Understanding the Real-World Impact of the Use of Three Alternate Nicotine-Delivery Products on Combustible Cigarette Use
Phase: PHASE2
Conditions: Nicotine Dependence
Sponsor: University of Wisconsin, Madison

 
 
 
 
 
 
 
 
 
 
 
Impact of Alternative Nicotine-Delivery Products on Combustible Cigarette Use 
NCT04084210 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI: Megan E. Piper, PhD 
Protocol Version 2/17/2021 
 
 
 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
Study Overview and Design 
This research will enroll 225 adult smokers in a mixed design study with a within-
subjects factor (active nicotine patch vs. placebo patch) and a between-subjects factor 
(alternative products: VLNCs, Juul e-cigs, or no product). Participants will be randomized to 
receive either 4 weeks of VLNCs, 4 weeks of Juul e-cigs, or no alternative product. After one 
week practicing with the alternative product, participants will complete the first of two 7-day 
switching trials during which they will be asked to refrain from smoking their own cigarettes and 
encouraged to use the alternative product to which they have been assigned (although the no 
alternative product group will not have any other products to use). See Figure 3. All participants 
will be given 8 patches (active nicotine or placebo, in counterbalanced order, with one extra in 
case of mishaps) to use during the Switch Week. After this first Switch Week, they will smoke 
normally for one week and then have their second Switch Week using the other type of patch 
(active or placebo; see Figure 3). We opted to use a 7-day switching phase and only repeat it 
once to minimize the attrition that was problematic in other studies with longer experimental 
phases (e.g., three 10-day switching phases produced 45% attrition in the non-step down VLNC 
group112). Participants will complete ecological momentary assessments (EMAs) on 
smartphones at prior to and during the 4 weeks of product use. EMA targets include own 
cigarette use, alternative product use, withdrawal symptoms, rewarding value of product use 
(e.g., taste, buzz), and environmental and affective context of any tobacco product use. We will 
then conduct a 3-month follow-up to assess own cigarette and e-cig use, risk perceptions, and 
future use intentions. This design addresses the six critical methodological issues for 
understanding the impact of alternative products outlined by Villanti et al.113: 1) rigorously 
assesses the key outcome (conventional cigarettes smoked); 2) assesses product use during 
switching; 3) uses appropriate control/comparison groups; 4) measures product exposure/use 
that precedes switching; 5) evaluates the dose and duration of the product exposure/use; and 6) 
has clear evaluation of the type and quality of the products used (e.g., satisfaction).  
This mixed design study (within-subjects Patch factor: active nicotine and placebo patch; 
between-subjects Product factor: VLNC, e-cigarette, or no alternative product) will allow us to 
address key questions identified in the RFA-OD-18-002. Specifically, we will assess the 
potential “impact of novel and/or potential modified risk tobacco products on tobacco behavior” 
and provide data that estimates the real-world impact of potential regulatory actions. To address 
these questions, this research will focus on the following aims: 
Primary Aim: Examine the ability of VLNCs and e-cigarettes to substitute for smokers’ 
usual cigarettes compared to each other and to no alternative product use in real-world settings 
(between-subjects effects) and whether these effects are influenced by active nicotine 
replacement (interaction with within-subject factor).  
Secondary Aims: Examine the main effects of VLNCs and e-cigarette use compared to 
each other and to no product use as well as their interaction with active vs. placebo patch on: 1) 
the use of study alternative products, and 2) mechanisms underlying product use (e.g., 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
withdrawal alleviation, taste, satisfaction). We will also explore the contexts that promote or 
inhibit switching from conventional cigarettes to alternative products and whether participants’ 
risk perceptions and key person factors (e.g., gender, race, education, psychiatric comorbidity) 
influence switching, alternative product use, and the potential mechanisms that drive such use 
behavior. 
Recruitment and Study Entry 
Participants from the greater Madison and Milwaukee, WI areas will be recruited via 
media recruitment methods (i.e., TV, newspaper, and earned media) that have recruited 
thousands of smokers86,87. We will also use Internet/paid Facebook advertisements that have 
been successful in our recent e-cig studies that recruited 422 smokers willing to provide EMA 
data during seven 2-week assessment periods over 2 years101 and 74 dual users willing to 
reduce combustible cigarette use and switch to using only e-cigs50. Specifically, we will place 
Facebook ads in the Madison and Milwaukee markets, with keywords likely to reach smokers in 
the general public. Facebook will charge us per click on the ad. We do not plan to target a 
specific subpopulation beyond smokers in general. Finally, we will use word of mouth referrals 
from participants. We believe it is feasible to recruit 225 smokers for this study within 18 
months. 
Interested individuals will be asked to call the study telephone number and leave their 
name and telephone number, or leave their name and contact information on our secure 
website link from the Facebook page, to be called for a phone screen. Potential participants who 
pass the phone screen will be invited to attend a study session at the UW-CTRI Madison or 
Milwaukee office, where they will learn more about the study, have eligibility confirmed, and 
provide written informed consent.  
Inclusion/Exclusion 
Eligibility criteria include: 1) ≥ 21 years old; 2) able to read and write English; 3) no plans 
to quit smoking in the next 30 days; 4) not currently taking smoking cessation medication; 5) 
willing and medically able to use nicotine patches, very low nicotine cigarettes, and e-cigarettes; 
6) not currently in treatment for psychosis or bipolar disorder; 7) smoking ≥ 5 cigarettes per day 
for the past 6 months; 8) exhaled carbon monoxide (CO) > 5 ppm; 9) no e-cig use within the last 
month; and 10) not currently pregnant or breastfeeding. We chose to exclude recent e-cig users 
to minimize the likelihood that participants would chose to use their own e-cig vs. the study e-
cig. We opted not to exclude ever e-cig users to enhance the external validity of these findings. 
Analyses will examine the influence of prior e-cig use. It should be noted that use of other 
tobacco products (e.g., cigars, chew, snus) will not be exclusionary to enhance the external 
validity of the findings, but we will track such use. Incarcerated individuals will not be enrolled in 
this study. If study staff members learn that a participant is incarcerated at a time point 
subsequent to enrollment, the participant will be withdrawn.   
Study Visits and Phone Contacts 
Interested smokers will complete a phone screen to determine initial eligibility. 
Potentially eligible smokers will attend an Orientation visit where they will receive a detailed 
description of the study and provide written informed consent. Participants will then provide a 
breath sample to verify eligibility (CO > 5 ppm). Eligible participants will then be invited to 
complete the visit and complete baseline assessments. Participants will also be trained to use 
the smartphone to complete daily assessments, using the training that was effective in our prior 
research, and will schedule future study visits (see Table 1). At Visit 1, participants will be 
randomized to receive VLNCs, e-cigs, or no alternative product and will be trained to use the 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
product [if applicable]. The study database will randomize participants, stratified by clinic, 
gender, and race [White vs. Non-White], to enhance scientific rigor and reproducibility. 
Participants will use their alternative products as they would like for one week to become 
comfortable with the product114. Participants will also provide a urine sample for cotinine 
assessment and be given eight study patches to use during Switch Week 1 when all participants 
will be asked to abstain from using their own cigarettes for the week. At Visit 2, all participants 
will complete assessments, provide a breath sample for CO assessment and a urine sample for 
cotinine assessment, receive feedback on their compliance with the smartphone assessments. 
All participants will then attend a mid-Switch Week visit (Visit 3) and an end-of-Switch Week visit 
(Visit 4) to assess biomarkers (a breath sample for CO assessment and a urine sample for 
cotinine). At Visit 4, the end of Switch Week 1, all participants will be told that they can smoke 
as usual for a week. In addition, all participants will be given the other type of patch (active or 
placebo) and asked to use these patches at the start of Switch Week 2 (Visit 5) when they are 
asked to abstain from smoking their own cigarettes for a week. As during the prior Switch Week, 
all participants will attend visits mid-week and at the end of the week to assess biomarkers 
(Visits 6 and 7). To enhance reproducibility, we will attempt to schedule appointments at the 
same time of day (i.e., within a 2-hour window) for each participant so that there is consistent 
time for product use prior to providing the biological samples across study visits. We opted to 
use a 7-day switching period to provide a stronger test of the ability of these alternative products 
to substitute for cigarettes than in our prior study50 (A.5.1), but to minimize the retention 
problems seen in studies with longer switches112. There are also strong theoretical and empirical 
reasons to suspect that withdrawal and other motivations for cigarette use will be strongest in 
the first 7 days of switching, and this design will allow sampling of the full range of work/non-
work environments for most participants115. Participants will complete a follow-up assessment 
call at 3 months. The baseline visit will last 2 hours, but subsequent visits will last <30 minutes. 
Table 1. Study Assessments 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
Participants will carry a smartphone to complete EMAs from Orientation through all 4 weeks of 
product use.  
After providing consent at the Orientation visit, study staff will ask if the participant gives 
the study permission to stay in touch with them and send them reminders about upcoming study 
contacts during the study via email and/or text message. The staff member will remind them that 
email and text messaging are generally not a secure way to communicate about their health as 
there are many ways for unauthorized users to access email and text messages. The staff 
member will also inform them that they do not have to provide their email address or text 
message number to participate in this study.  
Assessments  
          To address the primary aim of examining whether VLNCs and e-cigs serve as effective 
substitutes for conventional cigarettes, and whether use of these alternative products interacts 
with nicotine replacement, we will conduct extensive assessments of participants’ use of their 
own cigarettes, their use of their assigned alternative products, use contexts, and potential 
motivators for such use behavior (e.g., withdrawal, reward value of products, risk perceptions). 
We will also assess person factors and beliefs that may provide insight into who is able and 
willing to use these alternative products to substitute for cigarettes and which mechanisms 
might be more relevant for which smokers. To the extent possible we will use measures from 
the PhenX Toolkit, a collection of broadly validated measures, to enhance the ability to 
harmonize data from this study with other studies. See Table 1 for the timing of assessments. 
          Baseline assessments. At the Orientation visit, participants will complete assessments 
of basic demographics, motivation and self-efficacy for smoking cessation, and tobacco use 
history using items from our previous research86,87,121 and the PhenX Toolkit. This will include a 
detailed assessment of the timing and use of all non-cigarette tobacco and nicotine products. 
We will assess lifetime and past year psychiatric comorbidity using a validated self-report 
instrument122 as well as psychiatric vulnerability using the validated self-report Anxiety 
Sensitivity Index-III and the Distress Tolerance Survey. We will also assess alcohol and 
marijuana use. Participants will complete two validated measures of cigarette dependence, the 
Fagerström Test of Cigarette Dependence (FTCD123,124) and the Brief Wisconsin Inventory of 
Smoking Dependence Motives (Brief WISDM125). We will assess risk perceptions of 
conventional cigarettes, VLNCs, e-cigs, and patches using items that target the four key 
constructs identified by the Tobacco Centers of Regulatory Science (TCORS) network: 1) 
perceptions of benefits, 2) harm perceptions, 3) addiction perceptions, and 4) perceptions of 
social norms126. These assessments will be repeated at Visit 7 and the 3-month follow-up call. 
We will also assess future intentions to use VLNCs, e-cigs, and the patch. 
          Visit assessments. At each study visit, participants will complete assessments of affect 
using the well-validated Positive and Negative Affect Scale (PANAS127), withdrawal symptoms 
using the validated Wisconsin Smoking Withdrawal Scale (WSWS128), and craving using the 
Brief Questionnaire of Smoking Urges (QSU-Brief129,130) from the PhenX Toolkit. At Visits 1 
through 7 participants will complete the modified Cigarette Evaluation Scale (mCES71,131,132) for 
cigarettes and at Visits 2 through 7 they will complete the mCES for their assigned alternative 
product based on their reactions in the last 24 hours. The 12 items of the mCES assess product 
satisfaction, psychological reward, aversion, enjoyment of respiratory tract sensations, and 
craving reduction. We will use timeline follow-back methods133,134 to assess daily use of 
participants’ own cigarettes, assigned alternative products, and patch if the visit occurs during a 
Switch Week. These data will be used to supplement EMA reports in case of missing EMA data. 
Participants will also be asked at all visits except Visit 1 (when they will not have any study 
products or medication yet) about any possible adverse events from using VLNCs, e-cigs or the 
patches135. At the final visit (Visit 7), we will again assess acceptability, risk perceptions, and 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
intentions to use cigarettes, VLNCs, e-cigs, and patches. We will also assess how the Juul e-cig 
compares to other e-cigs participants have used, including what they like or do not like Juul, 
using a combination of questionnaires and open-ended questions to provide additional 
information regarding Juul acceptability among adults. 
The primary outcome in this research is the number of their own cigarettes participants 
smoke during the Switch Weeks, although we will also examine the proportion of cigarettes 
replaced as a tertiary outcome. We will be clear with participants that we want them to do their 
best to switch completely from their own cigarettes during the two Switch Weeks, but that it is 
very important for us to know if, and when, they smoke any of their own cigarettes. Research 
has shown that self-reports of switching behavior are higher than biochemically confirmed 
reports of switching84,136, given the high rates of non-compliance and misreporting30. To 
enhance the validity and scientific rigor of the self-report of smoking their own cigarettes, we will 
conduct carbon monoxide (CO) and cotinine assays. Participants will be told that these tests are 
used to reflect conventional cigarette and alternative product use, and we will emphasize the 
importance of accurate reporting of cigarette and alternative product use.  
We cannot biochemically verify abstinence from conventional cigarettes in this research 
due to the experimental conditions and the clearance rates of CO and cotinine. Specifically, we 
cannot biochemically verify complete substitution in the VLNC group during the active patch 
Switch Week because VLNCs still produce CO and cotinine is a nicotine metabolite that cannot 
distinguish the source of nicotine (i.e., from a combustible cigarette vs. a nicotine replacement 
product). Further, CO can be used to biochemically verify abstinence only within the last 12-18 
hours, given its short half-life (4.5 hours137), making it impossible to verify smoking that might 
have occurred more than one day prior to the assay. Cotinine’s half-life is 10-30 hours138, 
making it impossible to detect recent abstinence from nicotine products. Therefore, at each visit, 
participants will provide a breath sample for CO assessment and a urine sample for cotinine 
assay to evaluate changes in exposure to combustible and nicotine products. Trained study 
staff at UW-CTRI will collect the participant’s urine and follow procedures according to NicAlert 
directions (see product insert) to get a test reading within the same day. All samples and test 
results will be labeled with the date of collection and the subject's numerical ID. Urine will be 
disposed of after cotinine levels are read and recorded.  
We will use an exhaled CO < 6 ppm to indicate recent abstinence from combustible 
products, based on Perkins’ cut-off of <5 ppm using a Breathco CO monitor139, which is similar 
to the Vitalograph brand, and produces CO values approximately 1-2 ppm lower than the 
Bedfont Smokerlyzer monitors140 we will use in this research. Cotinine will be assessed using 
NicAlert strips, an immunochromatographic assay that uses monoclonal antibody-coated gold 
particles and a series of avidity traps to quantify cotinine level. We will use the <100 ng/ml cut-
off for non-tobacco users recommended by NicAlert to indicate abstinence from nicotine. The 
NicAlert strips have 91% specificity and 92% sensitivity at this cut-off compared to liquid 
chromatography-mass spectrometry141. To maintain the patch double-blind and enhance the 
scientific rigor, study staff who have no contact with participants will conduct the urine assays. 
 
 
Ecological momentary assessments. We will assess cigarette and alternative product 
use in real time in the real-world environment (i.e., ecological momentary assessment [EMA]) 
using a smartphone app we have used in our prior research. Participants can choose to have 
the app downloaded on their own smartphone or they will be given a smartphone at the 
Orientation visit and will be trained to press a button marked “Cigarette” every time they start a 
new cigarette and to press one marked “JUUL” or “Study Cigarette” every time they use a VLNC 
or e-cig (which they will be able to use after Visit 1). Participants randomized to receive no 
alternative product will just record their cigarette use. Daily, each time someone presses a 
product use button (either to say they used the alternative product or to say they smoked their 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
own cigarette), there is approximately a 30% chance a more comprehensive assessment (3 
minutes) will be triggered that will include: 1) time since prior use of cigarette/alternative 
product), 2) use context (e.g., smoking prohibited, others vaping/smoking, home, work), activity, 
and withdrawal symptoms and affect prior to use, and 3) individual items from the mCES that 
tap potential mechanisms (e.g., product satisfaction, psychological reward, aversion, enjoyment 
of respiratory tract sensations, and craving reduction). The comprehensive assessments will be 
specific for each type of use event (i.e., cigarettes, VLNCs, and e-cigs). All participants will 
complete an evening assessment prior to going to bed. Evening reports (5 minutes) will assess: 
affect, withdrawal, use of cigarettes and alternative products, overall satisfaction with 
cigarettes/alternative products, use of patch during Switch Weeks, smoking cues, stressors, and 
pleasure in daily activities. Participants will spend less than 25 minutes each day recording use 
events and answering questions, eliminating the problems of recall bias or participants prefilling 
or back-filling a traditional daily diary. This approach is more rigorous than relying on 
participants to document their use of non-experimental products using a paper and pencil log142. 
We have conducted numerous EMA studies and will use the strategies that have been 
successful in our earlier work: training in assessments, ability to briefly postpone assessments, 
use of counters, etc.50,86,143. This frequency of assessment is of moderate intensity relative to 
protocols used in our prior work86.  
 
 
Follow-up assessment call. Three months after Visit 1, participants will complete a 
brief follow-up assessment call to assess current smoking, use of any alternative products, 
motivation and self-efficacy for smoking cessation, risk perceptions, and future plans to use 
VLNCs, e-cigs, and patches. 
 
Participants who are interested in quitting smoking after Visit 7 will be offered the 
Wisconsin Tobacco Quit Line toll-free number? (1-800-QUIT-NOW 784-8669) and the phone 
number(s) for smoking cessation studies being conducted at our Center.  
Alternative Products and the Nicotine Patch 
           The goal of this research is to examine the potential impact of alternative tobacco 
products on the use of conventional cigarettes, alone and in combination with nicotine 
replacement, to simulate a potential regulatory scenario in which a variety of tobacco and 
nicotine products are available that vary in degree of risk, similarity to cigarettes, and 
acceptability. Therefore, we opted to use two products that have shown potential to substitute 
for traditional cigarettes: very low nicotine content cigarettes (VLNCs) and the Juul e-cig. 
VLNCs. Participants randomized to receive VLNCs will receive NIDA’s reduced nicotine 
cigarettes with 0.03 (±0.01) mg of nicotine with a tar yield of 9±1.5 via NIDA’s Drug Supply 
Program (NOT-DA-14-004). These cigarettes have been characterized by Richter and 
colleagues116. Participants will be able to choose either menthol or non-menthol VLNC’s 
consistent with prior research (e.g., 100) and to enhance the external validity of these findings. 
Participants will be instructed to smoke the VLNCs the same way they would their own 
cigarettes and will be given enough VLNCs to completely substitute for their own cigarettes 
during the Switch Weeks (i.e., if they smoke 20 cigarettes per day, they will receive enough 
VLNCs to be able to smoke 20 VLNCs per day).  
One real-world safety concern with VLNC use is that it might result in compensatory 
smoking or oversmoking and increased exposure to carcinogens117. However, many studies 
have shown that smokers engage in minimal or no compensatory smoking73,82,83,102,118. If 
participants in this condition need more VLNCs, they will be provided with additional VLNCs at 
subsequent study visits. However, we will monitor compensatory smoking by examining both 
VLNCs smoked/day as well as carbon monoxide (CO) levels. Participants found to be smoking 
more than twice their usual cigarettes/day or who demonstrate a CO ≥100 ppm will be 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
discontinued from the study protocol. Research has also shown that there is no increased risk 
with respect to cardiovascular biomarkers or exposure to toxicants among smokers using 
VLNCs67,97,119,120 and this study will produce a very brief exposure (i.e., only 4 weeks, which is 
less than the 6 weeks used by other studies67,83,97).  
E-cigarettes. Participants randomized to receive e-cigs will receive a Juul e-cig and 4 
weeks of pods. Each Juul pod of e-liquid contains 0.7ml nicotine by volume / 5% nicotine by 
weight. Participants will be given a choice of four flavors: tobacco and menthol. To enhance 
external validity, participants will be allowed to choose different flavors at each study visit if they 
wish. Each pod is considered to be the equivalent of 1 pack of cigarettes. Therefore, 
participants will be provided enough pods to match their daily cigarette use. As with the VLNCs, 
if participants assigned to this condition need more pods, they will be given more pods at the 
subsequent study visits. Participants will be instructed in how to use the Juul at Visit 1, and 
encouraged to practice using the Juul during the first week so that they feel comfortable using it 
during the Switch Weeks and are able to titrate their nicotine consumption. 
Nicotine patches. During the Switch Weeks, all participants will receive 8 patches (7 
days’ worth plus one extra in case of mishaps), placebo patches for one Switch Week and 
active patches for the other, in counterbalanced order. Both staff and participants will be blind to 
patch type. Active patch dosing will be based on the package insert: >10 cigs/day = 21 mg 
patch and ≤10 cigs/day = 14 mg patches. We opted to use a placebo control, rather than a no-
patch control, to ensure that the NRT effects were due to nicotine replacement per se rather 
than expectancies. Using nicotine patches will provide critical information regarding whether a 
steady-state nicotine replacement interacts with an ad lib alternative product’s ability to replace 
conventional cigarettes. We opted to use the highest dose of nicotine patch appropriate based 
on daily smoking to maximize the potential effect of nicotine replacement. However, if 
participants experience symptoms of nicotine overdose (e.g., nausea, dizziness), they will be 
told to remove the patch. Our prior research suggests that the majority of smokers are able to 
tolerate both a 21 mg patch and ad lib use of other nicotine replacement86,87. We are currently 
conducting a study with active and placebo patches, and the two types of patches are visually 
identical. We will use the same vendor for this research. 
All study products (nicotine and placebo patches, JUUL e-cigarettes, and very low 
nicotine cigarettes) will be received from vendors at the Center for Tobacco Research and 
Intervention Madison office. Products stored in a locked room or cabinet at the Madison and 
Milwaukee research sites until processed and portioned for dispensing. Dissemination bags 
containing processed study product will be labeled with Study ID and participant initials and 
stored in secure, locked cabinets, closets or rooms in Madison and Milwaukee. Study staff with 
no contact with participants will process and portion out the study products to maintain the 
double-blind on the patches. Participants will be asked to return all unused patches, VLNCs and 
JUUL pods as well as the JUUL device at the end of the study. Participants in the JUUL 
condition will also be asked to return used JUUL pods at each study visit.  
Promoting Continued Experimental Participation 
 
 
We will promote participation and adherence to study procedures using strategies that 
were effective in our prior research. We will: 1) allow flexibility in scheduling144-146; 2) provide 
participants with a single, consistent liaison144,147,148; 3) ensure that research staff are culturally 
sensitive149,150; 4) send reminder letters prior to the Month 3 follow-up call and make reminder 
calls to remind participants about their Orientation Visit and Visits 1, 2 and 5; and 5) 
compensate participants for their time147. Specifically, participants will be paid $20 for 
completing each of the 8 study visits and the 3-month follow-up call (up to $180), and $200 for 
completing 80% of the EMA prompts or $150 for completing 75% of the EMA prompts. 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
Participants may receive up to $380 in total compensation. Finally, participants will be invited to 
share their email or mailing address to receive a copy of the final research results. 
Analytic Plan  
The primary aim of this research is to examine the ability of VLNCs and e-cigs to 
substitute for smokers’ usual cigarettes compared to each other and to no alternative product 
use (Product between-subjects effects) and whether these effects are influenced by steady-
state nicotine (Patch within-subjects factor: active vs. placebo patch). The primary analysis 
model will consist of a mixed analysis of variance (ANOVA) with three levels of the Product 
between-subjects factor (VLNCs, e-cigs, no alternative product) and two levels of the Patch 
within-subjects factor (active nicotine patch, placebo patch). To address the primary aim, we will 
explore statistically significant main or interaction effects in the mixed ANOVA by means of 
unadjusted simple main effects, interaction contrasts, and pairwise comparisons156,157. 
Specifically, we will examine the main effect of Product to evaluate the hypothesis that 
participants who do not have an alternative product will report smoking significantly more of their 
own cigarettes during the Switch Weeks compared to those who have VLNCs or e-cigs. We will 
also conduct a pairwise comparison to explore whether there is a significant difference in the 
number of conventional cigarettes smoked in the VLNC vs. e-cig conditions. We will use the 
main effect of Patch (active vs. placebo) to evaluate the hypothesis that participants will report 
smoking fewer of their own cigarettes during Switch Weeks when they receive active nicotine 
patches compared to placebo patches. We will also test the Patch x Product interaction, with 
follow-up pairwise comparisons, to examine whether steady-state nicotine produces a 
differential effect on the number of conventional cigarettes smoked, based on which alternative 
product a participant was assigned to receive. 
The primary outcome is the number of conventional cigarettes smoked during each 
Switch Week. Based on the literature and our own research, it is possible this outcome will not 
be normally distributed (i.e., a substantive proportion of participants may smoke no conventional 
cigarettes during a Switch Week). Therefore, prior to conducting main analyses, we will examine 
the distributional characteristics of the primary outcome to determine if a transformation is 
needed (e.g., if the distribution substantially deviates from a normal distribution).  
The secondary outcome is number of VLNCs or JUUL pods used during each switch 
week. This research will also examine the main effects for Product and Patch and the Product X 
Patch interaction effect on other exploratory outcomes: 1) the proportion of conventional 
cigarettes replaced; 2) the use of alternative tobacco products; 3) use contexts; and 4) potential 
mechanisms such as rewarding value of the alternative products and conventional cigarettes, 
alleviation of withdrawal symptoms, and taste. We will also explore the impact of person factors 
(e.g., sex, education, psychiatric comorbidity, dependence) and risk perceptions on the primary, 
secondary, and exploratory outcomes. We will include these variables as covariates in the 
analyses, and we will include covariate interaction terms with the between- and within-subjects 
factors (e.g., sex x Product; sex x Product x Patch) to determine whether these individual 
difference variables moderate the ability of the alternative products to substitute for conventional 
cigarettes. To examine use contexts and putative mechanisms driving alternative product use 
and substitution for conventional cigarettes, we will use the daily EMA data from the evening 
reports as well as data from the quasi-random daily assessments that will be collected during 
the Switch Weeks as described above as the exploratory outcome variables. One set of 
analyses will test summary versions of the outcomes (e.g., means or counts across the Switch 
Weeks); another set of more fine-grained analyses will preserve the intensive longitudinal data 
(ILD) aspect of the EMA data collected during each of the 7 days of the Switch Weeks. For the 
summary versions of the outcomes, the alternative product use outcome will consist of the 
mean alternative product use events per day reported during the Switch Weeks and the context 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
and mechanisms variables will be based on means across the 7 days of the Switch Weeks. For 
these summary outcomes, we will use statistical models similar to the analyses described above 
for the primary outcome. For the ILD outcomes, we will create one set of outcomes based on 
the evening report that assesses experiences across the full day and another set based on the 
3 quasi-random comprehensive assessments that occur during the day. For the ILD versions of 
the outcomes, we will use conditional growth curve models that permit slope and intercept 
parameters to be evaluated across the 7 days of the Switch Weeks as a function of group; these 
models also permit examination of other forms of change over time (e.g., linear, quadratic, 
cubic). We will explore two main approaches to growth curve modeling: a multilevel modeling 
(MLM) approach158 and a structural equation modeling (SEM) approach159. Although similar, 
each of these modeling approaches has advantages and disadvantages160 that we will exploit in 
exploratory analyses. While we are not powered to detect mediation due to funding limitations, 
we will conduct exploratory mediation analyses to provide information for future research on 
whether these mechanisms mediate the effects of alternative product use on the use of 
conventional cigarettes.  
Power for Primary Aim Hypotheses 
With attrition-adjusted n=54 per group for a between-subjects pairwise comparison, the 
study is powered to detect a difference of 3.3 cigarettes (SD=6); a corresponding within-
subjects pairwise comparison (SD=6, correlation=0.5) is powered to detect a difference of 2.8 
cigarettes. Thus, we feel that a total N=225 provides adequate power to detect predicted 
effects.  
Protection of Human Subjects 
Human Subjects Involvement and Characteristics. A total of 225 participants 
smokers will be recruited to participate in the proposed research. Specific eligibility 
requirements are: 1) ≥ 21 years old; 2) able to read and write English; 3) no plans to quit 
smoking in the next 30 days; 4) not currently taking smoking cessation medication; 5) willing 
and medically able to use nicotine patches; 6) not currently in treatment for psychosis or bipolar 
disorder; 7) smoking ≥ 5 cigarettes per day for the past 6 months; 8) exhaled carbon monoxide 
(CO) > 5 ppm; 9) no e-cig use within the last month; and 10) not currently pregnant or 
breastfeeding. Use of other tobacco products (e.g., cigars, chew, snus) will not be exclusionary, 
but we will track such use. Vulnerable populations (e.g., children under 18, prisoners) will not be 
included in the proposed research.  
Sources of Materials. Participants in this study will provide data for the express 
purpose of research. Data collected from participants in this research will consist of: 1) answers 
to questionnaires and interviews assessing tobacco use history, demographics, nicotine 
dependence, affect and psychiatric history, and risk perceptions of cigarettes and alternative 
products; 2) recording of their own cigarette use and alternative product use and responses to 
ecological momentary assessment (EMA) prompts on a smartphone; 3) breath samples to 
permit determination of carbon monoxide, which reflects smoking status; and 4) urine samples 
to assess biomarkers of exposure to nicotine. All data are retained in the study database. The 
study database access is limited by physical and password protection to those staff members 
and investigators directly involved in the study and under the supervision of the UW IRB. 
Potential Risks. Risks associated with this research are judged to be minimal. None of 
the physiological, self-report, or behavioral measures constitute a significant risk. Withdrawal for 
the Switch Weeks is associated with a number of unpleasant symptoms such as sleep 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
disturbance, hunger, craving, and negative mood. These symptoms are quickly reversed once 
the participant smokes their own cigarettes. These symptoms will also be alleviated to some 
degree by the alternative products and the active nicotine patches. Most smokers have tried to 
quit in the past and are familiar with these phenomena. Participants will be informed about the 
likely effects of smoking withdrawal. The risks of VLNCs are no greater than the risks of 
smoking their own cigarettes, although there is the potential for compensatory smoking or 
oversmoking. The risks of using e-cigarettes have been deemed to be less than smoking a 
conventional cigarette (National Academy of Sciences, 2018). However, participants may 
experience sore throat or dry mouth. Recently the FDA has reported that users of e-cigarettes 
have experienced seizures, mostly among adolescent and young adult users. The risks 
associated with the nicotine patch are sufficiently minimal that they are available over the 
counter. The nicotine patch is generally well tolerated, but up to 50% of participants may have a 
local skin reaction, and rarely, individuals may have a more systemic allergic reaction. Although 
most smokers have tolerance to nicotine, symptoms of acute nicotine toxicity (nausea and 
vomiting) are possible, especially in conditions where participants receive e-cigarettes and the 
active nicotine patch.  
Finally, there is a small risk of loss of confidentiality. This could occur through a number 
of possible avenues, all highly unlikely due to the data security measures in place. The 
University of Wisconsin’s Center for Tobacco Resesarch and Intervention (UW-CTRI) computer 
system is linked to the UW network through a firewall, which is managed by the School of 
Medicine and Public Health network team, via a fiber link which is maintained by the UW 
Division of Information Technology. No data are stored on individual computer hard drives. All 
data are transmitted from the point of collection to the UW-CTRI server through secure, 
encrypted web connection. There are rare occasions when, due to a loss of internet access or 
computer hardware failure, data are collected in paper forms, which could be taken or lost. In 
addition, consent forms are obtained in paper copy; these forms contain the participant name 
and signature. Finally, the University of Wisconsin and the National Cancer Institute may inspect 
the signed consent forms. Because of this possible need to release information to these parties, 
we cannot guarantee absolute confidentiality.  
Participants will be informed about all of these risks prior to providing written informed 
consent. 
Adequacy of Protection Against Risks 
 
Recruitment and Informed Consent. Participants will be recruited from the greater 
Madison and Milwaukee, WI areas via the media recruitment methods (i.e., TV, newspaper, and 
earned media) that have recruited thousands of smokers. We will also use Internet/Facebook 
advertisements that have been successful in our recent e-cig studies. Interested potential 
participants will contact the study via phone. Study staff will call interested potential participants 
within 48-72 hours to introduce the study, assess interest and screen for eligibility. If the person 
is interested and eligible, an in-person Orientation Visit will be scheduled. At this visit, the 
smoker will learn about general requirements for participation (e.g., need to switch from using 
their own cigarettes for 2 7-day Switch Weeks, participation in assessments) as well as risks 
associated with nicotine withdrawal, alternate product use, patch use, and the possible loss of 
confidentiality. Study staff will then provide each study candidate with an IRB-approved 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
informed consent document. Study candidates will read the informed consent document and will 
be given an opportunity to ask any questions regarding study participation. A research staff 
member will read the consent form to the study candidate if needed or desired. The consent 
form will include necessary HIPAA language. Participants will be required to sign the consent 
form and will then be given a copy of the consent form.  
Protection Against Risk. Risks related to alternative products and the nicotine patch 
will be minimized through close monitoring. The PI will be responsible for routine monitoring of 
unanticipated health events. This risk protection includes procedures for monitoring of all events 
through scheduled biweekly meetings with study staff and review of written documentation. 
Unanticipated health event assessment, recording, reporting and investigation will be 
accomplished through staff training, structured/standardized assessments of untoward 
occurrences/events, and regular monitoring the PI. The PI has ultimate responsibility for 
ensuring that unanticipated health events are detected and reported in a timely manner. Health 
events that raise concerns (e.g., allergic reaction, symptoms suggestive of nicotine toxicity) will 
be immediately reported to the PI who will determine an appropriate course of action.  
The U.S. Centers for Disease Control and Prevention (CDC) and the Food and Drug 
Administration (FDA) are investigating recent reports of serious lung disease associated with 
the use of vaping/e-cigarette devices. Many of the illnesses are related to vaping THC products. 
The FDA has advised people to avoid buying vaping products on the street, to refrain from 
vaping THC or other oils, and to not modify or add any substance to vaping products purchased 
at stores. We will tell all participants that if they use a vaping device/e-cigarette products, they 
should watch for symptoms such as cough, shortness of breath, chest pain, nausea, vomiting, 
diarrhea, abdominal pain, fatigue, fever, and weight loss, and get medical attention right away 
for any health concerns. They can also call their local poison control center at 1-800-222-1222. 
To facilitate safety, participants who are not be medically appropriate to use the nicotine 
patch will not be included in the study (e.g., no previous allergic reactions). Once enrolled, study 
protocols will assess side effects and unanticipated health events at all study visits and follow-
up contacts. We will recommend using a lower dose patch or no patch if the participant 
experiences symptoms of nicotine toxicity or other troublesome side effects during their Switch 
Weeks. If participants in the VLNC condition are found to be smoking more than twice their 
usual cigarettes/day or have an exhaled CO ≥ 100 ppm, they will be discontinued from the study 
protocol. We will refer participants their primary care provider as needed. Should excessive risk 
to study participants be determined, the study will be stopped and all participants notified in a 
manner appropriate to the nature of the risk.  
Confidentiality of participant data and information will be accomplished by using 
participant ID numbers as unique identifiers, allowing us to keep participant data separate from 
identifying information. The UW-CTRI Information Technology Administrator, Jonah Stankovsky, 
manages the hardware, data, security, and infrastructure below the firewall. Access to the 
network is limited to only UW-CTRI owned and actively managed devices. All devices 
automatically lock and are password protected after 15 minutes of inactivity. All portable devices 
are encrypted for data security and no PHI is stored on local devices. All data stored on the 
network file server is limited by the principle of least privilege. With respect to the study 
smartphones, to provide confidentiality and HIPAA compliance, UW-CTRI uses MDM software 
(mobile device management software) in said study to protect and collect subject data.  All 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
mobile devices that are provided to subjects are deployed with password protection, MDM 
software, encryption, and other lockdown features. Each device returned to UW-CTRI from 
subjects are wiped and factory reset, then redeployed with the above features and then minimal 
features to complete data collection per study design. The minimal features that are enabled on 
each device are phone, text messenger and data collection app. There will be no data stored on 
the UW-CTRI mobile devices, it will be directly transferred from the app to a secure UW-CTRI 
server.  
 As stated above, no data are stored on individual computer hard drives. All data are 
transmitted from the point of collection to the UW-CTRI server through secure, encrypted web 
connection. On those rare occasions when, due to a loss of internet access or computer 
hardware failure, data are collected in paper forms, these forms will be stored securely at UW-
CTRI until the data are able to be entered into the database and the paper document will then 
be disposed of securely. No identifying data other than a participant ID number is entered on 
any data form. Consent forms are obtained in paper copy; these forms contain the participant 
name and signature. These are retained in secure files at the clinic where they are collected and 
then transported to the UW-CTRI office, where they are securely stored. 
Finally, no publications or presentations resulting from this research program will contain 
any identifying information about individual participants.  
Potential Benefits of the Proposed Research to the Participants and Others 
There are no specific benefits for smokers participating in this study, beyond the benefit 
of helping inform scientists and FDA regulators about the ability of these alternative products to 
serve as substitutes for conventional cigarettes and whether this is influenced by the presence 
of steady-state nicotine.  
Importance of the Knowledge to be Gained 
The results from this research will provide important insight into how well very low 
nicotine cigarettes and e-cigarettes serve as a substitute for conventional cigarettes and how 
this is influenced by the presence of steady-state nicotine. Further, these data will inform 
scientists and regulators about the potential mechanisms that may support the use of alternative 
products. This information will aid scientists and regulatory bodies in understanding the real-
world impact of potential regulatory policies regarding access to safer nicotine sources and 
reducing the addiction potential of combustible tobacco products.  
 
As outlined above, the risks of this study are minimal and limited to the discomfort of 
withdrawal, the use of alternate products and the nicotine patch, and the small risk of breach of 
confidentiality. The potential study impact on informing the science and policy debate over 
nicotine regulation far outweigh these risks.  
Data and Safety and Monitoring Plan 
Monitoring study progress and the safety of participants. The Principal Investigator is 
responsible for routine monitoring of the progress of this research. This includes scheduled 
biweekly meetings with study staff and review of written documentation. Data reviewed at these 
meetings will include the number and type of participants enrolled, the number and reasons for 
exclusions from enrollment, the number treated and the stage of intervention, summary of 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
adverse events (AEs), and individual review of serious adverse events (SAEs) and study 
participation. In addition, SAEs or AEs that raise concerns (e.g., allergic reaction, significant 
change in mood or suicidality) will be immediately reported to the study physician who will 
determine an appropriate course of action, which may include discontinuation of study products. 
As data become available, the Principal Investigator will review the data on a regularly 
scheduled basis (initially weekly and later monthly) to determine progress. To facilitate 
participant safety, study participants must meet study inclusion and exclusion criteria. Once 
enrolled, study protocols will assess the presence of AEs and SAEs at all study contacts, with 
the exception of the final assessment call 3 months after the use of study products. Should 
either excessive risk to study participants be determined, the study will be stopped and all 
participants notified in a manner appropriate to the nature of the risk and/or lack of benefit. 
When taking that step the Principal Investigator will consult with the IRB and NCI. 
Plans for the reporting of unanticipated health events. This DSMP requires that the 
Principal Investigator notify NIH and the University of Wisconsin IRB in a timely manner 
(consistent with IRB and NIH policies) of the occurrence of any SAE or any AE that is severe, 
unexpected, and possibly related to study products or protocol. Because this study involves a 
pharmaceutical agent, if an SAE might be related to study patch use, both the Food and Drug 
Administration (FDA) and the manufacturer will also be notified within five days of investigators 
becoming aware of the event. Examples of SAE would be untoward medical or intervention 
occurrences that result in death, are life-threatening, require hospitalization or prolonging of 
existing hospitalization, create persistent or significant disability/incapacity, or involve congenital 
abnormality/birth defects. Unanticipated problems will be monitored and reported to the DSMC. 
These are events that meet the following criteria: 1) suggest the research places subjects or 
others at increased risk of harm, 2) are unexpected (in terms of nature, severity or frequency) 
given the research procedures that are described in the study-related documents, and 3) 
possibly related to study participation. Any SAE will be queried and reported if it meets the 
definition of unanticipated problem. The Principal Investigator will also be responsible for the 
accurate documentation, investigation and follow-up of all study-related adverse events. 
Adverse event assessment, recording, reporting, and investigation will be accomplished through 
staff training, structured/standardized assessments of untoward occurrences/events, and 
regular monitoring by the Principal Investigator and study physician. The Principal Investigator 
has ultimate responsibility for ensuring that SAEs are detected and reported in a timely manner. 
Additionally, the IRB will receive an annual report of all SAEs and AEs meeting the criteria listed 
above. 
Plans for assuring that any action resulting in a temporary or permanent suspension of 
an NIH-funded research is reported to the NIH grant program director responsible for the 
grant. The NIH grant program director will be notified within five days if the Principal 
Investigator deems it necessary to suspend this research. In the case of a temporary 
suspension, the Principal Investigator will develop a plan for continuation of the project and 
discuss this plan with the NIH grant program director in a reasonable time frame.   
Plans for assuring data accuracy and confidentiality and protocol compliance. The 
Principal Investigator, supported by CTRI analysis staff will develop plans for assuring data 
accuracy and protocol compliance. Such plans will include data verification and protocol 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
compliance checks. The Data Manager and IT Manager shall be responsible for ensuring that 
the data for the project are securely stored, that storage is in compliance with University and 
federal regulations and that no unauthorized persons have access (electronic or physical) to any 
participant-identifiable data. All HIPAA regulations and guidelines will be followed, and all study 
staff must complete approved human subjects and HIPAA training programs.  
Data and Safety Monitoring Committee 
In addition to the protections outlined in the DSMP (above), this research project will have an 
independent Data Safety and Monitoring Committee (DSMC). The DSMP specifies overall 
monitoring that will be conducted by Principal Investigator, including timely reporting of AEs and 
SAEs. Every six months, the DSMC will convene to review the overall safety data, as well as 
data on safety summarized by treatment condition. As per NIH guidelines, the objective of these 
reviews will be to determine whether continued conduct of the research poses any undue risk 
for participants. 
The existing DSMC is chaired by Dr. James Cleary, leader of the Cancer Control Program of the 
UW Comprehensive Cancer Center. Dr. Cleary is an experienced physician and clinical trial 
researcher with no involvement in any of this project’s research activities. Dr. Cleary is joined on 
the DSMC by Dr. James Sosman and Dr. Burke Richmond. Dr. Sosman is Associate Professor 
of Medicine and Medical Director of the HIV/AIDS Comprehensive Care Program at UW 
Hospital and Clinics who has previously collaborated on a clinical trial of smoking cessation with 
UW-CTRI. Dr. Richmond is an otolaryngologist who has served on independent DSMBCs for 
Phase II and III trials involving a nicotine vaccine. Neither has direct involvement with any of the 
proposed research. The Principal Investigators will report to the DSMC; the three DSMC 
members will make the final determinations as to study continuation. 
ClinicalTrials.gov Requirements 
This research project will be registered with clinical trials.gov prior to the enrollment of the first 
subject. Final data (including outcomes and adverse events) will be reported to clinicaltrials.gov 
within 1 year of the conclusion of the trial. 
 
 
References 
1. 
U.S. Department of Health and Human Services. The health consequences of smoking - 
50 years of progress: A report of the Surgeon General. Atlanta, GA2014. 
2. 
National Institute on Drug Abuse. Tobacco, nicotine, and e-cigarettes: is nicoitne 
addictive? 2018. https://www.drugabuse.gov/publications/tobacco-nicotine-e-
cigarettes/nicotine-addictive. Accessed 29 June, 2018. 
3. 
World Health Organization. Addiction to nicotine. Gender, women, and the tobacco 
epidemic. Geneva: World Health Organization; 2010:137-149. 
4. 
Zeller M, Hatsukami D. The Strategic Dialogue on Tobacco Harm Reduction: a vision 
and blueprint for action in the US. Tob Control. 2009;18(4):324-332. 
5. 
U.S. Food and Drug Administration. FDA's plan for tobacco and nicotine regulation. 
2017. https://www.fda.gov/tobaccoproducts/newsevents/ucm568425.htm. Accessed 28 
June, 2018. 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
6. 
Tengs TO, Ahmad S, Savage JM, Moore R, Gage E. The AMA proposal to mandate 
nicotine reduction in cigarettes: a simulation of the population health impacts. Prev Med. 
2005;40(2):170-180. 
7. 
Fiore M, Baker T. Reduced-nicotine cigarettes-a promising regulatory pathway. N Engl J 
Med. 2015;373(14):1289-1291. 
8. 
Xu X, Bishop EE, Kennedy SM, Simpson SA, Pechacek TF. Annual healthcare spending 
attributable to cigarette smoking: an update. Am J Prev Med. 2015;48(3):326-333. 
9. 
Lee YO, Hebert CJ, Nonnemaker JM, Kim AE. Multiple tobacco product use among 
adults in the United States: Cigarettes, cigars, electronic cigarettes, hookah, smokeless 
tobacco, and snus. Prev Med. 2014;62C:14-19. 
10. 
Guydish J, Tajima B, Pramod S, et al. Use of multiple tobacco products in a national 
sample of persons enrolled in addiction treatment. Drug Alcohol Depend. 2016;166:93-
99. 
11. 
Soneji S, Sargent J, Tanski S. Multiple tobacco product use among US adolescents and 
young adults. Tob Control. 2016;25(2):174-180. 
12. 
Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction. The 
implications for tobacco regulation. New England Journal of Medicine. 1994;331(2):123-
125. 
13. 
World Health Organization. WHO Framework Convention on Tobacco Control. 2003. 
http://www.who.int/fctc/text_download/en/. Accessed 6 June 2018. 
14. 
Dunn WL. Motives and incentives in cigarette smoking. Plaintiff’s exhibit P-5171. 
Cipollone v. Ligget. Litication documents 3.4 TPLR 3.362 (internal memorandum, Philip 
Morris Tobacco Company). 1991. 
15. 
Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco use and dependence: 2008 
update. Rockville, MD: U.S. Department of Health and Human Services, U.S. Public 
Health Service; 2008. 
16. 
U.S. Congress. H.R.1256 - Family Smoking Prevention and Tobacco Control Act. 2009. 
https://www.congress.gov/bill/111th-congress/house-bill/1256. Accessed 6 June 2018. 
17. 
Abrams DB, Glasser AM, Pearson JL, Villanti AC, Collins LK, Niaura RS. Harm 
minimization and tobacco control: reframing societal views of nicotine use to rapidly save 
lives. Annu Rev Public Health. 2018;39:193-213. 
18. 
Action on Smoking and Health. Health inequalities and smoking. 2016. 
http://ash.org.uk/information-and-resources/briefings/ash-briefing-health-inequalities-
and-smoking/. Accessed 8 June 2018. 
19. 
Mackenbach JP. What would happen to health inequalities if smoking were eliminated? 
BMJ. 2011;342:d3460. 
20. 
Voigt K. Smoking and social justice. Public Health Ethics. 2010;3(2):91-106. 
21. 
Piper ME, Rodock M, Cook JW, Schlam TR, Fiore MC, Baker TB. Psychiatric diagnoses 
among quitters versus continuing smokers 3 years after their quit day. Drug Alcohol 
Depend. 2013;128(1-2):148-154. 
22. 
Harker K, Cheeseman H. The stolen years: the mental health and smoking action report. 
2016. http://ash.org.uk/information-and-resources/reports-submissions/reports/the-
stolen-years/. Accessed 6 June 2018. 
23. 
Federico B, Costa G, Kunst AE. Educational inequalities in initiation, cessation, and 
prevalence of smoking among 3 Italian birth cohorts. Am J Public Health. 
2007;97(5):838-845. 
24. 
Centers for Disease Control and Prevention. Tobacco-related disparities. 2018. 
https://www.cdc.gov/tobacco/disparities/index.htm. Accessed 6 June 2018. 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
25. 
American Lung Association. Women and tobacco use. 2018. http://www.lung.org/stop-
smoking/smoking-facts/women-and-tobacco-use.html. Accessed 6 June 2018   
26. 
Cummins SE, Zhu SH, Tedeschi GJ, Gamst AC, Myers MG. Use of e-cigarettes by 
individuals with mental health conditions. Tob Control. 2014;23 Suppl 3:iii48-53. 
27. 
Park SH, Lee L, Shearston JA, Weitzman M. Patterns of electronic cigarette use and 
level of psychological distress. PLoS One. 2017;12(3):e0173625. 
28. 
Spears CA, Jones DM, Weaver SR, Pechacek TF, Eriksen MP. Use of electronic 
nicotine delivery systems among adults with mental health conditions, 2015. Int J 
Environ Res Public Health. 2016;14(1). 
29. 
Kruse GR, Kalkhoran S, Rigotti NA. Use of electronic cigarettes among U.S. adults with 
medical comorbidities. Am J Prev Med. 2017;52(6):798-804. 
30. 
Donny EC, Hatsukami DK, Benowitz NL, Sved AF, Tidey JW, Cassidy RN. Reduced 
nicotine product standards for combustible tobacco: building an empirical basis for 
effective regulation. Prev Med. 2014;68:17-22. 
31. 
Smith TT, Hatsukami DK, Benowitz NL, et al. Whether to push or pull? Nicotine 
reduction and non-combusted alternatives - Two strategies for reducing smoking and 
improving public health. Prev Med. 2018. 
32. 
Abrams DB. Promise and peril of e-cigarettes: can disruptive technology make cigarettes 
obsolete? JAMA. 2014;311(2):135-136. 
33. 
Henningfield JE. The tobacco endgame: it's all about behavior. Prev Med. 2014;68:11-
16. 
34. 
The National Academies of Sciences Engineering Medicine. Public health consequences 
of e-cigarettes. 2018. http://nationalacademies.org/hmd/Reports/2018/public-health-
consequences-of-e-cigarettes.aspx. Accessed 6 June 2018. 
35. 
Glasser AM, Collins L, Pearson JL, et al. Overview of electronic nicotine delivery 
systems: a systematic review. Am J Prev Med. 2017;52(2):e33-e66. 
36. 
Adkison SE, O'Connor RJ, Bansal-Travers M, et al. Electronic nicotine delivery systems: 
international tobacco control four-country survey. Am J Prev Med. 2013;44(3):207-215. 
37. 
Ayers JW, Ribisl KM, Brownstein JS. Tracking the rise in popularity of electronic nicotine 
delivery systems (electronic cigarettes) using search query surveillance. Am J Prev Med. 
2011;40(4):448-453. 
38. 
Bao W, Xu G, Lu J, Snetselaar LG, Wallace RB. Changes in electronic cigarette use 
among adults in the United States, 2014-2016. JAMA. 2018;319(19):2039-2041. 
39. 
Schoenborn CA, Gindi RM. Electronic cigarette use among adults; United States, 2014. 
NCHS Data Brief, No 2017. 2015. https://www.cdc.gov/nchs/data/databriefs/db217.pdf. 
Accessed 14 May 2018. 
40. 
Centers for Disease Control and Prevention. QuickStats: Cigarette smoking status 
among current adult e-cigarettes users by age group - National Health Interview Survey, 
United States, 2015. 2016. https://www.cdc.gov/mmwr/volumes/65/wr/mm6542a7.htm. 
Accessed 14 May 2018. 
41. 
D'Ruiz CD, Graff DW, Robinson E. Reductions in biomarkers of exposure, impacts on 
smoking urge and assessment of product use and tolerability in adult smokers following 
partial or complete substitution of cigarettes with electronic cigarettes. BMC Public 
Health. 2016;16:543. 
42. 
O'Connell G, Graff DW, D'Ruiz CD. Reductions in biomarkers of exposure (BoE) to 
harmful or potentially harmful constituents (HPHCs) following partial or complete 
substitution of cigarettes with electronic cigarettes in adult smokers. Toxicol Mech 
Methods. 2016;26(6):443-454. 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
43. 
Pulvers K, Emami AS, Nollen NL, et al. Tobacco consumption and toxicant exposure of 
cigarette smokers using electronic cigarettes. Nicotine Tob Res. 2018;20(2):206-214. 
44. 
Poland B, Teischinger F. Population modeling of modified risk tobacco products 
accounting for smoking reduction and gradual transitions of relative risk. Nicotine Tob 
Res. 2017;19(11):1277-1283. 
45. 
Levy DT, Borland R, Lindblom EN, et al. Potential deaths averted in USA by replacing 
cigarettes with e-cigarettes. Tob Control. 2018;27(1):18-25. 
46. 
Polosa R, Caponnetto P, Morjaria JB, Papale G, Campagna D, Russo C. Effect of an 
electronic nicotine delivery device (e-Cigarette) on smoking reduction and cessation: a 
prospective 6-month pilot study. BMC Public Health. 2011;11:786. 
47. 
Caponnetto P, Campagna D, Cibella F, et al. EffiCiency and Safety of an eLectronic 
cigAreTte (ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized 
control design study. PLoS One. 2013;8(6):e66317. 
48. 
Wagener TL, Meier E, Hale JJ, et al. Pilot investigation of changes in readiness and 
confidence to quit smoking after e-cigarette experimentation and 1 week of use. Nicotine 
Tob Res. 2013. 
49. 
Goniewicz ML, Gawron M, Smith DM, Peng M, Jacob P, 3rd, Benowitz NL. Exposure to 
nicotine and selected toxicants in cigarette smokers who switched to electronic 
cigarettes: a longitudinal within-subjects observational study. Nicotine Tob Res. 
2017;19(2):160-167. 
50. 
Jorenby DE, Smith SS, Fiore MC, Baker TB. Nicotine levels, withdrawal symptoms, and 
smoking reduction success in real world use: A comparison of cigarette smokers and 
dual users of both cigarettes and E-cigarettes. Drug Alcohol Depend. 2017;170:93-101. 
51. 
Adriaens K, Van Gucht D, Baeyens F. Differences between dual users and switchers 
center around vaping behavior and Its experiences rather than beliefs and attitudes. Int J 
Environ Res Public Health. 2017;15(1). 
52. 
Bullen C, McRobbie H, Thornley S, Glover M, Lin R, Laugesen M. Effect of an electronic 
nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user 
preferences and nicotine delivery: randomised cross-over trial. Tob Control. 
2010;19(2):98-103. 
53. 
Dawkins L, Corcoran O. Acute electronic cigarette use: nicotine delivery and subjective 
effects in regular users. Psychopharmacology (Berl). 2013. 
54. 
Dawkins L, Turner J, Hasna S, Soar K. The electronic-cigarette: effects on desire to 
smoke, withdrawal symptoms and cognition. Addict Behav. 2012;37(8):970-973. 
55. 
Perkins KA, Karelitz JL, Michael VC. Effects of nicotine versus placebo e-cigarette use 
on symptom relief during initial tobacco abstinence. Exp Clin Psychopharmacol. 
2017;25(4):249-254. 
56. 
Tucker MR, Laugesen M, Bullen C, Grace RC. Predicting short-term uptake of electronic 
cigarettes: effects of nicotine, subjective effects and simulated demand. Nicotine Tob 
Res. 2017. 
57. 
Etter JF, Bullen C. Electronic cigarette: users profile, utilization, satisfaction and 
perceived efficacy. Addiction. 2011;106(11):2017-2028. 
58. 
Majeed BA, Weaver SR, Gregory KR, et al. Changing perceptions of harm of e-
cigarettes among U.S. adults, 2012-2015. Am J Prev Med. 2017;52(3):331-338. 
59. 
Truth Initiative. What is juul? 2018. https://truthinitiative.org/news/what-is-juul. Accessed 
8 June 2018. 
60. 
Rolfe D. Reynolds brands gain ground on top-selling Marlboro; Juul reaches 54% market 
share. Winston-Salem Journal. 2018. http://www.journalnow.com/business/reynolds-

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
brands-gain-ground-on-top-selling-marlboro-juul-reaches/article_5c040731-0c29-590e-
85b3-c7cfc79b3f58.html. Accessed 8 June 2018. 
61. 
Huang J, Duan Z, Kwok J, et al. Vaping versus JUULing: how the extraordinary growth 
and marketing of JUUL transformed the US retail e-cigarette market. Tob Control. 2018. 
62. 
Barshad A. The juul is too cool. The New York Times. 2018. 
https://www.nytimes.com/2018/04/07/style/the-juul-is-too-cool.html. Accessed 8 June 
2018. 
63. 
Lawler RM. Vaporization startup Pax Labs Introduces juul, Its next-gen e-cigarette. 
2015. https://techcrunch.com/2015/04/21/pax-juul/. Accessed 8 June 2018. 
64. 
Pankow JF, Kim K, McWhirter KJ, et al. Benzene formation in electronic cigarettes. 
PLoS One. 2017;12(3):e0173055. 
65. 
Kee C. Everything you need to know about the JUUL, including the health effects. 
BuzzFeed News. 2018. https://www.buzzfeed.com/carolinekee/juul-ecigarette-vape-
health-effects?utm_term=.qnZyKjvQj0#.jd3amvyAvX. Accessed 8 June 2018. 
66. 
Valleau WD. Breeding low-nicotine tobacco. J Agricult Res. 1949;78(7):171-181. 
67. 
Hatsukami DK, Kotlyar M, Hertsgaard LA, et al. Reduced nicotine content cigarettes: 
effects on toxicant exposure, dependence and cessation. Addiction. 2010;105(2):343-
355. 
68. 
Walker N, Bullen C, McRobbie H. Reduced-nicotine content cigarettes: Is there potential 
to aid smoking cessation? Nicotine Tob Res. 2009;11(11):1274-1279. 
69. 
Walker N, Howe C, Bullen C, et al. The combined effect of very low nicotine content 
cigarettes, used as an adjunct to usual Quitline care (nicotine replacement therapy and 
behavioural support), on smoking cessation: a randomized controlled trial. Addiction. 
2012;107(10):1857-1867. 
70. 
Pacek LR, Joseph McClernon F, Denlinger-Apte RL, et al. Perceived nicotine content of 
reduced nicotine content cigarettes is a correlate of perceived health risks. Tob Control. 
2017. 
71. 
Denlinger-Apte RL, Joel DL, Strasser AA, Donny EC. Low nicotine content descriptors 
reduce perceived health risks and positive cigarette ratings in participants using very low 
nicotine content cigarettes. Nicotine Tob Res. 2017;19(10):1149-1154. 
72. 
Mercincavage M, Lochbuehler K, Villanti AC, Wileyto EP, Audrain-McGovern J, Strasser 
AA. Examining risk perceptions among daily smokers naive to reduced nicotine content 
cigarettes. Nicotine Tob Res. 2018. 
73. 
Donny EC, Houtsmuller E, Stitzer ML. Smoking in the absence of nicotine: behavioral, 
subjective and physiological effects over 11 days. Addiction. 2007;102(2):324-334. 
74. 
Dawkins L, Corcoran O. Acute electronic cigarette use: nicotine delivery and subjective 
effects in regular users. Psychopharmacology (Berl). 2014;231(2):401-407. 
75. 
Guillot CR, Stone MD, Geary BA, et al. Pharmacological, sensorimotor, and expectancy 
effects on tobacco withdrawal: a preliminary study. Hum Psychopharmacol. 
2015;30(5):364-371. 
76. 
Keith DR, Kurti AN, Davis DR, Zvorsky IA, Higgins ST. A review of the effects of very low 
nicotine content cigarettes on behavioral and cognitive performance. Prev Med. 
2017;104:100-116. 
77. 
Higgins ST, Bergeria CL, Davis DR, et al. Response to reduced nicotine content 
cigarettes among smokers differing in tobacco dependence severity. Prev Med. 2018. 
78. 
Buchhalter AR, Acosta MC, Evans SE, Breland AB, Eissenberg T. Tobacco abstinence 
symptom suppression: the role played by the smoking-related stimuli that are delivered 
by denicotinized cigarettes. Addiction. 2005;100(4):550-559. 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
79. 
Hatsukami DK, Heishman SJ, Vogel RI, et al. Dose-response effects of spectrum 
research cigarettes. Nicotine Tob Res. 2013;15(6):1113-1121. 
80. 
Becker KM, Rose JE, Albino AP. A randomized trial of nicotine replacement therapy in 
combination with reduced-nicotine cigarettes for smoking cessation. Nicotine Tob Res. 
2008;10(7):1139-1148. 
81. 
Rose J, Behm F. Effects of low nicotine content cigarettes on smoke intake. Nicotine 
Tob Res. 2004;6(2):309-319. 
82. 
Donny EC, Jones M. Prolonged exposure to denicotinized cigarettes with or without 
transdermal nicotine. Drug Alcohol Depend. 2009;104(1-2):23-33. 
83. 
Donny EC, Denlinger RL, Tidey JW, et al. Randomized trial of reduced-nicotine 
standards for cigarettes. N Engl J Med. 2015;373(14):1340-1349. 
84. 
Nardone N, Donny EC, Hatsukami DK, et al. Estimations and predictors of non-
compliance in switchers to reduced nicotine content cigarettes. Addiction. 
2016;111(12):2208-2216. 
85. 
Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. 
Cochrane Database Syst Rev. 2012;11:CD000146. 
86. 
Piper ME, Smith SS, Schlam TR, et al. A randomized placebo-controlled clinical trial of 5 
smoking cessation pharmacotherapies. Arch Gen Psychiatry. 2009;66(11):1253-1262. 
87. 
Baker TB, Piper ME, Stein JH, et al. Effects of nicotine patch vs varenicline vs 
combination nicotine replacement therapy on smoking cessation at 26 weeks: a 
randomized clinical trial. JAMA. 2016;315(4):371-379. 
88. 
Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking 
cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 
2013(5):CD009329. 
89. 
Bolt DM, Piper ME, Theobald WE, Baker TB. Why two smoking cessation agents work 
better than one: role of craving suppression. J Consult Clin Psychol. 2012;80(1):54-65. 
90. 
Donny EC, Chaudhri N, Caggiula AR, et al. Operant responding for a visual reinforcer in 
rats is enhanced by noncontingent nicotine: implications for nicotine self-administration 
and reinforcement. Psychopharmacology (Berl). 2003;169(1):68-76. 
91. 
Olausson P, Jentsch JD, Taylor JR. Repeated nicotine exposure enhances reward-
related learning in the rat. Neuropsychopharmacology. 2003;28(7):1264-1271. 
92. 
Palmatier MI, Evans-Martin FF, Hoffman A, et al. Dissociating the primary reinforcing 
and reinforcement-enhancing effects of nicotine using a rat self-administration paradigm 
with concurrently available drug and environmental reinforcers. Psychopharmacology 
(Berl). 2006;184(3-4):391-400. 
93. 
Palmatier MI, Liu X, Matteson GL, Donny EC, Caggiula AR, Sved AF. Conditioned 
reinforcement in rats established with self-administered nicotine and enhanced by 
noncontingent nicotine. Psychopharmacology (Berl). 2007;195(2):235-243. 
94. 
Dawkins L, Powell JH, West R, Powell J, Pickering A. A double-blind placebo controlled 
experimental study of nicotine: I--Effects on incentive motivation. Psychopharmacology 
(Berl). 2006;189(3):355-367. 
95. 
Dawkins L, Powell JH, West R, Powell J, Pickering A. A double-blind placebo-controlled 
experimental study of nicotine: II--Effects on response inhibition and executive 
functioning. Psychopharmacology (Berl). 2007;190(4):457-467. 
96. 
Cook JW, Piper ME, Leventhal AM, Schlam TR, Fiore MC, Baker TB. Anhedonia as a 
component of the tobacco withdrawal syndrome. J Abnorm Psychol. 2015;124(1):215-
225. 
97. 
Hatsukami DK, Hertsgaard LA, Vogel RI, et al. Reduced nicotine content cigarettes and 
nicotine patch. Cancer Epidemiol Biomarkers Prev. 2013;22(6):1015-1024. 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
98. 
Rose JE. Nicotine and nonnicotine factors in cigarette addiction. Psychopharmacology 
(Berl). 2006;184(3-4):274-285. 
99. 
Rose JE, Uhl GR. Disrupting nicotine reinforcement: From cigarette to brain. In: Uhl GR, 
ed. Addiction Reviews 2008. Annals of the New York Academy of Sciences. Malden: 
Blackwell Publishing; 2008:233-256. 
100. 
Hatsukami DK, Luo X, Dick L, et al. Reduced nicotine content cigarettes and use of 
alternative nicotine products: exploratory trial. Addiction. 2017;112(1):156-167. 
101. 
Piper ME, Baker TB, Benowitz NL, Kobinsky K, Jorenby D. Dual users compared to 
smokers: demographics, dependence, and health risks. under review. 
102. 
Hatsukami DK, Donny EC, Koopmeiners JS, Benowitz NL. Compensatory smoking from 
gradual and immediate reduction in cigarette nicotine content. Cancer Epidemiol 
Biomarkers Prev. 2015;24(2):472-476. 
103. 
Buu A, Hu Y-H, Piper ME, Lin H-C. The association between e-cigarette use 
characteristics and combustible cigarette consumption and related symptoms: results 
from a national longitudinal study. Addict Behav. in press. 
104. 
Wong S-W, Lin H-C, Piper ME, Siddiqui A, Buu A. Measuing characteristics of e-
cigarette consumption among college students. J Am Coll Health. in press. 
105. 
Piper ME, Cook JW, Schlam TR, et al. A randomized controlled trial of an optimized 
smoking treatment delivered in primary care. Ann Behav Med. 2018;[Epub ahead of 
print]. 
106. 
Piper ME, Vasilenko SA, Cook JW, Lanza ST. What a difference a day makes: 
differences in initial abstinence response during a smoking cessation attempt. Addiction. 
2017;112(2):330-339. 
107. 
Lanza ST, Vasilenko SA, Liu X, Li R, Piper ME. Advancing the understanding of craving 
during smoking cessation attempts: a demonstration of the time-varying effect model. 
Nicotine Tob Res. 2014;16 Suppl 2:S127-134. 
108. 
Liu X, Li R, Lanza ST, Vasilenko SA, Piper M. Understanding the role of cessation 
fatigue in the smoking cessation process. Drug Alcohol Depend. 2013;133(2):548-555. 
109. 
Piper ME, Schlam TR, Cook JW, et al. Tobacco withdrawal components and their 
relations with cessation success. Psychopharmacology (Berl). 2011;216(4):569-578. 
110. 
Bekiroglu K, Russell MA, Lagoa CM, Lanza ST, Piper ME. Evaluating the effect of 
smoking cessation treatment on a complex dynamical system. Drug Alcohol Depend. in 
press. 
111. 
Piper ME, Cook JW, Schlam TR, et al. Toward precision smoking cessation treatment II: 
Proximal effects of smoking cessation intervention components on putative mechanisms 
of action. Drug Alcohol Depend. 2017;171:50-58. 
112. 
Mercincavage M, Wileyto EP, Saddleson ML, Lochbuehler K, Donny EC, Strasser AA. 
Attrition during a randomized controlled trial of reduced nicotine content cigarettes as a 
proxy for understanding acceptability of nicotine product standards. Addiction. 
2017;112(6):1095-1103. 
113. 
Villanti AC, Feirman SP, Niaura RS, et al. How do we determine the impact of e-
cigarettes on cigarette smoking cessation or reduction? Review and recommendations 
for answering the research question with scientific rigor. Addiction. 2018;113(3):391-404. 
114. 
McQueen A, Tower S, Sumner W. Interviews with "vapers": implications for future 
research with electronic cigarettes. Nicotine Tob Res. 2011;13(9):860-867. 
115. 
Hughes JR. Effects of abstinence from tobacco: valid symptoms and time course. 
Nicotine Tob Res. 2007;9(3):315-327. 
116. 
Richter P, Steven PR, Bravo R, et al. Characterization of SPECTRUM variable nicotine 
Research cigarettes. Tob Regul Sci. 2016;2(2):94-105. 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
117. 
Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P, 3rd. Nicotine and 
carcinogen exposure with smoking of progressively reduced nicotine content cigarette. 
Cancer Epidemiol Biomarkers Prev. 2007;16(11):2479-2485. 
118. 
Hammond D, O'Connor RJ. Reduced nicotine cigarettes: smoking behavior and 
biomarkers of exposure among smokers not intending to quit. Cancer Epidemiol 
Biomarkers Prev. 2014;23(10):2032-2040. 
119. 
Benowitz NL, Dains KM, Hall SM, et al. Progressive commercial cigarette yield 
reduction: biochemical exposure and behavioral assessment. Cancer Epidemiol 
Biomarkers Prev. 2009;18(3):876-883. 
120. 
Benowitz NL, Dains KM, Hall SM, et al. Smoking behavior and exposure to tobacco 
toxicants during 6 months of smoking progressively reduced nicotine content cigarettes. 
Cancer Epidemiol Biomarkers Prev. 2012;21(5):761-769. 
121. 
Piper ME, Fiore MC, Smith SS, et al. Identifying effective intervention components for 
smoking cessation: a factorial screening experiment. Addiction. 2016;111(1):129-141. 
122. 
Tedeschi GJ, Cummins SE, Anderson CM, Anthenelli RM, Zhuang YL, Zhu SH. 
Smokers with self-reported mental health conditions: a case for screening in the context 
of tobacco cessation services. PLoS One. 2016;11(7):e0159127. 
123. 
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The Fagerstrom Test for 
Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J 
Addict. 1991;86(9):1119-1127. 
124. 
Fagerstrom K. Determinants of tobacco use and renaming the FTND to the Fagerstrom 
Test for Cigarette Dependence. Nicotine Tob Res. 2012;14(1):75-78. 
125. 
Smith SS, Piper ME, Bolt DM, et al. Development of the Brief Wisconsin Inventory of 
Smoking Dependence Motives. Nicotine Tob Res. 2010;12(5):489-499. 
126. 
Gibson LA, Creamer MR, Breland AB, et al. Measuring perceptions related to e-
cigarettes: Important principles and next steps to enhance study validity. Addict Behav. 
2018;79:219-225. 
127. 
Watson D, Clark LA, Tellegen A. Development and validation of brief measures of 
positive and negative affect: The PANAS scales. J Pers Soc Psychol. 1988;54(6):1063-
1070. 
128. 
Welsch SK, Smith SS, Wetter DW, Jorenby DE, Fiore MC, Baker TB. Development and 
validation of the Wisconsin Smoking Withdrawal Scale. Exp Clin Psychopharmacol. 
1999;7(4):354-361. 
129. 
Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges 
(QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001;3(1):7-16. 
130. 
Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on 
smoking urges. Br J Addict. 1991;86(11):1467-1476. 
131. 
Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. 
Confirmatory factor analyses and reliability of the modified cigarette evaluation 
questionnaire. Addict Behav. 2007;32(5):912-923. 
132. 
Westman EC, Levin ED, Rose JE. Smoking while wearing the nicotine patch: Is smoking 
still satisfying? [abstract]. Clin Res. 1992;40:871a. 
133. 
Sobell LC, Sobell MB, Leo GI, Cancilla A. Reliability of a timeline method: Assessing 
normal drinkers' reports of recent drinking and a comparative evaluation across several 
populations. Br J Addict. 1988;83(4):393-402. 
134. 
Robinson SM, Sobell LC, Sobell MB, Leo GI. Reliability of the Timeline Followback for 
Cocaine, Cannabis, and Cigarette Use. Psychol Addict Behav. 2012. 
135. 
Soule EK, Nasim A, Rosas S. Adverse effects of electronic cigarette use: a concept 
mapping approach. Nicotine Tob Res. 2016;18(5):678-685. 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
136. 
Benowitz NL, Nardone N, Hatsukami DK, Donny EC. Biochemical estimation of 
noncompliance with smoking of very low nicotine content cigarettes. Cancer Epidemiol 
Biomarkers Prev. 2015;24(2):331-335. 
137. 
Sandberg A, Sko¨ ld CM, Grunewald J, Eklund A, Wheelock AM. Assessing recent 
smoking status by measuring exhaled carbon monoxide levels. PLoS ONE. 
2011;6(12):e28864. 
138. 
Benowitz NL. Biomarkers of environmental tobacco smoke exposure. Environ Health 
Perspect. 1999;107 Suppl 2:349-355. 
139. 
Perkins KA, Karelitz JL, Jao NC. Optimal carbon monoxide criteria to confirm 24-hr 
smoking abstinence. Nicotine Tob Res. 2013;15(5):978-982. 
140. 
Raiff BR, Faix C, Turturici M, Dallery J. Breath carbon monoxide output is affected by 
speed of emptying the lungs: implications for laboratory and smoking cessation 
research. Nicotine Tob Res. 2010;12(8):834-838. 
141. 
Yeh E, Levasseur G, Kaiserman MJ. Evaluation of urinary cotinine immunoassay test 
strips used to assess smoking status. Nicotine Tob Res. 2011;13(11):1045-1051. 
142. 
Krebs NM, Allen SI, Veldheer S, et al. Reduced nicotine content cigarettes in smokers of 
low socioeconomic status: study protocol for a randomized control trial. Trials. 
2017;18(1):300. 
143. 
Piper ME, Federman EB, McCarthy DE, et al. Efficacy of bupropion alone and in 
combination with nicotine gum. Nicotine Tob Res. 2007;9(9):947-954. 
144. 
Cotter RB, Burke, J.D., Loeber, R., & Navratil, J.L. Innovative retention methods in 
longitudinal research:  a case of the developmental trends study. J Child Fam Stud. 
2002;11:485-498. 
145. 
Navaratil JL, Green, S. M., Loeber, R., & Lahey, B. B. Minimizing subject loss in a 
longitudinal study of deviant behavior. J Child Fam Stud. 1994;3:89-106. 
146. 
Stouthamer-Loeber M, Van Kammen, W., Loeber, R. The nuts and bolts of implementing 
large-scale longitudinal studies. Violence Vict. 1992;7(1):63-78. 
147. 
McKenzie M, Tulsky JP, Long HL, Chesney M, Moss A. Tracking and follow-up of 
marginalized populations: a review. J Health Care Poor Underserved. 1999;10(4):409-
429. 
148. 
BootsMiller BJ, Ribisl KM, Mowbray CT, Davidson WS, Walton MA, Herman SE. 
Methods of ensuring high follow-up rates: lessons from a longitudinal study of dual 
diagnosed participants. Subst Use Misuse. 1998;33(13):2665-2685. 
149. 
Janson SL, Alioto ME, Boushey HA. Attrition and retention of ethnically diverse subjects 
in a multicenter randomized controlled research trial. Control Clin Trials. 2001;22(6 
Suppl):236S-243S. 
150. 
Siddiqui O, Flay BR, Hu FB. Factors affecting attrition in a longitudinal smoking 
prevention study. Prev Med. 1996;25(5):554-560. 
151. 
Graham JW. Missing data analysis: making it work in the real world. Annu Rev Psychol. 
2009;60:549-576. 
152. 
Hedeker D, Gibbons RD. Longitudinal data analysis. Hoboken, NJ: Wiley; 2006. 
153. 
Collins LM, Schafer JL, Kam CM. A comparison of inclusive and restrictive strategies in 
modern missing data procedures. Psychol Methods. 2001;6(4):330-351. 
154. 
Schafer JL, Graham JW. Missing data: our view of the state of the art. Psychol Methods. 
2002;7(2):147-177. 
155. 
Muthén LK, Muthén BO. Mplus User’s Guide. Seventh Edition. Vol Muthén & Muthén.: 
Los Angeles, CA; 2012. 
156. 
Keppel G, Wickens TD. Design and analysis: a researcher’s handbook. 4th ed. Upper 
Saddle River, NJ: Pearson Prentice Hall; 2004. 

PROTOCOL 
“Understanding the real-world impact of the use of three  
alternate nicotine-delivery products on combustible cigarette use” 
PI: Megan E. Piper; UW-CTRI Grant: R01CA239309 
 
Version Date: 2.17.2021 
157. 
Winer BJ, Brown DR, Michels KM. Statistical principles in experimental design. 3rd ed. 
New York: McGraw Hill; 1991. 
158. 
Singer JD, Willett JB. Applied longitudinal data analysis: modeling change and event 
occurrence. Oxford: Oxford University Press; 2003. 
159. 
Bollen KA, Curran PJ. Latent curve models: a structural equation perspective. Hoboken, 
NJ: Wiley; 2006. 
160. 
Curran PJ, Obeidat K, Losardo D. Twelve frequently asked questions about growth 
curve modeling. J Cogn Dev. 2010;11(2):121-136.