2222222 for reminders. Reply or appt may be canceled.”); (2) SR + Information Provision 
(IP): Subjects will receive personalized messages designed to target injunctive norms regarding participating in research 
(e.g., “[Name], wondering why you should volunteer for research? Many find it a rewarding way to advance science and 
be a part of a community http://j.mp/2222222.”); (3) SR + Contingency Management (CM): CM will be provided in the 
form of a randomization table with a high proportion of numbers that correspond to “chips” with little ($1) monetary 
value. Participants draw by choosing numbers between 1-500 upon completion of an objectively verified target behavior 
(e.g., attending an Intake visit), and bonuses are often provided for continued performance. A similar strategy has been 
successful in augmenting visit compliance in several treatment studies. All text reminders will be delivered using the Way 
2 Health (W2H) software platform. Upon completion of all requirements for a given visit, participants will receive 5 lottery 
“draws” for that visit. Attendance at all visits earns participants bonus draws upon completion of the study. Failure to 
attend a visit without prior approval or failure to complete all visit requirements results in no draws for that visit. The 
lottery contains 500 “chips” (numbers that correspond to monetary values within a table): 250 have a value of $0, 219 
have a value of $1, 30 have a value of $5, and 1 has a value of $100. The study completion bonus will be 5 extra draws. 
Thus, at each visit, subjects will have the opportunity to make 5 draws, for maximum possible earnings of $120; (4) SR + 
IP + CM (IC): In this group, subjects will receive the targeted text messages and receive CM. The design of our study allows 
us to examine each strategy independently as well as combined to evaluate the optimal approach. 
 
 
3. Study Duration  
Length of Subject’s Participation in Study 
Subjects will participate in study related activities for approximately 4 months from initial eligibility assessment in the 
clinic through follow-up. A subject’s length of participation may be affected by center or subject scheduling conflicts. 
Additionally, subjects may be contacted after study participation to clarify self-report data collected during their active 
participation, or for the collection of additional data or samples, if necessary, for data analysis. The Recruitment & 
Retention Pilot Study will conclude when all participants have completed the study. 
 
Projected date of completion of the proposed study  
We expect to complete accrual in approximately 63 months, with visit completion by June 2022. We expect to obtain our 
numbers in this timeframe by enrolling approximately 6 subjects per month. 
 
Duration - Rhythm Monitoring Sub-study 
Duration of enrollment in the cardio monitoring sub-study will be equivalent to the duration of the parent study 
(approximately 4 months).  However, participants will only be required to wear the monitoring device for four weeks total 
throughout the course of the study. Recruitment for the sub-study ended in March 2020. 

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DRUGS OR DEVICES 
Transdermal Nicotine 
Subjects will receive TN in accordance with FDA guidelines based on self-reported number of cigarettes per day. The patch 
will be Nicoderm CQ as used in our previous clinical trials (Lerman et al., 2004; Schnoll et al., 2010). Patches will be 
dispensed several times throughout study participation and subjects will be instructed to begin using the patches the 
morning of the TQD (Figure 1). Because wearing nicotine patches at night may cause sleep disturbance (i.e., vivid dreams) 
(Jorenby et al., 1995; Richmond et al., 1994; Staner et al., 2006)), subjects will be instructed that they may remove the 
patch before going to sleep.  
All patches will be purchased from a University of Pennsylvania approved vendor (GlaxoSmithKline). Upon receipt, an 
inventory will be performed, and a drug receipt log will be completed and signed by the person accepting the shipment. 
Study staff will count and verify that the shipment contains all the items noted in the shipment inventory. To ensure patch 
inventory is kept up to date, an on-going inventory will also be performed as patches are distributed. Patches will be stored 
in a double locked location (i.e., in a locked cabinet in a locked room) at room temperature. 
 
Non-invasive Rhythm Monitoring (Sub-study only) 
The device, developed by iRhythm Technologies Inc (San Francisco, CA), is a FDA-approved, compact (123 x 53 x 10.7 mm), 
lightweight (34 grams), and water-resistant, patch-based, lead wire-free, single-use ECG monitor that adheres to the left 
upper chest and provides 14 days of continuous beat-to-beat ECG data. The device has higher fidelity recordings and larger 
storage capabilities that can provide full disclosure ECG recordings beyond traditional 24-48 hour monitors (i.e., Holter). 
All rhythm monitoring devices will be purchased from iRhythm Technologies. At the end of the 2-week monitoring period, 
participants will return the device using a pre-labeled, prepaid mailer to the iRhythm Clinical Center (Lincolnshire, IL), 
which is an Independent Diagnostic Testing Facility where the data are analyzed. A digital signal-processing algorithm, 
which has been approved by the FDA for clinical use with oversight by Certified Cardiac Technicians, will characterize 
potential arrhythmias by detection of the heart rate, irregularity, and morphology. 
 
SUICIDAL IDEATION AND BEHAVIOR 
The C-SSRS will be administered in-person or remotely (phone call or videoconference) as part of the Intake tasks by a 
trained member of the staff. Individuals who endorse current (past month) suicidal ideation or two or more lifetime suicide 
attempts will be ineligible to participate. Any participant that reports a suicide attempt more than 2 years before 
enrollment will be evaluated by senior clinical staff (PM, Stephanie Josephson, LCSW, or Dr. Ashare) to assess final 
eligibility based on the complete psychological profile ascertained at the intake session. Because these assessments may 
cause an adverse emotional reaction, staff will be trained to deal with such reactions and to provide additional referrals if 
needed. If necessary, referrals to appropriate psychological services will be provided. 
 
STUDY PROCEDURES 
1. Procedures 
 
Initial Eligibility Screening. 
Recruited subjects will complete an initial eligibility assessment in the HIV/AIDS clinic or over the telephone. This 
assessment reduces the likelihood that participants attend an Intake Session only to learn that they are ineligible or to 
allow us to ascertain physician’s clearance should the participants have a medical condition that requires approval (e.g., 
mild hypertension). If a potential participant cannot be reached by phone, staff may send a text for the purposes of 
scheduling an initial eligibility screening phone call. This will help to reach potential participants who express interest in 
the study but do not answer phone calls from unrecognized numbers or do not regularly listen to voicemail messages. 
Texts will be sent from a central study account and not from the personal cellphones of any research staff. 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. Those participants who remain initially eligible will move forward with 
eligibility-determining tasks as part of the Intake session, which will be completed remotely and in-person. The Intake 

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session must occur within 60 days of the initial eligibility screening or the participant will have to be re-screened.  Subjects 
will be contacted via phone call, text message, e-mail and/or postal mail to remind them about their scheduled intake visit 
date and time. 
 
Visit Reminders. 
Participants will receive study visit reminders 24 – 48 hours prior to their scheduled study sessions by text via the W2H 
software platform. Participants who cannot receive text reminders or who do not agree to receive text reminders will still 
be able to participate and will receive reminders via phone call or email. 
 
Way to Health (W2H) is a software platform developed by the Penn Center for Health Incentives and Behavioral Economics 
(CHIBE), operated through a partnership between CHIBE and the Penn Medicine Center for Health Care Innovation and 
housed on Penn Medicine Academic Computing Services (PMACS) servers. W2H is an integrated, cloud-based platform 
that blends behavioral science with scalable digital technology to improve clinical outcomes. W2H automates many 
research functions necessary for conducting randomized controlled trials of healthy behavior interventions. 
 
Remote Study Participation. 
All study sessions can be conducted remotely with the exception of some Intake tasks, Lab 1 and Lab 2. We believe this 
will enable us to continue collection of data in a rigorous way while maintaining the safety of subjects. In the event that a 
participant is unable to attend an in-person visit, either due to personal reasons or office closure, procedures will be 
modified to allow for remote collection of data. The procedure for visit reminders will remain the same. Participants will 
be contacted via call or text to remind them of the time of their session, as well as to remind them that the session will be 
conducted by phone. Staff will call participants to complete all measures that can be completed by phone. If collected on-
site using session paperwork, these data will be stored in the participants’ charts and locked in secure filing cabinets, as is 
standard procedure. In the event that research staff are off-site, paperwork will be completed via RedCap. If RedCap is 
unavailable, they will utilize Pulse Secure to enable a secure, remote connection to their desktops and the secure server. 
Data collected remotely will be stored on our secure server, and later transcribed to paper measures and stored in 
participant charts or entered into RedCap. Items that are typically dispensed to participants at certain visits may be mailed 
to the participant, including a ClinCard for payment purposes, counseling binders and nicotine patches. If it is anticipated 
that a participant will have to begin the treatment phase of the study remotely (i.e. begin counseling and receive patches), 
the study physician will be consulted to ensure it is safe to proceed.  
 
Intake Session (Week 0): Consent, Eligibility Determination, Baseline Measures.  
Subjects who pass the pre-screening will be asked to complete tasks to determine their eligibility for the study. Tasks 1-6 
listed below may be completed remotely by phone or by videoconference using BlueJeans (HIPAA-compliant), to reduce 
the length of in-person tasks. If remote, measures will be administered using RedCap surveys. The tasks may take up to 3-
3.5-hours if completed entirely in-person. Subjects will be asked to: 
1. Complete the consenting process remotely (per procedure outlined in the Consent Process section) or in-person. 
Staff will review the consent form and answer all questions. Staff will then administer a comprehension 
questionnaire and review incorrect answers as needed. If completed remotely, subjects who are unable to provide 
an electronic signature may be mailed a physical version of the consent that must be mailed back to us prior to 
continuing with the Intake tasks. 
2. Complete mental status examinations (Mini International Neuropsychiatric Interview, and CSSRS and MADRS, 
YMRS, Bipolar Disorder Additional Screener, if necessary) with a trained research staff member. 
3. Complete the Shipley Institute of Living Scale. 
4. Complete a medical history and concomitant medication review and baseline measures to assess 1) background 
variables that may serve as covariates and will allow for the assessment of the study’s external validity (e.g., 
smoking history, demographics), 2) mediators (e.g., affect, craving), and 3) baseline smoking behavior. HIV 
uninfected participants will also complete a brief High Exposure Risk questionnaire.  

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5. Complete a COVID-19 experience survey. 
6. Cardio monitoring sub-study only: Complete additional cardiac medical history screening and health-behavior 
related measures.  
7. Provide urine specimens for drug and (if applicable) pregnancy tests. Participants who test positive for study 
prohibited drugs (see Exclusion Criteria above and Measures below) may be ineligible. Approximately 8mL of the 
urine sample provided will be stored for analysis of nicotine metabolites. If the sample collection/storage is 
unsuccessful, this may be attempted again at a later time point. 
8. Complete a carbon monoxide (CO) breath assessment to control for prior tobacco exposure.  The handheld device 
uses a disposable mouthpiece, reports CO in parts per million (ppm), and takes about 3 minutes. 
9. Complete a blood pressure assessment.  
10. HIV-negative only: Complete an on-site HIV test with a nurse trained to administer HIV testing and to do required 
reporting and counseling should a participant test positive for HIV. 
11. Provide one 10ml blood sample (2 teaspoons) to assess nicotine metabolite ratio (cotinine and 3-hydroxycotinine). 
12. Provide one 8ml blood sample (2 teaspoons) for examining biomarkers of neuroinflammation.     
 
HIV-positive participants will be asked to provide lab work to confirm recent viral load of less than or equal to 1000 
copies/mL and CD4+ counts of greater than or equal to 200 cells/mm3 within 12 months prior to enrollment. If a participant 
is unable to provide lab work, their clinic may be contacted to obtain the necessary documentation. 
 
If eligible at this point, subjects will schedule their first laboratory session (Week 1). 
 
Laboratory Session 1 (Week 1). This visit should occur within eight weeks of Intake. Allowances may be made for staff or 
subject scheduling conflicts. This in-person visit is expected to last 1-1.5 hours. During this visit, participants will: 
1. Provide urine specimens for drug and (if applicable) pregnancy tests (See Exclusion Criteria above and Measures 
below).   
2. Provide a CO sample. 
a. During the smoking session: To standardize smoking across participants, they will smoke a cigarette 
about 30-40 minutes prior to beginning the cognitive task battery, as in our past studies (Ashare and 
Hawk, 2012; Ashare et al., 2014; Ashare et al., 2013a; Tsaur et al., 2015) 
b. During the abstinent session: Participants must have CO readings less than 10ppm or less than 50% 
CO reading taken at Intake in order to be eligible for the study. 
3. Complete questionnaires (see Table 1. Study Measures). Measures may be completed remotely via RedCap to 
reduce the length of in-person tasks. 
4. MADRS, YMRS, Bipolar Disorder Additional Screener, if necessary. Screening measures may be completed 
remotely via RedCap to reduce the length of in-person tasks. 
5. Complete a 1-hour battery of computer tasks which may include tasks assessing working memory (n-back), 
executive function (Stroop task), response inhibition (stop-signal task), and delay discounting. 
 
Laboratory Session 2 (Week 2). Participants will complete the same activities they completed at Laboratory Session 1 in 
the alternate smoking condition. The following activities may also take place: 
1. Cardio monitoring sub-study only: participants may have the non-invasive rhythm monitoring device applied by 
trained research staff. Participants will be instructed to wear the device for two weeks after which time they will 
return the device using the study provided pre-paid envelope.  
2. Participants will be provided with an iCO monitor (carbon monoxide reader) and will be instructed on how to use 
it. They will be asked to use this device to measure and report their carbon monoxide levels for the counseling 
and follow-up sessions.  
a. The device connects to a smartphone or tablet and uses an app that they would download to display 
readings. If they are unable to use this device and report abstinence following the Pre-Quit session, they 

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may be asked to come to our center to complete the carbon monoxide assessment. We will use the 
recommended biochemically verified 7-day point prevalence abstinence variable which is defined as: (a) 
no self-reported smoking (not even a puff of a cigarette) for at least the 7 days prior to the assessment, 
and (b) biochemical verification of abstinence via breath CO (Hughes et al., 2003). 
b. This device is intended for single use as it cannot be sanitized. We will ask that participants not share the 
device with friends or family to reduce the risk of contamination. 
3. Participants may receive a binder containing all information necessary for their counseling sessions. If preferred, 
this paperwork may also be mailed or emailed to the participant. 
 
Behavioral Counseling (Week 3-Week 8).  
All subjects will receive manual-based counseling from a counselor trained and supervised by the PM or Dr. Ashare. The 
counseling protocol is based on PHS guidelines for smoking cessation treatment (Fiore et al., 2008), used in our studies 
with smokers with HIV (IRB Protocol #815435), cancer patients (Schnoll et al., 2010a), and the general population of 
smokers (Schnoll et al., 2010b; R01 DA025078). Counseling is included given its efficacy at helping smokers quit (Fiore et 
al., 2008) and to increase study retention. The counseling sessions are designed to enhance awareness of the harmful 
effects of smoking, assist the person in developing skills to quit and avoid relapse, and instruct the smoker on TN use. 
Counseling is provided to all participants until Week 8. Counseling will be provided by phone or videoconference primarily, 
and counselors are not blind to participant group status. Sessions can be arranged at convenient times for the participants, 
including evenings.  
 
Pre-Quit Session (Week 3): The counseling program begins at Week 3 with a 1-hour “pre-quit” counseling session to 
prepare for the target quit day. This session focuses on reviewing the participant’s history and experience with quitting as 
well as beliefs about smoking, quitting and perceived barriers to cessation. A quitting plan is initiated and involves 
identifying smoking triggers and strategies to increase the chance for success, including relying on social support to quit 
smoking and altering behaviors associated with smoking. TN will be mailed to the participant or dispensed prior to this 
session and the counselor will discuss the role of TN in withdrawal symptom management and provide directions on how 
to use TN.  
 
Target Quit Day Session (Week 4): Participants will receive a 30-minute “quit-day” session to review the initial quit 
attempt, identify potential reasons for relapse, and review a plan for avoiding tempting situations. Adherence to nicotine 
patch use recommendations will be emphasized. 
 
Relapse Prevention Sessions (Weeks 5-8): Participants will then receive 4 additional 20-minute booster sessions at Weeks 
5 through 8 which focus on either reinforcing success and reviewing the quit plan or reestablishing a quit date and 
restarting the cessation process. The counseling sessions are designed to enhance awareness of the harmful effects of 
smoking, assist the person in developing skills to quit and avoid relapse, and instruct the smoker on varenicline use. 
 
Cardio monitoring sub-study only: At Week 8 participants may have the non-invasive rhythm monitoring device applied 
by trained research staff. If necessary, they may be mailed the device and a staff member will contact them to walk through 
the application remotely. The application will be identical to the one at Lab session 2. Participants will be instructed to 
wear the device for two weeks after which time they will return the device using the study provided pre-paid envelope. 
 
All counseling sessions may be audio-taped and a random 15% of sessions will be assessed for protocol adherence.  
 
Transdermal Nicotine (Weeks 4-12). 
All participants will receive transdermal nicotine (TN) to aid in quitting smoking. TN is available over the counter and is 
very well tolerated. Participants will use “the patch” in a tapering fashion as recommended by the manufacturer. 
Participants who smoke 10 or more cigarettes per day will adhere to the following dosing guidelines: 21 mg for 4 weeks; 
14 mg for 2 weeks and 7 mg for 2 weeks. Participants who smoke between 5 and 9 cigarettes per day will follow a modified 

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dosing regimen: 14 mg for 6 weeks and 7 mg for 2 weeks. Participants who smoke between 1 and 4 cigarettes per day will 
also follow a modified dosing regimen: 7 mg for the full 8-week schedule. The 8-week regimen will commence the morning 
of the 2nd counseling session (week 4; TQD). Participants will be instructed not to smoke beginning that morning and apply 
a patch. Directions and rationale for use will be discussed during the pre-quit counseling session (week 3). Use is reviewed 
at every post-TQD session and TN will be distributed weekly. If a participant does not have enough patches to continue 
with their treatment schedule (e.g., used two patches in one day should one fall off), additional supplies of nicotine 
patches may be mailed or picked up by the participant, if appropriate. 
 
End of Treatment Follow-up Visit (Week 12).  
This visit may be used for biochemical verification of self-reported abstinence at EOT (week 12; Figure 1), the primary 
outcome measure for Aim 2. All participants will be asked to complete measures of smoking rate, CO (using iCO monitors 
if provided) and self-report questionnaires (see Measures).  
 
End of Recruitment and Retention Pilot Debriefing Call.  
After the participant has completed their final visit (due to completion, withdrawal or ineligibility), study staff will reach 
out to all participants enrolled in the recruitment and retention pilot to provide additional details about their participation 
in the pilot. 
 
Bradbury-Sullivan Center Visits 
HIV-positive participants recruited at the Bradbury-Sullivan Center who are unable to travel to our center in West 
Philadelphia without added burden, will have their in-person visits carried out at Bradbury-Sullivan to facilitate their 
participation in the study. The in-person portion of the Intake and Lab 1 visits will be combined to reduce the number of 
in-person visits. The Lab 2 visit will be carried out the following week. The Bradbury-Sullivan Center has guaranteed space 
to carry out proper sample collection and disposal for urine drug screens, as well as other visit tasks listed above, while 
maintaining a safe distance from subjects. Blood draws and storage of samples will not be carried out for visits conducted 
at Bradbury-Sullivan. The items that staff will carry to the center in a locked bag are listed below: 
1. Encrypted laptop 
2. Urine drug/pregnancy screens 
3. Blood pressure monitor 
4. Carbon monoxide monitoring device 
5. Subject chart 
 
Post-Study Follow-up 
If necessary, subjects may be contacted after study participation to clarify self-report data collected during their active 
study participation, or for the collection of additional data or samples. Although procedures are in place to ensure data 
accuracy during active participation, there are instances when it may be necessary to conduct a post-study follow-up to 
collect samples which would further support analysis and/or data accuracy when analyzing study outcomes. If study staff 
are unable to contact a subject for follow-up, no further action will be taken. 
 
COVID-19 Quitting Experience Survey 
Enrolled participants who completed their study participation (EOT visit) as of 3/30/2020 may be contacted to complete 
a survey, intended to capture their experience quitting smoking during the COVID-19 pandemic. These 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. For participants enrolled after June 8, 2020, this survey will be administered 
as part of the Intake tasks.  
 
Regardless of time point, participants will be asked to provide verbal consent for the recording of the survey before 
administration. If a participant does not consent to completing the survey or being recorded, the survey will not be 
administered. The survey will be recorded using staff recorders (typically used for recording counseling sessions). All 

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recordings will be stored on our secure server, and only staff will have access to those files. Recordings will be deleted 
once all data analysis is complete, approximately one year following the start of collection. Recordings will be used to 
ensure participant responses were captured exactly when the data is reviewed. Staff will complete the survey via RedCap 
(i.e. reading off questions and recording answers), and no other personal information will be collected. 
 
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 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. 
 
Side Effect Monitoring. 
The research team has a licensed, clinical social worker and physician to review initial eligibility and to monitor and address 
side effects during the trial. To reduce risk for adverse events, we will carefully assess eligibility to ensure that individuals 
with pre-existing conditions that can increase adverse event risk are excluded.  
 
We will also frequently assess participant treatment reactions with established symptom checklists. These assessments 
are conducted before and during the 8-week treatment phase by a research staff member. Blood pressure assessments 
will be completed at the Intake and Lab sessions to establish safety for the treatment phase. 
We will use an established coding and reporting system for side effects also used in our previous TN trials (Schnoll et al., 
2015; Schnoll et al., 2010). In this system, personnel are trained to administer side effects measures. If a side effect report 
or a score on an established scale indicates a safety concern, Drs. Ashare and Leone will be notified per the Safety 
Monitoring and Reporting Protocol and will assume responsibility for the determination of a course of action (e.g., 
continue to monitor, stop TN). Participants are given contact information so that, if an adverse event occurs, they can 
contact study staff 24-hours a day. These side effects are also coded and managed by Drs. Ashare and Leone. Serious 
adverse events are reported to the IRB, NIDA, and FDA in accordance with DSMP reporting procedures and participants 
may be referred to a PENN out-patient department or to the ER.  
 
Screening/Covariate Measures. 
 
Demographics and Smoking History. Standard questionnaires will be administered remotely or in-person at the Intake visit 
to collect the following data: demographics (age, gender, marital status, education), age at smoking initiation, cigarette 
brand, length of prior abstinence periods and current smoking rate. 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 (Heatherton et al., 1991).  The FTND scale has satisfactory internal consistency (Cronbach's alpha=. 
64) and high test-retest reliability (r=. 88) (Pomerleau et al., 1994). 
 
Urine Drug Screen. The urine drug screen will be administered at Intake, Lab session 1 and Lab session 2. The urine drug 
screen requires about 30ml of urine and indicates whether the subject has recently taken any of the following: cocaine, 
PCP, amphetamines, methamphetamines, tricyclic antidepressants, ecstasy, opiates, methadone, benzodiazepines, THC, 
and barbiturates. Participants with a positive urine drug screen for cocaine, methamphetamines, PCP, barbiturates, 
ecstasy (MDMA) may be deemed ineligible. The rationale for excluding these participants is because one of the primary 
outcomes in this study is cognitive function. Thus, excluding individuals who screen positive for substances that may 
interfere with their ability to perform the cognitive tasks (e.g., barbiturates may slow reaction times) reduces this potential 
source of variability. In an effort to remain CLIA-compliant, results from urine drug screening 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.  
 
Urine Pregnancy Test. At the Intake, Lab 1 and Lab 2 sessions, participants will be supplied with a simple, CLIA-waived 
urine pregnancy screen and informed that pregnant women are not advised to participate in this research study. 

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Participants 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. 
 
Blood Pressure 
At the Intake, participants presenting with elevated blood pressure (i.e., systolic blood pressure greater than 159 and/or 
diastolic blood pressure greater than 99) will have a second blood pressure reading taken after a ten-minute period in 
which the participants will be instructed to sit comfortably.  If, after the second reading, systolic blood pressure remains 
greater than 159 and/or diastolic remains greater than 99, the participant will be ineligible for the study. Participants may 
be invited back for another Intake at least 2 weeks after starting a physician approved blood pressure regimen. 
 
Blood pressure will also be measured at the Lab 1 and Lab 2 sessions. If participants present with elevated blood pressure 
(above 159 mmHg systolic and/or 99 mmHg diastolic) at any of these visits, the participant will not receive TN at the Pre-
Quit visit without approval from the SP or their physician’s written approval. 
 
Shipley Institute of Living Scale. All participants will complete the Shipley Institute of Living Scale (SILS) at the Intake visit, 
remotely via phone/videoconferencing or in-person. The SILS is a self-administered test designed to assess general 
intellectual functioning in adults and adolescents and to aid in identifying cognitive impairments (Zachary, 2000). 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).  A trained member of the study staff will score the test.  The SILS correlates with 
the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Estimated IQ Test. The SILS is considered a highly reliable 
assessment tool; with a good total score internal consistency (Cronbach’s alpha= .92). 
 
Medical History 
A medical history will be conducted remotely or in-person as part of the Intake Session to review for any contraindications 
listed previously. The medical history review will be completed by a research staff member. For the HIV-infected group, 
duration since HIV/AIDS diagnosis, mode of transmission, and viral load and CD4+ counts will also be assessed. Current 
medication usage will be tracked at each time-point. 
 
HAART Adherence  
For the HIV+ group only: HAART adherence will be assessed with a self-report measure and confirmed with a TLFB report 
at each session following Intake. 
 
Nicotine Metabolic Rate (3-HC/cotinine ratio/TNE).  
One baseline blood sample will be collected at Intake and analyzed for nicotine metabolites to determine rate of 
nicotine metabolism. Nicotine is metabolized to cotinine and then to 3-HC by the P450 (CYP) 2A6 enzyme (Nakajima et 
al., 1996). The 3-HC/cotinine ratio is a stable measure of the rate of nicotine metabolism, which influences response to 
nicotine dependence treatments (Lerman et al., 2006; Patterson, Schnoll et al., 2008). Evidence also suggests that HIV-
infected smokers metabolize nicotine faster than HIV-uninfected smokers (Earla et al., 2014). Therefore, the NMR will be 
evaluated as a potential moderator of abstinence-induced cognitive deficits and as a covariate in relapse analyses.  
Urinary concentrations of NIC and its nine metabolites will be analyzed using liquid chromatography tandem mass 
spectrometry, as described previously (T. Taghavi et al., submitted manuscript). Urine samples will be diluted and 
prepared using solid-phase extraction adapted from a previously established method (Miller et al., 2010). The limit of 
quantification was 1 ng/ml for all compounds. The primary outcome is Total nicotine equivalents (TNE), in nanomole per 
milligram creatinine, will be calculated as the molar sum of NIC and all nine metabolites (COT, 3HC, NIC-GLUC, COT-
GLUC, 3HC-GLUC, NNO, CNO, NNIC, and NCOT) and will be corrected using scaled creatinine data. Urinary creatinine 
concentrations will be determined using a colorimetric assay according to protocol provided in the Creatinine Assay Kit 
(MAK080) purchased from Sigma-Aldrich (St. Louis, MO) with a SynergyMX Analyzer (BioTek, Winooski, VT). The 

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biosamples of individuals who complete the Pre-Quit visit will be sent to the laboratory of Dr. Rachel Tyndale at the 
University of Toronto for analysis. These analyses will be exploratory. 
 
Neuroinflammation. 
The 8.5 mL blood sample collected at Intake will be used to explore the association of biomarkers of neuroinflammation 
(e.g., C-Reactive Protein; Brain-Derived Neurotrophic Factor; Interleukin-6) with smoking status and cognition. Whole 
blood will be collected in one SST tube and centrifuged at 3100 RPM for 10 minutes for serum extraction. If separation is 
not complete, the sample will be centrifuged at the same RPM for an additional 5 minutes. Four 0.5mL serum aliquots will 
be stored in 2 mL Eppendorf tubes and stored at -80°C until analysis. The serum samples will be assayed by the Laboratory 
Biomarkers, Quantitative Pharmacology, Neuroimaging, and Neurobehavioral Characterization Core at the Penn Mental 
Health AIDS Research Center.  
 
HIV Lab Assessment and HIV testing 
For the HIV- group only: a rapid test for HIV infection to confirm HIV status will be conducted on-site by an experienced 
staff member using a drop of blood obtained through a finger stick. The results of the rapid test take approximately 20 
minutes. If the rapid test appears to be reactive, a follow-up confirmatory test will be conducted using blood obtained 
through regular blood drawing procedure.  The results of this follow-up test will take 5-7 days. 
 
Viral Load Assessment 
A viral load assessment, conducted as part of routine clinical care at Intake and again any time between Week 8 and Week 
12, will be ascertained through medical record review and recorded (HIV+ group only). 
 
Psychological and Subjective Measures. 
 
Psychiatric History  
Current major depression, lifetime prevalence of psychosis, bipolar disorder, schizophrenia, hypomanic/manic episodes, 
and substance abuse will be determined via self-report during the phone screen and via semi-structured interview using 
the Mini International Neuropsychiatric Interview (MINI). The MINI is a 10-15 minute structured interview developed by 
the World Health Organization to assess major DSM-IV Axis 1 psychiatric diagnoses. This instrument permits both current 
(past 30 days) and lifetime assessments of psychiatric illness, and recent data support its reliability and validity (Sheehan 
et al., 1998). The MINI will be administered by a trained research staff member at the Intake visit, remotely via 
phone/videoconferencing or in-person. There will be 100% review of paper MINIs by the project manager, Stephanie 
Josephson, LCSW, with relevant training, to maintain quality control. In the event the PM is unable to review MINIs this 
will be completed by the Principal Investigator, Rebecca Ashare, Ph.D. 
 
Suicidal Behavior and Ideation (C-SSRS).  
All participants will complete the C-SSRS (Screening Version) with a trained staff member at the Intake Visit, remotely via 
phone/videoconferencing or in-person. The C-SSRS is a structured interview that assesses the suicidal behavior and 
suicidal ideation in subjects (Posner et al., 2009; Posner et al., 2011). Occurrence of lifetime suicidal behavior is defined 
as having answered “yes” to at least 1 of the 4 suicidal behavior sub-categories (actual attempt, interrupted attempt, 
aborted attempt, and preparatory acts or behavior). Current suicidal ideation is defined as having answered “yes” to at 
least 1 of the suicidal ideation sub-categories (wish to be dead, non-specific active suicidal thoughts, active suicidal 
ideation with any methods without intent to act, active suicidal ideation with some intent to act [without specific plan], 
and active suicidal ideation with specific plan and intent) over the past month. 
 
HIV High Exposure Risk Questionnaire  
HIV negative participants will complete a brief HIV High Exposure Risk Questionnaire that assesses for recent new exposure 
to the virus. This information will be important toward understanding risk factors relevant to our HIV uninfected 
population. If a participant is deemed by the questionnaire to be recently at high risk of recent exposure, trained staff may 
recommend the participant seek additional testing.   

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Depression and Anxiety  
The Hospital Depression and Anxiety Scale (HADS) (Zigmond and Snaith, 1983), a 14-item self-report measure, will assess 
depression and anxiety symptoms. This scale correlates with clinical ratings of depression and anxiety (Zigmond and 
Snaith, 1983) and is used with HIV-infected individuals (Savard et al., 1998). Because depressive symptoms are associated 
with deficits in cognitive function (Gotlib and Joormann, 2010) and lower HAART adherence (Wagner et al., 2011), the 
HADS will be evaluated as a potential moderator of abstinence effects on cognitive function and relapse. The HADS will 
be administered at each visit following the Intake, remotely or in-person. 
 
Bipolar Disorder Symptoms 
If a diagnosis of bipolar disorder is self-reported or revealed via the MINI at intake, the Montgomery-Asberg Depression 
Rating Scale (MADRS), Young Mania Rating Scale (YMRS), and a Bipolar Disorder Additional Screener will be completed at 
all study sessions to evaluate and monitor the presence and severity of bipolar disorder symptoms.  An abbreviated version 
of the MINI may also be used to assess and monitor symptoms. These assessments will be completed remotely, or in-
person. 
 
Functional Impairment.  
The Patient’s Assessment of Own Functioning Inventory (PAOFI) will be used to assess cognitive difficulties in everyday 
life. The PAOFI assesses areas such as mental acuity, employment, social functioning, shopping, cooking, housekeeping, 
laundry, driving, use of public transportation, maintaining schedules, medication management, financial management, 
understanding media events, and child care (Chelune et al., 1986). The degree of functional impairment is used to 
distinguish between categories of HANDs (Antinori et al., 2007). This measure will be used to evaluate whether those with 
baseline functional impairment, or functional impairment during nicotine withdrawal, have more difficulty maintaining 
abstinence. This measure will be administered remotely or in-person. 
 
Positive and Negative Affect.   
The Positive and Negative Affect Schedule (PANAS) (Watson  et al., 1988), a 20-item Likert-format self-report measure, 
will be used to assess Positive Affect (PA; 10 items, e.g., enthusiastic, strong) and Negative Affect (NA; 10 items, e.g., 
distressed, upset), two dominant and generally orthogonal dimensions of affect. PA and NA (PANAS) will be assessed at 
all study visits (except Intake; remotely or in-person). PA and NA will be assessed using a 24-h time reference for all visits 
following the Intake. 
 
Withdrawal Symptoms.  
The Minnesota Nicotine Withdrawal Scale - Revised version (MNWS-R) (Hughes, 2007d) captures the current state of 
nicotine withdrawal (Hughes, 2007a; Hughes and Hatsukami, 1986). The scale assesses eight DSM-IV items of nicotine 
withdrawal including: dysphoria or depressed mood, insomnia, irritability/frustration/anger, anxiety, decreased heart 
rate, difficulty concentrating, restlessness, and increased appetite/weight gain.  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. This will be administered at all study visits (except Intake; remotely or in-person). Withdrawal will be assessed 
using a 24-h time reference for all visits following the Intake.  
 
Craving.  
The 10-item brief QSU questionnaire on smoking urges (Cox et al., 2001) will be used to assess craving for cigarettes during 
the medication run-up period. The QSU-B contains 2 subscales (anticipation of reward, relief from negative affect).  Craving 
has also been related to long-term cessation outcome in many, but not all, clinical studies (Killen and Fortmann, 1997). 
This will be administered at all study visits (except Intake; remotely or in-person). Similar to withdrawal symptoms, craving 
will be assessed using a 24-h time reference at all visits following the Intake.  
 
Sleep Quality. 
The Pittsburgh Sleep Quality Index (PSQI) is a 9-item measure that assesses the quality and patterns of sleep over the past 
month. It measures seven areas: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep 

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disturbances, use of sleep medication, and daytime dysfunction. Scoring is based on a 0 to 3 scale, whereby 3 reflects the 
negative extreme. A sum of 5 or greater indicates a poor sleeper (Buysse et al., 1989). The PSQI has good internal 
consistency (Cronbach’s alpha=0.83), validity, and reliability, and is sensitive to treatment (Backhaus et al., 2002; King et 
al., 1997). The outcome is the global PSQI score. 
 
Social Support. 
Social support during a smoking cessation attempt will be assessed with the abbreviated Partner Interaction Questionnaire 
(PIQ; Cohen and Lichtenstein, 1990). This 20-item version of the PIQ asks participants to rate the degree to which they 
expect certain behaviors from their spouse/partner, friend, or relative. It assesses for both positive (e.g., helps you think 
of substitutes for smoking) and negative behaviors (expressed doubt about your ability to quit/stay quit). 
 
Alternative Reinforcers.  
A 45-item version of the Pleasant Events Schedule (PES) (MacPhillamy and Lewinsohn, 1982) will be used to measure 
traditionally rewarding activities that occur in a person’s natural environment (Audrain-McGovern et al., 2011). The cross-
product score of frequency (0=none to 2=often) and level of enjoyableness (0=none to 2=very) for each item provides a 
measure of activity reward. Participants are also asked whether they associate the activity with smoking or the urge to 
smoke. If the activity is associated with smoking, it is considered a complementary reinforcer. If the activity is not 
associated with smoking, it is considered a substitute reinforcer. The cross products of substitute reinforcers are summed 
to provide a score for substitute alternative reinforcers and those for complementary reinforcers are summed to provide 
a score for complementary alternative reinforcers. Scores have been associated with depression (Audrain-McGovern et 
al., 2011), discriminate between ex-smokers and current smokers, and predict smoking abstinence in cessation treatment 
(Audrain-McGovern et al., 2009; Goelz et al., 2014). 
 
Risks and Benefits of Quitting. 
The 40-item PRBQ (McKee et al., 2005) uses a 7-point Likert Scale (1=no chance, 7=certain to happen) to assess the 
likelihood of six potential risks and six potential benefits of quitting occurring if the participant were to stop smoking. The 
risk subscales were: 1) Weight Gain (I will gain weight.); 2) Negative Affect (I will be more irritable.); 3) Difficulty 
Concentrating (I will be less able to concentrate.); 4) Social Ostracism (I will feel uncomfortable around smokers.); 5) Loss 
of Enjoyment (I will miss the taste of cigarettes.); 6) Craving (I will desire a cigarette.). The benefits subscales were: 1) 
Health; 2) Well-being; 3) Self-esteem; 4) Financial; 5) Physical Appeal; and 6) Social Approval. 
 
Subjective Cognitive Complaints. The PROMIS (Patient-Reported Outcomes Measurement Information System) is a set of 
person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. The 
PROMIS Short Form v2.0 Cognitive Function Abilities Subset 8a will be used to assess subjective cognitive complaints. Each 
of the 8 items are scores from 1 (Not at all) to 5 (Very much). This measure has been validated in medical outpatient 
samples (Saffer et al., 2015) and among those living with HIV (Solorio et al., 2016). 
 
Treatment Measures.  
 
Concomitant Medication Review.   
Subjects will be asked about their use of medications (over the counter and prescription) and substances that may alter 
subjects’ response to the study medication. The Study Physician/Health Care Provider will advise as to whether other 
medications being taken are contraindicated and prescribe appropriate action from there (i.e., discontinuation of the 
study medication). The concomitant medication review will be completed at every study visit following the Intake. 
 
TN Adherence.  
We will assess self-reported use of patches and may collect unused patches (if applicable) when participants report to our 
center for study tasks. Any patch adherence that was not collected during the treatment period will be collected at the 
follow-up assessment at Week 12. 
 
 

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Side Effects.  
A checklist of side effects based on the product insert will be administered to participants at all study visits after the Intake. 
Checklists will be reviewed by staff following completion to confirm participant description of any experienced side effect 
matches the severity chosen, based on the severity classifications outlined on the form. The frequency and severity of 
common side effects of TN (Schnoll et al., 2015; Schnoll et al., 2010) will be rated on a 0 (none) to 3 (severe) scale. An 
open-ended side effects question will also be included. Furthermore, participants will receive written instructions to call the 
Health Care Provider/Study Physician should they experience any severe side effects or adverse events between study visits. 
There are no known HAART/TN interactions.  
 
Neurocognitive Outcomes 
Neuropsychological tests will be administered in a quiet laboratory testing room on a Dell® desktop computer running the 
most recent and compatible version of Windows® at the CIRNA. Unless otherwise noted, all tasks will be administered via 
E-Prime 2.0 (Psychology Software Tools, Inc.). The computerized battery is administered in a random order using clickable 
icons. Total administration time is about 30 minutes. The outcomes and associated tasks are: 
 
Executive Function. Two tasks will be used to assess executive function: a working memory N-Back task and the Stroop 
test. In the traditional N-back task, sequences of letters or numbers are displayed, and subjects respond with a button 
press to a single target using the following rules.  During the 1-back condition, subjects respond if the image is identical to 
the one preceding it.  In the 2-back condition, they respond if the stimulus is identical to the one two trials before.  In the 
3-back condition they respond if the image is identical to the one three trials before. The version of the N-back used in 
this study utilizes fractal images in place of letters or numbers. The active baseline condition (0-back) is a simple target 
detection task. The primary outcomes will be total correct and correct reaction time (task duration: about 18 minutes).   
 
The Stroop test will be used to assess executive function. In the Stroop test (Stroop, 1935), participants view a series of 
words on a computer monitor and using the keyboard, are asked to press the key associated with the color of the word 
rather than the word itself. Congruent trials are trials in which the word and color match (e.g., the word “green” appears 
in the color green). Incongruent trials are trials in which, the words are printed in colors that do not match the colors of 
the words (e.g., the word "red" might appear in green). The primary outcome is the interference score, which is the 
reaction time to incongruent trials minus the reaction time to congruent trials and measures the ability to suppress a 
habitual response in favor of an unusual one, accounting for overall speed of naming. Task duration is 5 min. 
Verbal Learning and Memory. The Hopkins Verbal Learning Test – Revised (HVLT-R) assesses verbal learning and memory 
(immediate recall, delayed recall, delayed recognition) (Brandt, 1991). The task has been validated in individuals 16 to 92 
years old and within brain-disordered populations (e.g., Alzheimer’s disease, amnestic disorders) as a measure of verbal 
learning and memory (Benedict et al., 1998). There are six alternate forms, each consisting of a list of 12 nouns (targets) 
with four words drawn from each of three semantic categories. The semantic categories differ across the six forms, but 
the forms are very similar in their psychometric properties. The HVLT-R has high test-retest reliability, and its construct, 
concurrent, and discriminant validity have been well-established (Shapiro et al., 1999). Raw scores are derived for Total 
Recall, Delayed Recall, Retention (% retained), and a Recognition Discrimination Index. Verbal memory has been shown 
to be a cognitive domain negatively affected by HIV infection (Antinori et al., 2007; Robertson and Yosief, 2014; Woods et 
al., 2004). There are two primary outcomes: Total Recall and Delayed Recall. Task duration is 5-10 min with a 25-min delay. 
 
Response Inhibition. The Stop Signal Task (SST) is a measure of response inhibition used in previous work with smokers 
and shown to be sensitive to abstinence (Ashare and Hawk, 2012; Tsaur et al., 2015). In this task, participants are 
instructed to respond to left and right-facing arrows on the computer screen. Following practice trials, participants 
complete three 64-trial task blocks with stop signals (an 800-Hz, 100-ms, 70-dB tone) presented on 25% of trials. The initial 
stop delay in each block is 250ms and adjusts ±50ms depending on whether the participant successfully inhibits (Logan et 
al., 1997). Trials consist of a 500-ms warning stimulus, a 1,000-ms go signal (left- and right-facing arrows), and 1,000-ms 
blank screen inter-trial interval. The primary outcome is stop signal reaction time (SSRT), calculated as the mean RT on go-
trials (MRT) minus mean stop delay (MSD). Task duration is 10 min. 
 

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Delay Discounting Task. In this paradigm, participants choose between a smaller reward available immediately (e.g., $500 
today) and a larger reward available after a longer delay (e.g., $1000 in a month). In this task, people differ in their degree 
of delay discounting, the extent to which they forgo larger monetary magnitudes in the future in order to obtain immediate 
rewards. As in previous work, the delayed reward will be fixed (e.g., $1000) and the magnitude of the immediate reward 
adjusts based on the subject’s responses (Du et al., 2002). Subjects will make 42 choices (6 trials for each of 7 delays: 1 
day, 1 week, 1 month, 3 months, 1 year, 5 years, and 25 years). The primary behavioral outcome will be the subject’s 
discount rate. Discount rates will be estimated by fitting a logistic regression that assumes a person’s decisions are a 
stochastic function of the difference in subjective value between the two options (Wileyto et al., 2004). Keeping with 
standard behavioral findings (Kable and Glimcher, 2007, 2010; Kirby and Santiesteban, 2003; Mazur, 1987), we will assume 
that subjective value (SV) is a hyperbolic function of the reward amount (A) and delay (D): SV = A/(1+kD), where k is the 
participant’s discount rate. Larger values of k indicate a greater degree of discounting future rewards. Participants will be 
told that the questions are hypothetical and that they should make their choices according to what they would choose if 
they were going to receive that amount. Task duration: approximately 5 minutes. 
 
Outcomes Variables.  
 
Abstinence (primary).  
Smoking status will be assessed using the reliable and valid timeline follow-back method (Brown et al., 1998) and by using 
CO breath samples to biochemically verify the self-report as in prior work (Lerman et al., 2004; Lerman et al., 2015; Schnoll 
et al., 2015; Schnoll et al., 2010). Participants will be considered to be abstinent if they self-report abstinence (not even a 
puff of a cigarette) for >7 days prior to each assessment beginning 1-week post-TQD (week 4) and provide or report a CO 
measurement of less than 5 ppm (Cropsey et al., 2014; Perkins et al., 2013). As per convention, participants are assumed 
to be smoking if they self-report smoking, cannot be reached to provide data at the time-point, fail to provide a breath 
sample at the time-point, or provide a breath sample at the time-point > 5 ppm (Cropsey et al., 2014; Perkins et al., 2013). 
The primary outcome will be 7-day point-prevalence abstinence at EOT.  
 
Other Smoking Measures (secondary).  
The total number of days abstinent during the first 7 days following the TQD, confirmed with CO, will be a secondary 
outcome measure. We have shown that this measure is highly predictive of long-term abstinence (Ashare et al., 2013b). 
Other secondary smoking outcomes include: prolonged abstinence to EOT (week 12) where relapse is 7 consecutive days 
of self-reported smoking, after a 2-week grace period; continuous abstinence at EOT (no smoking between the TQD and 
the follow-up; time to 7-day relapse (no grace period); and lapse (smoking episodes not lasting 7 days) and recovery 
(return to 24-hour abstinence) events (see (Schnoll et al., 2010)).  
 
Cessation/Smoking Rate: Daily smoking (presence and rate) will be assessed at each visit after the Intake Session 
with the well validated timeline follow-back method (TLFB).  These data can be used to assess the timing and rates 
of lapses (smoking episodes not lasting 7 days), recovery events (return to abstinence), and relapse events, as well 
as to monitor changes in smoking rates (i.e., # cigarettes/day). These data will also be used to compute and assess 
secondary measures of smoking cessation (e.g., continuous and prolonged abstinence). 
 
Carbon Monoxide (CO) Test: Carbon monoxide will be measured by staff at Intake and the Lab sessions. Following 
Lab session 2, subjects will be asked to self-report their CO levels using an iCO device (carbon monoxide reader) 
that will be provided to them at Lab session 2. The iCO smokerlyzer (CoVita, Santa Barbara, CA) is a personal breath 
smokerlyzer monitor for use with a smartphone or tablet. It works in conjunction with the Smokerlyzer app on iOS 
and android phones or tablets. The iCO device provides biofeedback from a simple breath test, and it also allows 
users to track their progress. The app also provides an exhalation guide to coach users on the proper technique 
to ensure accurate results. The device can be connected to the users’ phone through the headphone jack or via 
Bluetooth. Participants with iOS devices who require adapters will be provided with them by staff. Participants 
who do not have a smartphone or tablet, or are unable to use the device, will be asked to report to our center for 
a carbon monoxide assessment if they report abstinence. Since the iCO device cannot be sanitized and does not 
come with changeable mouthpieces, participants will be advised to limit use of the device to only themselves.  

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Rhythm Monitoring Sub-Study Measures. 
 
Cardiac Supplemental Medical History. 
A supplemental medical history will be conducted remotely or in-person as part of the Intake tasks, to review for sub-
study eligibility. The supplemental medical history will be completed by a research staff member and any indications will 
be reviewed by the study PI/study physician to determine eligibility for the cardio monitoring sub-study. 
 
Risk Assessment Battery (RAB).  
This is a self-report questionnaire designed to assess high-risk behaviors associated with HIV transmission. The measure 
yields two scores: Drug Risk Behavior (e.g. sharing needles, IV drug use) and Sex Risk Behavior (e.g., exchanging sex for 
drugs, unprotected sexual activity). 
 
The BASIS-24.   
The BASIS-24 is a 24 item self-report inventory designed to measure mental health status from the patient’s point of view. 
The items cover 6 domains including: depression/functioning, interpersonal relationships, psychotic symptoms, 
alcohol/drug use, and emotional lability. 
 
The SF-12.   
This measure is used to assess health-related psychosocial functioning. This well-validated, self-report tool measures 8 
health-related dimensions: physical functioning, bodily pain, role limitations due to physical health problems, role 
limitations due to personal or emotional problems, general mental health, social functioning, energy/fatigue, and general 
health perceptions. 
 
Quick Inventory of Depressive Symptomatology- Self Report (QIDS).  
The QIDS is a 16-item self-report measure designed to assess the severity of depressive symptoms using the criterion 
symptoms designated by the DSM-IV. 
 
Atrial Fibrillation (AF) Burden. 
AF burden based on non-invasive rhythm monitoring device data collected during two different study period (weeks 0-2 
and weeks 8-10). Determination of AF will be confirmed by technicians with no knowledge of the present study, and only 
episodes of definite AF lasting > 30 seconds will be included (Solomon et al., 2016). These findings will be reviewed by Dr. 
Deo, who will be blinded to other clinical characteristics. We will calculate the cumulative burden of AF as the percentage 
of analyzable wear time spent in AF. Total analyzable wear time will be calculated from the point of activation to the point 
of last recorded analyzable signal. This method will provide us an opportunity to compare uniformly across participants 
who may have different amount of device wear time. 
 
Recruitment & Retention Pilot Outcomes 
 
Meeting Eligibility Criteria. 
The primary outcome is the percentage of subjects who meet final eligibility criteria (i.e., enrollment). We chose this as 
the outcome based on our data suggesting that subjects who meet these criteria are highly likely to reach ITT status. 
 
Impressions of Research. 
Attitudes towards research; motivations for participation; perceived risks/benefits of research; personal financial 
wellbeing and perceptions of influence or coercion will be assessed via text survey at baseline (following phone screen), 
mid-way through participation and at study completion. Study staff will attempt to contact subjects who withdraw or 
are lost-to-follow up to identify reasons for withdrawal. We will assess overall satisfaction with the study, acceptability 
of the frequency and content of messages (IP and IC groups only). For all models, a term will be included for individual 
study as well as other relevant covariates (e.g., sex, age, income). 
 
 
 

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Table 1. Study Time Points and Measures 
Study Week  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
12 
 
Session  
Phone 
Screen 
Intake 
L1 
L2 
PQ 
TQD 
C1 
C2 
C3 
C4 
EOT 
Post-
Study 
TREATMENT 
TN 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Counselingd 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
SCREENING/COVARIATES  
Demographics/Smoking Hx/FTNDd 
 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen  
 
X 
X 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Screen 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Blood Pressure 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Shipley IQd 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical Historyd 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Reviewd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adherence to Anti-retrovirals*d  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Nicotine Metabolite Ratio (urine and plasma) 
 
X 
 
 
 
 
 
 
 
 
 
 
Neuroinflammation 
 
X 
 
 
 
 
 
 
 
 
 
 
Viral Load Assessment* 
 
X 
 
 
 
 
 
 
 
Xa 
 
 
HIV Lab Assessment/HIV Blood Test+ 
 
X 
 
 
 
 
 
 
 
 
 
 
Debriefing Phone Call 
 
 
 
 
 
 
 
 
 
 
 
X 
PSYCHOLOGICAL AND SUBJECTIVE MEASURES  
Psychiatric Hx (MINI)d 
 
X 
 
 
 
 
 
 
 
 
 
 
Suicidality (C-SSRS)d 
 
X 
 
 
 
 
 
 
 
 
 
 
Bipolar Disorder Symptoms (MADRS, YMRS, additional screener)b d 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
HIV High Exposure Risk Questionnaire+ d  
 
X 
 
 
 
 
 
 
 
 
 
 
Depression/Anxiety (HADS) d 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Functional Impairment (PAOFI) d 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Affect (PANAS) d 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Nicotine Withdrawal (MNWS-R) d 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Smoking Urges (QSU-B) d 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Sleep Quality (PSQI) d 
 
 
X 
X 
 
X 
 
 
 
 
X 
 
Social Support (PIQ) d 
 
X 
 
 
 
 
 
 
 
 
X 
 
Alternative Reinforcers (PES) d 
 
X 
 
 
 
 
 
 
 
 
X 
 
Perceived Risks and Benefits of Quitting (PRBQ) d 
 
X 
 
 
 
 
 
 
 
 
 
 
Subjective Cognitive Complaints d  
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
Impact of COVID-19 on Smoking Survey d 
 
X 
 
 
 
 
 
 
 
 
 
Xf 
TREATMENT MEASURES 
TN Adherence d  
 
 
 
 
 
 X 
X 
X 
X 
X 
X 
 
TN Side Effects (SEC) d 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
NEUROCOGNITIVE OUTCOMES   
Executive Function (N-back, Stroop) 
 
 
X 
X 
 
 
 
 
 
 
 
 
Verbal Learning & Memory (HVLT) 
 
 
X 
X 
 
 
 
 
 
 
 
 
Response Inhibition (Stop task) 
 
 
X 
X 
 
 
 
 
 
 
 
 
Delay Discounting Task 
 
 
X 
X 
 
 
 
 
 
 
 
 
SMOKING OUTCOMES   
Carbon Monoxide (CO)e  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Smoking Rate (TLFB) d 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
RHYTHM MONITORING SUB-STUDY ONLY 
Cardiac Supplemental Medical History d 
 
X 
 
 
 
 
 
 
 
 
 
 
Risk Assessment Battery d 
 
X 
 
 
 
 
 
 
 
 
 
 
BASIS-24 d 
 
X 
 
 
 
 
 
 
 
 
 
 
SF-12 d 
 
X 
 
 
 
 
 
 
 
 
 
 
Quick Inventory of Depression Symptomatology d 
 
X 
 
 
 
 
 
 
 
 
 
 

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Rhythm Monitoring Device Applicationc 
 
 
 
X 
 
 
 
 
 
X 
 
 
RECRTUITMENT PILOT OUTCOMES 
% Eligible at Intake 
 
X 
 
 
 
 
 
 
 
 
 
 
Attitudes Toward Research 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Compared Riskiness Scale d 
X 
X 
 
 
 
 
 
 
 
 
 
 
Perceived Coercion Scale d 
 
X 
 
 
 
 
 
 
 
 
 
 
Previous Experience with Research Studies 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior Persuasion Questions d 
 
X 
 
 
 
 
 
 
 
 
 
 
Personal Financial Well-Being 
X 
 
 
 
 
 
 
 
 
 
 
 
Note. L1 and L2 = laboratory session 1 and 2, respectively; PQ = Pre-Quit visit; TQD = Target Quit Date; EOT = End-of-Treatment; MINI = Mini International Neuropsychiatric Interview; C-SSRS = 
Columbia Suicide Severity Rating Scale; HVLT = Hopkins Verbal Learning Test 
* HIV-infected group only 
+ HIV negative group only 
a A viral load assessment, conducted as part of routine clinical care any time between Week 4 and Week 12, will be ascertained through medical record review or contact with health clinic and 
recorded. 
bOnly administered if a diagnosis of bipolar disorder is self-reported or revealed via MINI at intake 
cRhythm monitoring devices are worn for two weeks. The second device may be mailed to participants for self-application if an in-person visit is not necessary. 
dMeasures will primarily be completed remotely via phone or videoconference to limit the length of in-person visits (if applicable) 
eWeeks 3-12, participants will self-report using the iCO device. If unable to use the device, and abstinence is reported, participants may be asked to come to our center for CO verification. 
fOnly administered to participants who were enrolled and active on 3/16/2020 and completed their EOT (Week 12) on or after 3/30/2020. 
 
2.  Statistical Analysis 
 
Power Analysis and Sample Size.  
Our study is a longitudinal between-subject design that seeks to test the following hypotheses: 1) that HIV+ smokers 
experience larger abstinence-induced cognitive deficits than HIV- smokers (Aim 1); 2) have lower quit-rates than HIV- 
smokers following standard treatment (Aim 2); and 3) that the association between HIV status and relapse is mediated by 
abstinence-induced cognitive deficits (Aim 3). We have designed our study to achieve 80% power, testing at a global 
α=0.05 for each of the hypothesis families (Figure 1). Our sample size of 300 was determined primarily by Aim 2. Based on 
prior work, we expect a ~15% difference in abstinence rates between HIV+ and HIV- smokers (Ferketich et al., 2013; 
Humfleet et al., 2013; Matthews et al., 2013; Silagy et al., 2004). With 150 HIV+ vs. 150 HIV- smokers, we have 80% power 
to detect a difference of ~15 percentage points in point-prevalence abstinence (60% vs. 45%, 50% vs. 35%, 40% vs. 25%), 
using a z-test on log-odds with a type 1 error of 5%. For Aim 1, we will test the HIV status by abstinence condition (24-h 
abstinence vs. smoking-as-usual) interaction for 5 cognitive measures using a linear regression with one between- and 
one within-subjects factor. We will correct for 5 tests using α=0.01. We have 80% power to detect medium effect sizes 
(Cohen’s d=0.4). For Aim 3, we will test whether abstinence-induced cognitive deficits predict quit rates and, using SEM, 
test whether cognitive deficits mediate the effect of HIV status on quitting. The primary aim will be to test the overall 
fraction of the effect mediated, which will be tested at α=0.05, which gives 80% power to detect small to medium effects 
(d=0.32). For our exploratory aim, the component individual deficits will be treated as secondary and tested individually 
as part of an exploratory analysis, also with a 5% type 1 error. To characterize cognitive deficits in HIV+ smokers, 150 
subjects will give us an estimate for each measure with a 95% CI that is 0.32 standard deviations wide (Upper – Lower 
limits). We will estimate the within-subject correlation for these as repeated measures, with a 95% CI that is 0.32 wide 
(Upper – Lower) if r=0, 0.24 if r=0.5, and 0.14 if r=0.75. Power was calculated using PASS software, NCSS, Kaysville, UT. 
 
Recruitment & Retention Pilot: 
Power is provided for our primary aim. The analysis will compare the enrollment rates between the four intervention 
arms, and examine main and interaction effects. For SR arm, we expect a 28% of subjects who schedule an Intake will be 
eligible and enroll (based on existing data across the four studies). With the proposed sample of 576, we have >80% power 
(α=.05) to detect a difference between the SR arm and the IP and CM arms of 12%, corresponding to an OR of 1.75. For 
the interaction term, we have 80% power (α=.05) to detect a departure from additivity of the main effects corresponding 
to a ratio of odds ratios (ORR) of 5.5. 
Sensitivity Analysis 
Given the substantial changes required to study procedures due to the COVID-19 pandemic, we will conduct a sensitivity 
analysis to evaluate the impact of the transition to remote visits on study results. We will utilize a ‘clustering’ approach 

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and assess the impact of clustering by analyzing outcomes with and without taking clustering into account: comparing the 
analysis that ignores clustering (i.e. assumes that the data are independent) to a method that will account for clustering 
(Thabane et al., 2013). To account for clustering, we will include a variable to compare subjects who completed the trial 
pre-COVID (all in-person) to those who completed the trial post-COVID (mostly remote visits with some in-person tasks). 
 
Data Analysis. 
Dr. Wileyto will conduct analyses using Stata, SAS, or R-Language software. Preliminary analyses will determine whether 
data meet distributional assumptions, and use appropriate transformations where they do not. We will also determine 
whether subject characteristics (e.g., gender, nicotine dependence, depression, NMR) are associated with HIV status or 
outcomes using either cross-tabulation (chi-square), t-tests, or correlations. Variables showing potential to predict 
outcome (p=0.2) will be tested for entry as controlling variables. In the event of items missing at random on survey 
measures, missing items will be imputed prior to calculating final scores using conditional means, estimated with an 
iterated version of Buck’s method (Gleason and Staelin, 1975). Dropout and missed sessions present a more serious issue.  
The best way to deal with this more serious missing data is to avoid the problem in the first place by keeping subjects 
connected to the trial and motivated to complete measures. Our clinical trials have a record of >80% compliance and 
retention rates, thanks to our monitoring of participants and use of incentives to offset costs for travel. Primary analyses 
will include all subjects who went through the laboratory phase and began NRT treatment; we will assume those who 
provide incomplete smoking data are smoking. This assumption is the convention in smoking cessation research, but can 
attenuate the differences between study groups. We will, in addition, conduct analyses with other missing data 
assumptions, including a completers only analysis, to examine the sensitivity of the primary findings to our assumptions. 
Aim 1. We will analyze neurocognitive data with multiple linear regression using a GLM framework. The outcomes will be 
cognitive deficits measured as a change in response values (see Section D.4.d. for description) due to abstinence challenge 
(24-h abstinence vs. smoking-as-usual). The hypothesized interaction effect of HIV+ status by abstinence condition will be 
tested by including dichotomous predictors, and examining the corresponding z-score. Although the groups will be 
matched on key variables, we may also include a small number of covariates (e.g., nicotine dependence, Shipley IQ) that 
show potential to control for error, admitted to the model at p=0.1. In conjunction with Aim 1, we will be estimating 
cognitive measures for the HIV+ group, within-subject correlations, and deficits that arise from abstinence challenge. We 
will summarize point estimates and provide 95% confidence intervals. 
Aim 2. We will analyze point-prevalence quit rates using logistic regression. The hypothesized effect of HIV status (HIV+ 
vs. HIV-) will be tested by including a dichotomous term using the z-score. A small number of other potential controlling 
variables will be tested for inclusion (p=0.1). Outcomes of the logistic regression analyses will be characterized by odds 
ratios (e.g., odds of quitting smoking) and 95% confidence intervals. Point-prevalence quit rates at EOT are the primary 
outcome. Secondarily, we will conduct logistic regression analyses for other assessments of quit rates, including prolonged 
and continuous abstinence. 
Aim 3. Assuming that we find a significant effect of HIV+ status on abstinence at EOT, we will use a correlational and 
regression-based path model approach for examining mediation of HIV status effects (MacKinnon et al., 2007). Candidate 
mediators include five cognitive performance task measures (Neurocognitive Outcomes and Table 1), and will be 
represented as pre-post differences, continuously distributed and treated as normal. The effects of HIV status on 
candidate mediators, and of mediators on outcome will be assessed using a generalized path model (Stata GSEM), with 
the model reporting standardized coefficients. The path model partitions the effect of group on outcome into direct (and 
unexplained) effects versus mediated effects. We will then test the overall mediation hypothesis using the proportion of 
group effect explained [87, 88, 90] and the strength of each mediating pathway as follows. We will estimate the model for 
HIV status predicting abstinence without mediators, to estimate the direct effect of status in the unadjusted model (
†ˆβ ). 
We will then test whether HIV status predicts the candidate mediators, and in turn, test whether mediators predict 
abstinence in an adjusted group effect model, and estimate the effect of HIV status in the mediator adjusted model (
. 
Finally, we will calculate the proportion of HIV status effect explained, which is calculated as 
(
)
*
†
ˆ
ˆ
1
β
β
−
; the standard 
error for this quantity is calculated using the delta method, and the mediation hypothesis will be tested using a z-test. The 

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primary analysis tested at α=0.05 will be global mediation – when all candidate mediators are included in the model, a 
significant proportion of the HIV status effect will be explained. We will also conduct a secondary analysis using products 
of the coefficients along each mediating path using a delta-method based z-test. 
Exploratory Aim. Using the path model described above we will quantify the proportion of variance explained by each 
cognitive domain (e.g., executive function, verbal memory, and response inhibition) in the relationship between HIV status 
and abstinence rates. Since this test is exploratory, we do not have specific hypotheses about which domain will account 
for more variance and these analyses will be used for hypothesis generating for future work. 
 
Power Analysis, Sample Size and Data Analysis Rhythm Monitoring Sub-Study. 
Sample Size.  
Our study is a longitudinal between-subject design that seeks to test the following hypotheses: 1) that HIV+ smokers have 
higher AF burden than HIV- smokers (Aim 1); 2) AF burden will be associated with worse cognitive function (Aim 2) and 
more depressive symptoms (Aim 3); and 3) that the association between AF burden and cognition and depression will be 
strong among HIV-infected smokers. Our sample size of 50 participants was determined primarily by Aim 1. Because we 
are interested in AF burden (a continuous measure) rather than a diagnosis of AF, we have 80% power to detect a medium 
to large effect size (d=0.7), using a t-test with a type 1 error of 5%. For Aims 2 and 3, we have 80% power to detect a 
correlation of r=0.4 between AF burden and cognition and depressive symptoms, with α=0.01 to correct for multiple 
outcomes. The current pilot data will be used to derive effect size estimates to support a larger clinical study. 
Data Analysis. 
Descriptive statistics (mean, median, standard deviation, skewness, frequency, etc) will be provided for each outcome 
measure from the rhythm monitoring device and for the sample characteristics (age, sex). Log-transformation will be 
considered for continuous outcomes with skewed distributions. Multiple comparisons will be corrected and 5% type I 
error will be maintained to guard against the problem of false positives due to multiple testing.  
Aim 1 will use linear regression with AF burden as the primary outcome and HIV status as a between-subjects factor. Cross-
sectional associations between arrhythmia burden and cognitive function (Aim 2) and depression indices (Aim 3) at 
baseline will be assessed using multivariable linear regression with HIV status as a between-subjects factor. All models will 
include relevant covariates (e.g., smoking rate, age, sex). For our exploratory aim, longitudinal associations between 
arrhythmia burden and cognitive and psychiatric measures will be assessed using multivariable linear regression relating 
a) arrhythmia at baseline and b) changes in arrhythmia burden to changes in cognitive function/psychiatric measures. We 
will test the HIV status by time interaction and include a dichotomous variable for smoking status at end-of-treatment 
(abstinent vs. relapsed).  
 
3.  Confidentiality  
All subject information will be kept in a secure filing cabinet that is accessible only to authorized study personnel. All 
databases containing subject information will be password protected, and again, accessible only to authorized study 
personnel. Each subject will have a unique study ID number for all data collected. In all data sets we will use ID numbers, 
only. A separate data set linking names with ID numbers will be accessible only by the senior project staff.  All 
communications about subjects will use the ID number only and never include names or other personal information. All 
data will be stored until all analyses are completed. No data will be shared with any unauthorized party (i.e., aside from 
study personnel and regulatory officials). Any publication of data will not identify subjects by name or with an identifier 
that could be used to reveal identity. 
 
Data collected in MS Access and REDCap databases will be stored on a secure server administered by the Penn Medicine 
Academic Computing Services (PMACS) organization 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 will also be employed so a user has access only to the functions necessary to complete applicable operations 
appropriate for their role in the trial. Additional measures to prevent unauthorized external access to the database 

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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. Daily backups are 
performed to protect data against accidental destruction or corruption. 
 
Remote study sessions will be conducted via phone or via BlueJeans, which is a HIPAA-compliant platform with security 
features including a room lock to ensure that communications within the platform remain private. 
Data will be accessible the study Principal Investigator, Co-Investigators, the Study Physician, other study staff and the 
UPenn IRB and Office of Human Research. 
 
iRhythm Technologies Inc. will retrieve and process the stored ECG data from the rhythm monitoring device.  These data 
will be transmitted to study investigators at the University of Pennsylvania for analysis. The participant study identification 
number will be the only identifier utilized.  Participants will receive immediate notification of any serious arrhythmias 
discovered by the study staff and will be encouraged to follow up with their PCP.   
How will confidentiality of data be maintained?  Check all that apply. 
 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 sign statements agreeing to protect the security and 
confidentiality of identifiable information. 
 Whenever feasible, identifiers will be removed from study-related information.  
 A Certificate of Confidentiality will be obtained, because the research could place the subject at risk of criminal or civil liability or 
cause damage to the subject’s financial standing, employability, or liability. 
 A waiver of documentation of consent is being requested, because the only link between the subject and the study would be the 
consent document and the primary risk is a breach of confidentiality.  (This is not an option for FDA-regulated research.)  
 Precautions are in place to ensure the data is secure by using passwords and encryption, because the research involves web-based 
surveys.   
 Audio and/or video recordings will be transcribed and then destroyed to eliminate audible identification of subjects.  
 Other (specify): 
 
The PMACS will be the hub for the hardware and database infrastructure that will support the project and is where the 
W2H web portal is based. W2H uses a role-based access control (RBAC) approach to assure that participant confidentially 
and study integrity is preserved. The PMACS provides a secure computing environment for a large volume of highly 
sensitive data. 
 
4. Subject Privacy/Protected Health Information 
The following personal health information will be collected as part of this study: 
• 
Name, address, telephone number, email address 
• 
Date of birth 
• 
Social Security Number (W-9 form) 
• 
Some personal information that may be considered sensitive, such as medical history, psychological history, 
alcohol use history, etc.  
• 
Results from physical examinations, tests or procedures, including urine drug screening 
• 
Information on smoking, cognition, or HIV-related biomarkers from the urine and blood samples provided at the 
Intake Session  
• 
Medical Record Number 
• 
Results from HIV testing for individuals who must have their HIV status confirmed on-site 
• 
Results from cardio rhythm monitoring (if applicable) 
 

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Every possible precaution, as described above, will be taken to ensure that the privacy of subjects’ personal health 
information will be maintained. Potential participants will be contacted over the phone after responding to recruitment 
advertisements. Participants will undergo an initial phone screening where preliminary eligibility for the research study 
will be determined. Only if a participant is initially eligible, will they complete Intake tasks, remotely or in-person, to 
confirm eligibility. All in-person screenings and participant sessions will be conducted in private rooms with a trained 
member of the research staff. All data collected over the phone or in-person will be collected by research staff who have 
completed the CITI Protection of Human Subjects Research Training as well as HIPAA Compliance Training. Information 
will never be recorded with identifiers other than study ID. Results will not be communicated to other personnel or to the 
subjects. Data will be accessible to the Study Investigators, Study Physician, study staff, UPenn IRB, Office of Clinical 
Research, authorized UPenn staff (e.g. accounting and billing matters, provide treatment, etc.). 
 
Future Use of Data and/or Biospecimens. 
Participants will be given the option to let us store their biospecimens (blood and urine) and information for use in future 
research. This storage may be for an indefinite amount of time. The information and samples provided may be shared 
with other research institutions, e.g. The Abramson Cancer Center at Penn, or researchers working with the NIH who want 
to learn more about nicotine addiction and/or better ways to help people quit smoking. Whole genome sequencing will 
not be conducted on samples. We will protect participant confidentiality by first labeling their information and samples 
with an identification number only (not their name). We will restrict access to the databases that hold their personal 
information. Their samples will be stored in a locked, private bank, which only authorized personnel will have access to. 
Permission to store their information and samples for use in future research is optional and they will indicate their choice 
at the end of the consent form. Participants may withdraw their permission at any time by contacting study staff and 
letting us know they no longer want their information and samples to be stored for use in future research. Participant 
samples may be used to create products, including some that may be sold and/or make money for others. If this happens, 
there are no plans to tell the participant, or to pay them, or to give any compensation to them or their family. Additionally, 
we will not follow up with participants about the specific research that will be done, and individual research results 
obtained as part of future research will not be shared with them. 
 
5.  Tissue Specimens 
Blood.  
Two samples (one 10 mL and one 8 mL) of blood will be drawn at the Intake visit to evaluate the nicotine metabolite ratio 
and neuroinflammatory markers. All specimens are to be collected solely for research purposes. For participants who must 
have their HIV status confirmed on-site, a finger-prick rapid blood test will be completed at Intake visit. Participants who 
attend visits at the Bradbury-Sullivan Center will not undergo a blood draw, and will only be HIV-positive, therefore no 
rapid test will be conducted. 
 
Urine.   
A urine sample will be required at the Intake Session, Lab Session 1, and Lab Session 2 for drug screenings. Subjects who 
test positive for study prohibited drugs will be deemed ineligible. All female participants of child-bearing potential will 
complete urine pregnancy tests. Approximately 8mL of the urine collected for drug screen will be stored to evaluate 
nicotine metabolites, unless the visit is conducted at the Bradbury-Sullivan Center, where storage will not be possible. This 
will be for research purposes only. 
 
6. Genetic Testing 
N/A 
 
RISK/BENEFIT ASSESSMENT 
1.  Potential Study Risks 
A detailed description of the study will be given to all subjects, which will include the risks of participation, assurance of 
full confidentiality, and the knowledge that their freedom to refuse participation or withdraw from the project will not 

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affect the availability of treatment at the University of Pennsylvania. Informed consent procedures will comply with 
current standards of the IRB at the University of Pennsylvania. Subjects can choose, as an alternative, to not enroll in this 
study. Adverse reactions will be assessed and reported as required by Federal law and the regulations of PENN.  
 
Blood Draw.  Blood draws may result in bruising and/or slight bleeding at the needle site. This is rare and happens 
infrequently.  Occasionally, blood drawing results in a feeling of faintness. This too is rare. A trained professional will draw 
blood, so the chances of these discomforts are minimal. Procedures are in place to ensure that PHI is not linked with the 
results of this research.   
 
HIV Testing.  Rapid HIV blood testing may result in mild pain from the finger stick and feelings of anxiety about HIV status 
results.  Staff members administering HIV tests will be trained to provide counseling and recommendations for continued 
care to participants should they receive a positive result.    
 
Assessments. Subjects may experience emotional distress during 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 assessments and will be trained to deal with such reactions and to provide 
additional referrals if needed. In addition, if assessments indicate psychiatric concerns, referrals to appropriate 
psychological services will be provided. 
 
Transdermal Nicotine (TN) Replacement Therapy. All participants will receive transdermal nicotine (TN) patch therapy to 
aid in quitting smoking. This therapy is available over the counter and is very well tolerated. Nausea, vomiting, weakness, 
dizziness, and rapid heartbeat occur rarely and are most often caused by continuing to smoke while using the patch. In 
some cases, nicotine patch use may delay wound healing and may contribute to the risk of peptic ulcer formation. Some 
individuals who use the patch experience minor skin irritation, such as redness, rash, or minor swelling, and insomnia and 
dream abnormalities. Sleep problems are a primary mechanism of interest. Participants who experience insomnia and/or 
dream abnormalities may be instructed to remove the patch during the night while sleeping. Symptoms of an allergic 
reaction may include difficulty breathing or rash. All of these reactions cease once the patch is removed.  
 
During the pre-quit counseling visit (week 3), the counselor will review the purpose of using the nicotine patch (e.g., to 
help manage withdrawal symptoms; not a substitute for behavioral quitting strategies), provide directions on how to use 
the patch (e.g., abstinence from smoking, patch location, time, activity, and potential skin reactions), and answer any 
questions.  
 
Increased blood pressure and heart rate are possible side effects of TN patch therapy. Blood pressure will be closely 
monitored at the Intake and Lab sessions prior to the treatment phase. Expanding the upper limit of the blood pressure 
to less than 160/100 does not increase the risk to subjects enrolled in this trial. The risk of increased blood pressure is no 
greater than the risk from smoking and quitting smoking will lower an individual’s risk. Irregular or rapid heartbeat and 
palpitations will also be screened for at each visit in the treatment phase. 
 
Participants will complete a patch side effects checklist at each visit. Staff/the PI will review the checklists for serious and 
persistent side effects. These will be communicated immediately to the study physician. Participants will be instructed to 
promptly discontinue the patch and contact the SP/PI if they experience severe or persistent local skin reactions (e.g., 
severe redness, itching, or swelling) at the site of patch application or a generalized skin reaction (e.g., raised patches, 
hives, or generalized rash). Any serious adverse reactions or significant side effects of TN will be medically evaluated by 
the study physician. Patch use by such individuals will be monitored and adjusted as needed. Based on our previous 
experience with NRT studies (Lerman et al., 2004; Schnoll et al., 2010), we expect few serious adverse events. 
Nevertheless, the study physician will be available to assist with any adverse events and participant safety issues. 

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Depending on the nature of the side effects the study physician may reduce the dose of the patch or recommend that the 
participant discontinue the patch. 
 
Reproductive Risks. Because transdermal nicotine 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 nurse a baby. If the woman is of 
childbearing potential, she must use an adequate form of contraception or abstain from sexual intercourse for the 
duration of the study. If the woman is pregnant or breast feeding, she may not participate in this study, and if she becomes 
pregnant during the study, transdermal nicotine will be immediately discontinued and the subject will be permitted to 
continue with counseling and assessments only. Women will be asked to take a pregnancy test at the intake session, as 
well as laboratory sessions 1 and 2. 
 
Withdrawal Syndrome. Many individuals who quit smoking exhibit a pattern of symptoms related to withdrawal from 
tobacco use. These symptoms include sadness and anxiety, irritability, anger, difficulty concentrating, appetite change and 
weight gain, insomnia, and decreased heart rate. 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., their duration, methods for reducing them).  
 
Non-invasive Rhythm Monitoring Device Risks. Based on extensive clinical and research experience, there are very 
minimal risks of 14-day ECG monitoring using the rhythm monitoring device. Mild skin irritation from the device and 
feelings of anxiety engendered by the knowledge that their cardiac rhythm is being monitored are possible. Any 
arrhythmia that occurs during the wear period will be evaluated at the time the device is analyzed. As noted above, Dr. 
Deo will review all iRhythm reports including the rhythm tracings and, along with Dr. Ashare, will contact any participant 
with 1) wide QRS tachycardia > 120 beats per minute (bpm) and sustained for > 30 seconds, 2) complete heart block, 3) 
sinus pauses > 3 seconds, 4) bradycardia less than 40 bpm and sustained for > 30 seconds, 5) AF/atrial flutter with average 
heart rate less than 40 bpm or > 180 bpm and sustained for 60 seconds, 6) narrow QRS tachycardia > 180 bpm and 
sustained for 60 seconds. If clinically warranted, Dr. Deo will refer participants to the Penn Arrhythmia Center for more 
formalized clinical assessment. 
 
Potential Loss of Confidentiality: Every attempt will be made by the investigators to maintain all information collected in 
this study strictly confidential.  We will store subject information in a secure room with limited access. Only people working 
on this research project can access subject information. We will control access to the computer files that hold this 
information. This information will not be released to anyone. When the results of the study are published, no names or 
identifying information will be used. 
 
2.  Potential Study Benefits 
All participants who enroll in this study will receive behavioral counseling to aid them in their effort to quit smoking.  They 
may also benefit from the knowledge that they are contributing in an important way to potentially furthering scientific 
knowledge concerning ways to improve cessation treatment for smokers.   
 
3.  Alternatives to Participation 
As an alternative to enrolling in this study, participants may choose to continue to smoke or to seek assistance with quitting 
smoking through other treatment programs located in their area, including contacting the national quit-line. At any point 
in this trial, subjects may decide not to continue in their participation.   
 
 
4.  Data and Safety Monitoring 
Who will monitor this study?  Check all that apply. 
 Principal Investigator 
 Sponsor or contract research organization 

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 NCI sponsored cooperative group 
 Cancer Center (if mandated by CTSMRC) 
 Medical monitor 
 Safety monitoring committee 
 Data and safety monitoring board 
 
Data and Safety Monitoring will be conducted by the Principal Investigators and the Study Physician. They will review all 
possible Adverse Events (AEs) and Serious Adverse Events (SAEs). They will ensure that this information is captured in a 
comprehensive manner and reported according to Good Clinical Practice (GCP). The Principal Investigators, Study 
Physician, and the research staff will oversee and complete the monitoring process.  Monitoring will be performed on an 
ongoing basis in accordance with the University of Pennsylvania Sponsor-Investigator Standard Operating Procedure PM 
004. 
 
The Principal Investigators are responsible for: 
1. Obtaining IRB review and approval of a clinical investigation before the investigation is initiated and ensuring 
continuing review of the study by the IRB in accordance with 21 CFR Part 56; 
2. Obtaining informed consent in accordance with 21 CFR Part 50; and 
3. Assuring that all staff and subjects understand and accept the obligations incurred in undertaking this study 
in accordance with 21 CFR Parts 812, 813 and any other applicable regulations.  
The research staff is 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 
corrections are done according to GCPs. Any inconsistencies/deviations will be documented on the CRFs and such findings 
will be reviewed at the weekly study meetings. 
 
The Project Manager will oversee staff training. Training will include a review of the study protocol, informed consent, 
telephone screen, CRFs and the procedures that are in place regarding session check-in, data collection, data entry and 
quality control. All applicable regulations will be reviewed and the roles/responsibilities of each staff member will be 
explained. All questions will be answered and the training will be documented in a training log, which will be initialed by 
those involved. The Project Manager will also confirm all appropriate documentation of informed consent and storage of 
consents in a separate consent binder, and will maintain the study regulatory binder. 
 
The Project Manager, PI, and Study Physician will work together to confirm eligibility criteria. The PI/PM will review charts 
for each subject to confirm eligibility and will document this review by signing/initialing and dating the final eligibility 
checklist in each chart. 
 
The data managers will be responsible for creating all CRFs and ensuring that all data will be entered and stored in a 
manner consistent with the design of the approved CRFs. They will also be responsible for developing the data 
entry/quality control producers for this study. 
a. Enrollment will be complete when 300 subjects (150 HIV+ and 150 HIV-) complete all study requirements.  On average, 
6 subjects will be enrolled per month. During the course of the study, safety and data quality monitoring will be 
performed on an ongoing basis in accordance with the University of Pennsylvania Sponsor-Investigator Standard 
Operating Procedure PM 004 and any findings will be reviewed on a regular basis with the Investigators at the regular 
study meeting. The monitoring will include a regular assessment of the number and type of serious adverse events. 
The first monitoring day will occur no more than two weeks after the first subject is entered. 
4.2 Adverse Event Reporting and Monitoring 
Adverse Event (AE) 
An Adverse Event (AE) is a subcategory of the broader category of "Unanticipated Problems Posing Risk to Subject or 
Others." An adverse event is defined as: 

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• 
Any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease occurring at any 
stage of the study 
• 
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 
• 
May include an exacerbation of a pre-existing condition, intercurrent illness or injury, drug interaction, drug 
overdose, failure of expected action or significant worsening of the disease under study 
• 
An event that may compromise the rights, safety, or welfare of research subjects 
 
Any event that could be characterized by the definitions above is an AE whether or not considered related to the study 
or product. 
 
Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious.  A serious adverse event 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 will be regarded as non-serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is the period from the initiation of any study procedures 
to the end of the study treatment follow-up.  For this study, the study treatment follow-up is defined as 7 days following 
the last administration of study treatment. A compilation of any Adverse Events will be provided in the annual and final 
progress reports to NIDA.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition will be recorded as an 
adverse event if the frequency, intensity, or the character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting condition.  At the end of the study, any 
new clinically significant findings/abnormalities that meet the definition of an adverse event must also be recorded and 
documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigators until the events are resolved, the subject is lost to 
follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, a research team member will instruct 

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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 adverse event that results in hospitalization or prolonged hospitalization will be documented and reported as a serious 
adverse event unless specifically instructed otherwise in this protocol.  Any condition responsible for surgery should be 
documented as an adverse event if the condition meets the criteria for and adverse event.  
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 will 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. 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed 
in the definition above. These should also usually be considered serious.  Other kinds of events can be labeled “serious 
adverse events” at the discretion of the investigator.   
To ensure no confusion or misunderstanding of the difference between the terms "serious" and "severe," which are not 
synonymous, the following note of clarification is provided: The term "severe" is often used to describe the intensity 
(severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as "serious," which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.  
 
Severity Grading Scale for Adverse Events  
Many disease specific groups have developed toxicity grading scales. For example, most cancer clinical trials use the 
Common Terminology Criteria for Adverse Events (CTCAE) developed by the NCI. The CTCAE provides a descriptive 
terminology which is utilized for adverse event reporting. A grading (severity) scale is provided for each adverse event 
term (http://ctep.info.nih.gov). If no guidelines exist, then the following scale can be used:  
• Mild:  Noticeable to the subject, does not interfere with the subject’s daily activities, usually does not require 
additional therapy, dose reduction, or discontinuation of the study.  
• Moderate:  Interferes with the subject’s daily activities, possibly requires additional therapy, but does not require 
discontinuation of the study.   
• Severe:  Severely limits the subject’s daily activities and may require discontinuation of the study.   This would include 
all adverse events defined as “serious adverse events”.  
 
Attribution/Association with the Drug or Intervention:   
An assessment of the relationship between the adverse event and the drug/intervention will be made for each 
occurrence by the Principal Investigator.   
Adverse Event Attribution Categories:  
• Unrelated - The AE is clearly NOT related to the intervention  
• Possible - The AE may be related to the intervention  
• Probably - The AE is likely related to the intervention  
• Definitely - The AE is clearly related to the intervention 

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4.3 Recording of Adverse Events 
At each contact with the subject after the Intake, the study research assistant will seek information on adverse events by 
specific questioning using a side effect checklist and, as appropriate, by examination. Side effects will be monitored 
through a two-pronged approach. First, participants will complete a side effects checklist (SEC) at each study visit after 
the Intake reporting with a frame of reference since their last study visit. The SEC will assess the frequency and severity 
of common side-effects associated with TN. These items will be rated by participants on a 0 (none) to 3 (severe) scale, and 
can be summed to provide an overall side effects index.   
 
Second, trained staff will ask participants a non-structured, open-ended question (SEC Open-ended) at each study visit 
with a one-week frame of reference to assess if participants are experiencing any additional symptoms or medical 
concerns that may be related to their participation in the study. 
 
Research staff are trained to inquire (time of onset, nature of issue reported, possible relation to transdermal nicotine 
treatment, review of previously reported side effects or concerns, etc.) about any notable side effects or medical concern 
reported by participants. Based on published reports using the 21, 14, and 7 mg doses of TN we expect few side effects 
and we expect these side effects to be mild and transient in nature. Any severe (or a pattern of moderate) side effects or 
notable medical concern will be treated as adverse events, and reported to the Study Physician to determine the severity 
of the AE, the relationship of the event to the study drug and decide the course of action for the study subject.  This 
consult, including all relevant information, will be documented via email. The Study Physician is knowledgeable of side 
effects related to transdermal nicotine and is qualified to manage possible side effects. Mild side effects will not be 
reported as adverse events, but will be recorded and monitored by study staff. 
All adverse events occurring during each study period will be recorded. 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 the cause. 
Serious adverse events that are still ongoing at the end of the study period must be followed up to determine the final 
outcome. Any serious adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation will be recorded and reported immediately. 
4.4 Reporting of Serious Adverse Events and Unanticipated Problems 
The following information about adverse events will be reported:   
• 
Study Identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association between the event and study treatment 
•  Welfare of subjects. 
4.5 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: 

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• Any adverse event (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 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 
Related to the research procedures (An event is “related to the research procedures” if in the opinion of the 
principal investigator or sponsor, the event was more likely than not to be caused by the research 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 
Concerning deaths that occur during the course of a research study, the following describes the more rapid reporting 
requirement of the Penn IRB for specific situations: 
• Report the event within 24 hours when the death is unforeseen (unexpected) and indicates participants or others 
are at increased risk of harm. 
• Report the event within 72 hours, for all other deaths, regardless of whether the death is related to study 
participation. 
 
For reportable deaths, the initial submission to the Penn IRB may be made by contacting the IRB Director or Associate 
Director. The AE/Unanticipated Problem Form is required as a follow up to the initial submission. 
 
Reporting SAEs  
• Penn Subjects (including subjects at networks, affiliates or investigator-initiated sites);   
All on-site grade 3 or higher AEs or ADRs regardless of attribution or expectedness will be submitted to the IRB within 30 
days.  SAEs or SADRs for Penn subjects regardless of attribution or expectedness will be submitted to the IRB within 10 
days. Reports will continue to be sent to the IRB for 90 days following the last date the subject received study 
treatment/therapy or was exposed to an investigational device.  All unexpected deaths or deaths related to the study 
agent(s)/device(s) must be reported within 24 hours. All other deaths should be reported within 30 days.   
 
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:  
o An interim analysis indicates that participants have a lower rate of response to treatment than initially 
expected. 

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o Safety monitoring indicates that a particular side effect is more severe, or more frequent than initially 
expected. 
o A paper is published from another study that shows that an arm of your research study is of no therapeutic 
value. 
o Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a 
research protocol. 
o Breach of confidentiality 
o 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 in the study. 
- 
Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be resolved by 
the research team. 
- 
Exception: A one time, intentional action or process that departs from the IRB and CTSRMC approved study 
protocol, intended for one occurrence. If the action disrupts the study progress, such that the study design or 
outcome (endpoints) may be compromised, or the action compromises the safety and welfare of study subjects, 
advance documented IRB approval is required. 
- 
For exceptions on Industry or Cooperative group sponsored protocols, written approval must be obtained from 
the Sponsor prior to submitting your exception request to the IRB. 
- 
For in-house studies with a Medical Monitor or Safety Monitoring Committee (not DSMB), approval must be 
obtained from the Medical Monitor or Safety Monitoring Committee prior to submitting your exception request 
to the IRB. 
- 
Deviation: A one time, unintentional action or process that departs from the IRB approved study protocol, 
involving one incident and identified retrospectively, after the event occurred. If the impact on the protocol 
disrupts the study design, may affect the outcome (endpoints) or compromises the safety and welfare of the 
subjects, the deviation must be reported to the IRB within 10 business days. 
 
Data, Safety and Monitoring Report.  The PI will provide a summary of the DSM report on an annual basis as part of the 
progress report. The DSM report will include the expected versus actual recruitment rates, treatment retention rates, any 
quality assurance or regulatory issues that occurred during the past year, summary of AEs and SAEs, and any actions or 
changes with respect to the protocol.   
 
Evidence of Training in Human Subject Research.  All research personnel associated with this study have completed the 
CITI-Protection of Human Subjects Research Training as well as HIPAA Compliance Training. 
 
5. Management of Information for Multi-center Research where a Penn Investigator is the Lead Investigator of a multi- 
center study, or Penn is the lead site in a multi-site study.  
This is a single-site study. 
 
6.  Risk/Benefit Assessment 
There is minimal risk for serious adverse events. The treatments and procedures used in this study have been shown to 
be relatively safe. TN has also been studied in several clinical trials and shown to be safe and efficacious. Nevertheless, 
there are risks in participating in this trial, which are described above. However, the risks of participating in this trial are 
offset by the potential benefits for participants and society. 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 with HIV/AIDS. All smokers will receive behavioral counseling for smoking cessation 
and TN.  
 

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SUBJECT COMPENSATION 
Subjects will be compensated for their time up to $380 (Table 2). This includes transportation expenses related to their 
participation in the study, with $10 for each in-person visit. In place of $10/session to cover travel expenses, subjects 
may elect to use a round-trip car ride service (i.e., Lyft) which will be arranged and paid for in full by the research study. 
If they choose to use the ride service, they will not receive $10 for travel reimbursement. For visits following the Lab 
sessions, subjects may only be reimbursed for travel if they come to our center for carbon monoxide verification after 
reporting abstinence. Travel will not be reimbursed for sessions completed entirely by phone.  
 
The “task completion” compensation will depend on participant compliance (arriving on time for in-person sessions, 
demonstrating effort during cognitive testing etc.). If a participant does not follow study instructions, the task 
completion compensation may be withheld.  
 
The Greenphire ClinCard will be the primary form of payment for this study. The ClinCard is a reloadable, pre-paid card 
for the purposes of compensation. Compensation will be loaded onto the ClinCard within 24 hours of completed visits. 
Staff may ask participants to provide a Social Security Number, or complete a W-9 for this purpose, after determining 
eligibility so that a ClinCard can be assigned. Clincards may be mailed to subjects following the eligibility determination for 
the study.  
 
If a participant is ineligible at any point during the study (including after Intake tasks) due to any of the above-mentioned 
criteria, they will only be compensated $10 for travel, if that had been asked to come to the center and opted out of the 
ride service.  
 
Participants enrolled in the cardio monitoring sub-study will receive a $40 bonus once cardio monitoring devices have 
been successfully returned. This will be done via a prepaid envelope provided after application. Participants who 
successfully refer others to the program (i.e., person referred to program completes initial phone screen) will be 
awarded $20 per referral, for a maximum of 3 referrals.  
 
Upon completion of all requirements for a given visit, participants randomized to CM will receive 5 lottery “draws” for 
that visit. Attendance at all visits earns participants bonus draws upon completion of the study. Failure to attend a visit 
without prior approval or failure to complete all visit requirements results in no draws for that visit. The study 
completion bonus will be 5 extra draws. Thus, at each visit, subjects will have the opportunity to make 5 draws, for 
maximum possible earnings of $120 per visit (and a maximum of $145 at the final visit if participants have earned the 
additional 5 draws). 
 
Week 
Study Visit 
Visit 
Compensation 
Task 
Completion 
Travel5 
Bonus 
Total 
Lottery6 
0 
Intake 
$20  
-- 
$10  
 
$30  
5 draws 
1 
Lab 1 
$40  
$10 
$10  
 
$60  
5 draws 
2 
Lab 2 
$40  
$10 
$10  
 
$60  
5 draws 
3 
Pre-Quit Visit 
$20  
$10 
– 
 
$30  
5 draws 
4 
Clinic Visit (TQD) 
$20  
$10 
– 
 
$30  
5 draws 
5 
Clinic Visit 
$20  
$10 
– 
 
$30  
5 draws 
6 
Clinic Visit 
$20  
$10 
– 
 
$30  
5 draws 
7 
Clinic Visit 
$20  
$10 
– 
 
$30  
5 draws 
8 
Clinic Visit 
$20  
$10 
– 
 
$30  
5 draws 
12 
Follow-Up (EOT) 
$40  
$10 
–  
 
$50  
Up to 10 
draws 
 
 
 
Study Total: 
$380  
 
N/A 
Cardio Device Return 
 
 
 
$801,2,3 
$80 
 

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Total w/ Cardio Device 
Return 
$460 
 
N/A 
Referral Bonus 
 
 
 
$604 
$60 
 
 
 
 
 
Total w/ Referrals 
$440 
 
 
1Eligible participants who consent to cardio monitoring sub-study ONLY 
2Devices are returned via mail using a pre-paid envelope that has been provided; compensation is loaded to ClinCard when devices have been 
received by iRhythm 
3Table shows compensation for both successful cardio device returns 
4 Table shows compensation for three successful referrals 
5 Only paid if subject opts-out of the round-trip car ride service for in-person visits; will be paid if you are asked to come to our center to verify 
abstinence for clinic visits or follow-up. 
6 Participants may be given 5 “draws” for the chance to earn additional monetary incentives. As a bonus for completing the study, participants will 
get an additional 5 draws during their final visit. 
 
Traveling via the Ride Service 
Participants may elect to use “Roundtrip”, which is a car ride service that partners with Lyft to coordinate roundtrip rides to 
study appointments. Participants will be asked for their preference when scheduling the Intake session via phone, and at 
each session preceding an in-person session once enrolled. Study staff will schedule each ride using participants’ first name, 
last name, and phone number via Roundtrip’s HIPAA compliant platform. Participants will receive a reminder call 24-48 
hours prior to their visit to confirm their visit, interest in using the ride service, and preferred pickup/drop-off locations. If the 
study staff cannot reach participants by 5pm the day prior to their visit, their ride will be cancelled. Participants will still be 
permitted to attend the visit and will receive $10 to cover travel expenses. If participants need to cancel a previously 
confirmed ride, they must do so by contacting the study staff immediately, preferably by 5pm the day before their 
appointment. If participants fail to notify study staff within this timeframe, they may no longer be permitted to use the ride 
service at future study visits. 
 
INFORMED CONSENT 
1. Consent Process 
A fully trained study staff member will obtain informed consent using the combined consent and HIPAA form approved 
by the PENN IRB. This process will take place before study data are collected and prior to any treatment. The consenting 
process may occur remotely or in person as part of the Intake session. If completed remotely, subjects will be contacted 
via Blue Jeans (HIPAA-compliant) for a videoconference or by phone. Reviewing the consent form will be completed using 
a RedCap survey. Staff will email or text the survey link to subjects. Whether in person or remote, staff will review the 
study description, and all study procedures, potential risks, and information about the study medication will be addressed. 
Subjects will be given the opportunity to read the consent form in full. Following this, subject questions will be answered, 
and staff will administer comprehension questions to ensure subject understanding. Any incorrect answers will be 
addressed by the staff member completing consent. If remote, subjects will indicate within the RedCap survey if they wish 
to participate and will then be prompted to enter their First and Last name and sign the form using their finger or mouse. 
Subjects who are unable to provide an electronic signature may be mailed a physical version of the consent that must be 
mailed back to us prior to continuing with the Intake tasks. If needed, staff may also ask subjects to sign a physical version 
of the form at their first in-person visit for record keeping. Subjects will be able to download their signed version of the 
form from RedCap, and staff will also download a version to be saved to the electronic regulatory binder on our secure 
server, or, printed and placed in our physical binder. If in-person, subjects will receive a physical copy of the combined 
consent and HIPAA form for their records. Subjects will also be given the PI and Study Physician’s contact information 
should they wish to speak to either of them 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 subjects 
will be considered competent to provide informed consent (i.e., they will be asked if they understand what they are 
consenting for). 
 

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In collaboration with IRB Protocol #820043, participants who consent to participate in the cardio rhythm monitoring sub-
study will also be asked to complete the PMHARC Database and Specimen Repository consent form. This consent allows 
participants to grant permission for the storage of their data and/or samples, as well as allow future contact regarding 
new studies.  
 
2.  Waiver of Authorization 
Verbal consent will be attained from participants via phone for contact that occurs after their study participation has 
ended. This contact will only be made to collect data that they have already consented to provide as part of the study, 
and no additional PHI will be collected. Participants will have the option to not answer additional questions related to 
their participation in the study. If we are unable to get into contact with a participant, the data will be marked as missing. 
 
 
RESOURCES NECESSARY FOR HUMAN RESEARCH PROTECTION 
 
Training and Quality Assurance 
Given ongoing smoking cessation trials (R01 DA033681), systems for training and QA are established to ensure accurate 
eligibility screening and recruitment, accurate data collection, entry, and management, and optimal delivery of the study 
protocol. A new Manual of Operations (MOP) will be devised for this study, given unique procedures and measures. Dr. 
Metzger, who coordinates behavioral research within the PENN CFAR, will assist with staff training to ensure that unique 
issues related to the population are integrated into the MOP. Training sessions will occur over the first 3 months and 
annually. Monthly team meetings will review progress, assess adherence, and determine the need for protocol changes 
or additional training/QA. A study-specific Data and Safety Monitoring Committee will provide oversight. The MOP will 
ensure that the trial is conducted in a uniform manner over time and across staff. The MOP will describe roles and 
responsibilities for personnel and provide a detailed description of procedures for each point of contact with participants. 
For each visit/week, a checklist of events (e.g., measures, counseling) will be created that will be completed by study 
personnel. CRFs will be created for each measure at each week, and every participant will have a study binder, with 
sections for every visit/week. Every visit will be “milestoned” (e.g., attended, missed, scheduled) to ensure proper tracking 
of participants through the trial. A treatment manual for counseling is developed and will be provided to the counselors. 
The PM/Dr. Ashare will train the counselors using mock participants and didactic instruction. Lastly, a manual for data 
collection and entry is developed for the RAs and the PM/Dr. Ashare will train the RAs and provide supervision. Ms. Ware, 
who oversees this DMS, has already developed this DMS for use in other smoking cessation trials. All training will involve 
didactic instruction in the MOP and mock sessions for all assessments, counseling, and the DMS by the Project Manager 
and Dr. Ashare. QA focuses on protocol adherence and data validity. We conduct 100% QA checks on study data. This 
involves comparison of all hard copy CRFs to computer data. In addition, we may audio-tape all counseling sessions and 
assess protocol adherence by selecting a random 15% of sessions for review.  

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References 
 
(2011) World Health Organization. Global summary of the AIDS epidemic. . 
Agaku IT, King BA, Dube SR (2014) Current cigarette smoking among adults - United States, 2005-2012. MMWR 
Morbidity and mortality weekly report 63:29-34. 
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