Clinical trial NCT04084210
Conditions: Nicotine Dependence
Sponsor: University of Wisconsin, Madison
Start date: 2020-09-09; Completion date: 2022-05-23
Enrollment: 209 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this research is to understand the potential impact of two new FDA strategies to ensure the availability of safer Alternative Nicotine Delivery Systems (ANDS) and to reduce the nicotine content in combustible cigarettes to non-addictive levels. Specifically, this research will examine how well ANDS and very low nicotine cigarettes (VLNCs) can work alone or in combination with the current strategy of providing a safe source of nicotine via nicotine replacement medications to reduce use of combustible cigarettes, in real-world settings.

The investigators will enroll 180 daily adult smokers who are not planning to quit smoking within the next 30 days into this mixed design study. Participants will be randomly assigned to one of three levels of the between-subjects factor: 1) VLNC cigarettes; 2) Juul e-cigarettes (with nicotine); or 3) no alternative product. Participants receiving an alternative product (VLNC or e-cigarettes) will be asked to use it for 4 weeks (Weeks 1 through 4). During Weeks 2 and 4 all participants will be asked to switch from their cigarettes to use only study products (i.e., Juul e-cigarettes, VLNCs, or no alternative product) and to use either an active nicotine or placebo patch (the within-subjects factor), provided in double-blind fashion and counterbalanced order. During Weeks 1 through 4, participants will use a smartphone to record, in the moment, each time they use their own cigarettes or any alternative product. For a random daily subset of use events, participants will complete additional questions about the internal and external context of their use (e.g., affect, any restrictions on smoking) and their response to use (e.g., withdrawal alleviation, taste, satisfaction). Using these data, the investigators will also examine the effects of these products on the rewarding value of smoking and possible mechanisms driving such behavior (e.g., withdrawal alleviation, satisfaction, taste).

This research will provide critical information regarding the potential impact of providing cigarettes with non-addictive levels of nicotine and safe ANDS, with or without nicotine replacement, in real-world settings on smokers' use of their usual cigarettes and other outcomes. Information on the short-term effects of products that could be accessible in the future will provide data that could inform regulatory policy decisions regarding the public health impact of safe ANDS and non-addictive cigarettes.

Detailed description:
Design and Objective: The primary goal of this research is to assess the ability of alternative products (VLNCs vs. e-cigs vs. no alternative product; between-subjects factor) to serve as a substitute for conventional cigarettes and how this is influenced by steady-state nicotine (nicotine vs. placebo patches; within-subjects factor). In addition, the investigators will explore the contexts in which participants are and are not able to switch from their conventional cigarettes. Such contextual information will provide insight into internal (i.e., withdrawal, expectancies) and external environments (i.e., being around smokers, smoking restrictions) that promote or interfere with switching behavior. The investigators will also explore person factors and beliefs that may drive alternative product use and substitution success. Person factors that may influence use behavior include sex (a key biological variable), education level, dependence, instrumental smoking motives (e.g., smoking for affect regulation, taste, or social experiences), and psychiatric comorbidity. Beliefs that may influence use behavior include beliefs about the safety and addiction potential of conventional cigarettes and the alternative products. Understanding the relation of person factors and beliefs with use behavior could inform regulatory actions related to product labeling and education. Finally, the investigators will explore potential mechanisms that might drive use behavior and support substitution.

This research will enroll 180 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, e-cigs, or no product). Participants will be randomized to receive either 4 weeks of VLNCs, 4 weeks of 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). All participants will be given patches (active nicotine or placebo, in counterbalanced order) to use during the Switch Week. After this first Switch Week, participants will smoke normally for one week and then have their second Switch Week using the other type of patch (active or placebo). Participants will complete Ecological Momentary Assessments (EMAs) on smartphones at baseline 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. The investigators will then conduct a 3-month follow-up to assess 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.: 1) rigorous assessment of the key outcome (conventional cigarettes smoked); 2) assessment of product use during switching; 3) use of appropriate control/comparison groups; 4) measurement of product exposure/use that precedes switching; 5) evaluation of the dose and duration of product exposure/use; and 6) clear evaluation of the type and quality of the products used (e.g., satisfaction).

Recruitment and Participants: Participants from the greater Madison and Milwaukee, Wisconsin areas will be recruited via media recruitment methods (i.e., television, newspaper, and earned media) that have recruited thousands of smokers. Investigators will also use Internet/Facebook advertisements that have been successful in recent e-cig studies that recruited 422 smokers willing to provide EMA data during seven 2-week assessment periods over 2 years and 74 dual users willing to reduce combustible cigarette use and switch to using only e-cigs. Given this, it is feasible to recruit 180 smokers for this study within 18 months.

Procedures and Measures: Interested smokers will complete a phone screen to determine initial eligibility. Potentially eligible smokers will attend an orientation visit where, after providing a breath sample to verify eligibility (CO \> 6 ppm), they will receive a detailed description of the study and provide written informed consent, and complete baseline assessments. At Visit 1, participants will be randomized to receive VLNCs, e-cigs, or no alternative product and will be trained to use the product. The study database will randomize participants, stratified by clinic, gender, and race \[White vs. Non-White\], to enhance scientific rigor and reproducibility. Participants will be trained to use the smartphone to complete daily assessments, using the training that was effective in prior research, and will schedule future study visits. Participants will use their alternative products as they would like for one week to become comfortable with the product. At Visit 2, 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, and be given study patches to use during Switch Week 1 when they will be asked to abstain from using their own cigarettes for the week. 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, participants will be told that they can smoke as usual for a week. Then, at the start of Switch Week 2 (Visit 5), participants will be given the other type of patch (active or placebo) and asked to abstain from smoking their own cigarettes for a week. As during the prior Switch Week, participants will attend visits mid-week and at the end of the week to assess biomarkers (Visits 6 and 7). The investigators 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. 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. Participants will carry a smartphone to complete EMAs from Orientation through all 4 weeks of product use.

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.

Arms: arm 1: Participants will be given Juul e-cigarettes for four weeks; in Switch Week 1, participants also will use active nicotine patches; in Switch Week 2, participants will use placebo patches. arm 2: Participants will be given Juul e-cigarettes for four weeks; in Switch Week 1, participants also will use placebo patches; in Switch Week 2, participants will use active nicotine patches. arm 3: Participants will be given very low nicotine cigarettes (VLNCs) for four weeks; in Switch Week 1, participants also will use active nicotine patches; in Switch Week 2, participants will use placebo patches. arm 4: Participants will be given very low nicotine cigarettes (VLNCs) for four weeks; in Switch Week 1, participants also will use placebo patches; in Switch Week 2, participants will use active nicotine patches. arm 5: Participants will be given no alternative nicotine delivery products but in Switch Week 1, participants will use active nicotine patches; in Switch Week 2, participants will use placebo patches. arm 6: Participants will be given no alternative nicotine delivery products for two weeks but in Switch Week 1 participants will use placebo patches; in Switch Week 2, participants will use active nicotine patches.
Interventions: intervention 1: Juul Electronic cigarette intervention 2: Very Low Nicotine Cigarettes intervention 3: Active Nicotine Patch intervention 4: Placebo Patch
Intervention descriptions: intervention 1: The juul e-cigarette pods contain 0.7 ml nicotine by volume / 5% nicotine by weight. intervention 2: These very low nicotine cigarettes (VLNCs) consist of reduced nicotine cigarettes containing 0.03 mg of nicotine; these VLNCs were obtained from National Institute on Drug Abuse (NIDA's) Drug Supply Program (NOT-DA-14-004). intervention 3: Active nicotine patches, with dosing based on the package insert (\>10 cigs/day = 21 mg patch and \<11 cigs/day = 14 mg patches). intervention 4: Placebo patch containing no nicotine.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
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. 


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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 


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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 


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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 


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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 


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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 


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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 


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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. 
 
 
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diagnosed participants. Subst Use Misuse. 1998;33(13):2665-2685. 
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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 
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Siddiqui O, Flay BR, Hu FB. Factors affecting attrition in a longitudinal smoking 
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Graham JW. Missing data analysis: making it work in the real world. Annu Rev Psychol. 
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Hedeker D, Gibbons RD. Longitudinal data analysis. Hoboken, NJ: Wiley; 2006. 
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Collins LM, Schafer JL, Kam CM. A comparison of inclusive and restrictive strategies in 
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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. 
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New York: McGraw Hill; 1991. 
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Singer JD, Willett JB. Applied longitudinal data analysis: modeling change and event 
occurrence. Oxford: Oxford University Press; 2003. 
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Bollen KA, Curran PJ. Latent curve models: a structural equation perspective. Hoboken, 
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Curran PJ, Obeidat K, Losardo D. Twelve frequently asked questions about growth 
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ICF_001.pdf: 
HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 1 of 11
University of Wisconsin-Madison
Consent to Participate in Research
and
Authorization to Use Protected Health Information for Research
Study Title for Participants: The Options Study
Formal Study Title: Understanding the real-world impact of the use of three alternate 
nicotine-delivery products on combustible cigarette use
Lead Researcher: Megan E. Piper, PhD, (608) 265-5472 
Where Lead Researcher works: Center for Tobacco Research and Intervention
_____________________________________
Invitation
We invite you to take part in a research study about people’s use of cigarettes and other 
forms of tobacco or nicotine. We are inviting you because you expressed an interest in 
sharing your experiences as a smoker.  
The purpose of this consent and authorization form is to give you the information you 
need to decide whether to be in the study. It also explains how health information will be 
used for this study and requests your authorization (permission) to use your health 
information.  Ask questions about anything in this form that is not clear. If you want to 
talk to your family and friends before making your decision, you can. When we have 
answered all your questions, you can decide if you want to be in the study.  This 
process is called “informed consent.”  
Important things to know about any research study:
<0000>
Taking part in research is voluntary. You can choose not to be in this study, or 
stop at any time. 
 
If you decide not to be in this study, your choice will not affect your healthcare or 
any services you receive. There will be no penalty to you. You will not lose 
medical care or any legal rights. 
___________________________________
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 2 of 11
More information about this study
Why are researchers doing this study?
The purpose of this research study is to understand how well electronic and low nicotine 
cigarettes can serve as a replacement or substitute for someone’s regular cigarettes. 
We also want to know whether nicotine from a nicotine patch can help make these a 
better substitute.  We are doing this research because the Food and Drug 
Administration needs more information on how different cigarettes are used in the real 
world.  
This study is being done at the University of Wisconsin Center for Tobacco Research 
and Intervention offices in Madison and Milwaukee. A total of about 225 people will 
participate in this study.  
Funding for this study is provided by the National Cancer Institute and the Food and 
Drug Administration. 
What will happen in this study?
If you decide to participate in this research study, the researchers will ask you to come 
to the research office 8 times over the next 4 weeks.  At each of these office visits you 
will complete different surveys. The surveys will include questions about your smoking 
and your use of study products, how dependent you are on nicotine, your mood, your 
thoughts about cigarettes and e-cigarettes, your health, your use of alcohol and 
marijuana, and basic demographic information (age, gender). You may skip any 
questions on the surveys or during interviews that you do not wish to answer. 
We will also ask you for a breath sample to measure carbon monoxide (a substance 
contained in cigarette smoke).  You will take a breath test that measures carbon 
monoxide in your lungs, which helps measure how much you smoke. After inhaling 
deeply and holding your breath for 15 seconds, you will breathe out into a disposable 
cardboard tube that will be placed over a sensor. Finally, we will ask you give us a urine 
sample for us to test to see how much nicotine is in your body.  We will ask you to 
urinate into a cup at the visit and we will use a test strip to measure the nicotine levels.  
Once the test is over your sample will be thrown out.
At your second study visit you will be randomly assigned (like flipping a coin) to get a 
JUUL e-cigarette, a low nicotine cigarettes, or no study product. You will be able to use 
your study product for 4 weeks, if you are assigned a product. You will be asked to 
return unused product as well as the JUUL, if you receive one, at the end of the study. 
Two times during this study you will be asked to not smoke your regular cigarettes for a 
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 3 of 11
week. We call these switch weeks. You can use your study product (if you have one) 
during switch weeks. You will also get a patch to wear each day during the switch 
weeks. One week the patch will have nicotine in it and the other week it won’t (a 
placebo patch). Neither you nor the staff will know whether you are getting a nicotine or 
a placebo patch the first week or the second week.
For the 4 weeks when you are on the study, we will ask you to record each time you 
smoke one of your cigarettes or use a study product (if you have one) in a smartphone 
app. At certain times the app will ask you to answer a few questions about your smoking 
or product use such as where you are and how you are feeling.  You will also be asked 
to answer questions each evening about your use of study products, number of your 
cigarettes you’ve smoked, and how you feel. The app will be provided to you as part of 
your study participation. If you have a smartphone with the Android operating system, 
you may choose to have the app installed on your phone but you will be responsible for 
the minimal data use. If you do not have an Android smartphone, or do not wish to use 
your own smartphone, the study will provide you with a smartphone. The study 
smartphone will only provide limited service and should only be used to complete the 
study assessments. You will not be responsible for the cost of the study smartphone 
data plan if you use a study smartphone.  You will need to return the study smartphone 
once the study is complete.
Finally, you will be asked to complete a 3-month follow-up phone call that will include 
answering questions about your smoking, your mood, your health, and your plans to 
quit smoking in the future.
Your participation during this first visit will last about 90 minutes and then future visits 
will last 30-60 minutes and the follow-up call will last about 15 minutes. The smartphone 
assessments should take about 5 minutes per day. This should result in about 18 hours 
of total participation time over the next 3 months.
Protected health information (PHI) used in this study
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 4 of 11
Protected health information, also called PHI, is information about your physical or 
mental health that includes your name or other information that can identify you, like 
your date of birth or medical record number. To do this study, we will use the following 
kinds of PHI:
 
Information about you, such as your birth date, home address, phone numbers 
(cell, home, work), email address and Social Security number (which is required 
by the IRS for participant payment)
 
Results of tests or procedures done as part of the study
 
Things you tell the researchers about your health
How long will I be in this study?
You will be part of the study for about 1 month while you are using study products and 
coming in for study visits.  After that, we would like to check on your smoking and health 
by calling you 3 months after you start the study.  During this follow-up call we will 
collect information about your smoking, health, mood, and thoughts about smoking, 
electronic cigarette use and quitting.
The researchers may take you out of the study, even if you want to continue, if
●
your health changes and the study is no longer in your best interest; this would 
include a significant increase in carbon monoxide or the number of study 
cigarettes smoked
●
you do not follow the study rules or no longer meet the requirements to be in the 
study
●
the study is stopped by the sponsor or researchers
●
you become incarcerated
Do I have to be in the study?  What if I say “yes” now and change my 
mind later?
No, you do not have to be in this study. Taking part in research is voluntary.  This 
means that you decide if you want to be in the study.  If you decide now to take part, 
you can choose to leave the study at any time.  
If you decide to be in the study, the researchers will tell you about new information or 
changes in the study that may affect your willingness to continue in the study.
Let the researchers know if you choose to leave the study.  
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 5 of 11
If you decide not to take part in the study, or if you choose to leave the study, your 
choice will not affect any treatment relationship you have with healthcare providers at 
UW-Madison, UW Health or any affiliated organizations, or any services you receive 
from them.  No matter what decision you make, and even if your decision changes, 
there will be no penalty to you. You will not lose medical care or any legal rights.
Your authorization for researchers to use your protected health information (PHI) does 
not have an end date.  However:
●
You can choose to take back your authorization for researchers to use your 
health information.  You can do this at any time before or during your 
participation in the research. 
●
If you take back your authorization, information that was already collected may 
still be used and shared with others, but the researchers will no longer be able 
to collect NEW information about you.  
●
If you take back your authorization, you will not be able to take part in the 
research study.
●
To take back your authorization, you will need to tell the researchers by 
writing to the Lead Researcher, Megan Piper, at 1930 Monroe St., Suite 200, 
Madison, WI  53711.
Will being in this study help me in any way?
Being in this study will not help you directly.  Your participation in the study may benefit 
other people in the future by helping us learn more about how well electronic cigarettes 
and low nicotine cigarettes can substitute for regular cigarettes. This is important 
information for the Food and Drug Administration as they try to develop public health 
regulations of the tobacco industry. 
This study is not a substitute for your regular medical care. You should continue to see 
your regular medical providers.
Will I receive the results of research tests?
All of the tests that are part of this study are for research purposes only. Because of 
this, we will not tell you or your doctors the results of these research tests.
What are the risks?
The main physical risks of this study are:
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 6 of 11
●
Withdrawal symptoms during the switch weeks such as craving, difficulty sleeping, 
negative mood, and hunger.
●
Common side effects from the nicotine patch such as skin irritation, trouble sleeping, 
and vivid dreams.
●
A rare risk of nicotine patch is an allergic reaction.  The allergic reaction could be life 
threatening.
●
Getting too much nicotine could cause nausea and vomiting (throwing up).
●
Some people using e-cigarettes have experienced seizures.
There is also a risk that your information could become known to someone not involved 
in this study. This study involves asking questions about illegal substances / drug use. 
There is a chance that someone outside of the study could find out about the answers 
to your questions. If that happens, this could expose you to legal risks or damage your 
reputation. We will try to keep others from getting this information by storing all of your 
information securely and limiting the number of people who have access to this 
information. 
Will being in this study cost me anything?
There will be no cost to you for any of the study activities or procedures. You would be 
responsible for any data costs that you incur if you decide to use your own smartphone 
during the study.
Will I be paid or receive anything for being in this study?
You will receive up to $380 over the course of this 3-month study. You will be paid:
 
$20 for completing each of the 8 study visits ($160 total if you complete all visits). 
 
$20 for completing the 3-month follow-up call
 
$200 for completing 80% of the EMA prompts and nightly assessments OR $150 
for completing 75% of the EMA prompts and nightly assessments.
What happens if I am injured or get sick because of this study?
If you are injured or get sick because of this study, medical care is available to you 
through UW Health, your local provider, or emergency services, as it is to all sick or 
injured people. 
 
If it is an emergency, call 911 right away or go to the emergency room. 
 
For non-emergency medical problems, contact your regular health care provider.
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 7 of 11
 
Call the Lead Researcher, Megan Piper, PhD, at 608-262-8673 to report your 
sickness or injury.
Here are some things you need to know if you get sick or are injured because of this 
research: 
 
If the sickness or injury requires medical care, the costs for the care will be billed 
to you or your insurance, just like any other medical costs. 
 
Your health insurance company may or may not pay for this care.
 
No other compensation (such as lost wages or damages) is usually available.
 
UW-Madison and UW Health do not have a program to pay you if you get sick or 
are injured because of this study.
 
By signing this consent form and taking part in this study, you are not giving up 
any legal rights you may have. You keep your legal rights to seek payment for 
care required because of a sickness or injury resulting from this study. 
We have strict rules to protect your personal information and protected health 
information (PHI).  We will limit who has access to your name, address, phone number, 
and other information that can identify you.  We will also store this information securely.  
The study has a Certificate of Confidentiality from the National Institutes of Health. A 
Certificate of Confidentiality prohibits researchers from disclosing information or 
biospecimens that may identify you in a legal proceeding or in response to a legal 
request without your consent. We may publish and present what we learn from this 
study, but none of this information will identify you directly without your permission.
However, we cannot promise complete confidentiality. Federal or state laws may permit 
or require us to show information to university or government officials and to study 
sponsors responsible for monitoring this study. These groups will maintain your 
confidentiality.  By signing this consent form, you are authorizing this access to your 
records. We may also have to tell appropriate authorities, such as child protective 
services or health care providers, if we learn during the study that you or others are at 
risk of harm (for example, due to child or elder abuse, or suicidal thoughts).
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at 
any time.
Authorizing the research team to use your PHI means that we can release it to the 
people or groups listed below for the purposes described in this form.  Once your health 
How will the researchers keep my research information confidential? 
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 8 of 11
information is released outside UW-Madison or UW Health it may not be protected by 
privacy laws and might be shared with others.  Also, with appropriate institutional 
permissions and confidentiality protections, we might use information that we collect 
during this study for other research or share with other researchers without additional 
consent or authorization from you or your legally authorized representative.  
Who at UW-Madison can use my information?
 
Members of the research team 
 
Offices and committees responsible for the oversight of research
Who outside the UW-Madison may receive my information?
 
U.S. Office for Human Research Protections 
 
The U.S. Food and Drug Administration (FDA)
 
The study sponsor, the National Cancer Institute
Will information from this study go in my medical record?
None of the information we collect for this study will go in your medical record.  The 
researchers are not required to release health information to you if it is not part of your 
medical record.
What if I have questions?
If you have questions about this research, please contact the Lead Researcher, Megan 
Piper, PhD., at 608-262-8673. If you have any questions about your rights as a research 
subject or have complaints about the research study or study team, contact UW Health 
Patient Relations at 608-263-8009.  The Patient Relations Representatives work with 
research subjects to address concerns about research participation and assist in 
resolving problems.
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 9 of 11
Agreement to participate in the research study
You do not have to sign this form. If you refuse to sign, however, you cannot take part in 
this research study.
If you sign the line below, it means that:
●
You have read this consent and authorization form.
●
You have had a chance to ask questions about the research study, and the 
researchers have answered your questions.   
●
You want to be in this study.
●
You give authorization for your protected health information to be used and 
shared as described in this form.
______________________________________________________________________
Printed Name of Research Participant
______________________________________________________________________
Signature of Research Participant
Date
______________________________________________________________________
Signature of Person Obtaining Consent and Authorization
Date
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University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 10 of 11
VOLUNTARY STATEMENT OF INTENT TO AVOID PREGNANCY 
According to the FDA and the manufacturers of the nicotine patch, this medication 
should not be used by pregnant women.  The risks of these medications to an unborn 
child are not fully known.  We ask study participants who are able to get pregnant or 
who believe that it is possible to get pregnant to agree to the statement below about 
avoiding pregnancy while taking study medication.  
I, _________________________________ (print name), agree to attempt to avoid 
pregnancy while I am taking study medication.  I will continue to employ medically 
acceptable means of contraception that have been approved by study staff.  These 
methods include abstinence from sex with men, condoms, diaphragm, birth control pills, 
injectable contraceptive (e.g., Depo-Provera), contraceptive implant (e.g., Implanon), 
IUD, hysterectomy, tubal ligation, sterilization, vasectomy, or being more than 1 year 
post-menopausal. I will immediately contact study staff if pregnancy is suspected. I am 
aware that I may decline to sign this statement; however, I cannot participate in this 
research study.
____________________________________                        ______________________ 
Signature of Participant                           
Date
**You will receive a copy of this form**
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison


HS IRB #: 2019-0252
Lead Researcher: Megan Piper, PhD, 608-265-5472
Version: December 30, 2021
Page 11 of 11
Email and Text Use
We are requesting your email address and text messaging number so we can send you 
reminders about study visits. Email and texting is generally not a secure way to 
communicate about your health as there are many ways for unauthorized users to 
access email and text messages. You should avoid sending sensitive, detailed personal 
information by email or text. Email and text messages should also not be used to 
convey information of an urgent nature. If you need to talk to someone immediately, 
please contact Project Principal Investigator Megan E. Piper, PhD at 608-265-5472. 
You do not have to provide your email address or text messaging number to participate 
in this study.
Email
 Yes, you may use email to contact me for this study.
 No, I do not want to be contacted by email.
Text
 Yes, you may use text messages to contact me for this study. I know that I will be 
responsible for all texting charges.
 No, I do not want to be contacted by text messages.
**You will receive a copy of this form**
IRB Approval Date: 1/14/2022              
University of Wisconsin – Madison