Comparative Abuse Liability of Cigarettes, E-cigarettes, and Heat-not-burn Devices Among African American and White Smokers
Phase: NA
Conditions: Tobacco Use Disorder
Sponsor: University of Kansas Medical Center

 
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University of Kansas Medical Center  
RESEARCH PROTOCOL INVOLVING HUMAN SUBJECTS  
TEMPLATE WITH GUIDANCE 
 
Version date: May 11, 2021 
Principal Investigator: Nikki L. Nollen, PhD 
Study Title: Comparative Abuse Liability of Cigarettes, E-cigarettes, and Heat-not-burn 
devices among African American and White Smokers 
Co- Investigator(s): Eleanor Leavens, PhD; Matt Mayo, PhD; Matthias Salathe, MD 
 
I. 
Purpose, Background and Rationale 
A. Aim and Hypotheses  
1. Use of electronic cigarette (e-cigarette) and heat-not-burn (HNB) products is 
continuing to proliferate in the US. In fact, e-cigarette use is expected to 
surpass combustible cigarette smoking rates in the next two years. The US 
FDA has regulatory authority to set appropriate product standards for e-
cigarettes and heat-not-burn products with the goal of maximizing public 
health. Initial data suggest that these products present reduced harm 
compared to combustible cigarette smoking, but the comparative abuse 
liability and interest in use by smokers, particularly as a function of product 
flavor, remains largely unknown. These questions are critical in helping the 
FDA impose meaningful and effective regulations on these products. African 
American (AA) smokers are showing increased interest in these new and 
emerging products. Research suggests AA smokers take larger puffs and 
inhale more deeply than whites. Therefore, data are needed to understand if 
AA smokers will also use e-cigarettes and HNB devices in such a way that 
could inadvertently increase harm in the long run. Additionally, research is 
urgently needed to understand whether these products (if shown to be less 
harmful than cigarettes), would be an acceptable alternative to traditional 
smoking and how product flavor (tobacco vs. menthol) impacts use patterns 
and preference. The current study is not a cessation study and does not aim 
to induce long-term uptake of the study products. The objective of the study 
is to test the acute pharmacokinetic profile of these products during a 65-
minute use period with each product across three to four study visits.  
2. Aim 1: Understand the abuse liability of heat-not-burn devices, e-cigarettes, 
and combustible cigarettes in terms of nicotine delivery, puff patterns 
(topography), and reductions in nicotine withdrawal/craving. H1: Combustible 
cigarettes will show the fastest and greatest nicotine delivery, followed by e-
cigarettes, and heat-not-burn devices. H2: Topography measures will be 
greatest for cigarettes, followed by e-cigarettes, and heat-not-burn devices. 
H3: Use of cigarettes will be associated with the greatest reduction in 
symptoms of nicotine withdrawal and craving. 
Aim 2: Examine resultant toxicant exposure of heat-not-burn devices, e-
cigarettes, and combustible cigarettes. H1: Exhaled carbon monoxide will be 
greatest for cigarettes, followed, by heat-not-burn devices and e-cigarettes 
(no exposure). 

 
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Aim 3: Understand the comparative acceptability of tobacco and menthol 
flavored e-cigarettes among menthol cigarette smokers. H1: Menthol 
cigarette smokers will show increased topography measures when using the 
menthol (vs. tobacco) flavored e-cigarette. H2: Menthol cigarette smokers will 
show increased acceptability and more positive subjective effects when using 
the menthol (vs. tobacco) flavored e-cigarette. 
Exploratory Aim: Understand differences in abuse liability of e-cigarettes, HNB 
products, and cigarettes as measured behaviorally in a concurrent choice 
task.  
B. Background and Significance 
1. Study Significance: Electronic cigarettes (e-cigarettes) and heat-not-burn 
(HNB) devices have been introduced to the US market in the past 15 years. 
The US Food and Drug Administration (FDA) is tasked with regulating these 
emerging products in order to maximize public health. To do this, data are 
needed regarding product effects including abuse liability (nicotine delivery, 
addiction potential, and reductions in nicotine withdrawal/craving), product 
demand, and resultant toxicant exposure.  Further, research suggests that 
these products present reduced harm to the user compared to combustible 
cigarettes. If this is continually shown to be the case, they may be a less 
harmful alternative to smoking combustible cigarettes. However, it remains 
unclear whether they are an acceptable alternative to smokers and whether 
smokers would choose to use them in place of combustible cigarettes, 
particularly as a function of flavor (menthol vs. tobacco). Moreover, as more 
smokers transition to these new and emerging products, it is important to 
understand how underserved populations will use these products. African 
American (AA) smokers bear a disproportionate burden of smoking-related 
diseases and represent an understudied population with a propensity to use 
products in a way that is different compared to the majority population. AA 
smokers take larger puffs and inhale more intensely on cigarettes than 
whites. Therefore, data are needed specific to this population to understand 
how to maximize public health while avoiding harm to underserved 
populations, such as AA smokers. The long-term goal of this research is to 
provide data urgently needed by the public health community and policy 
makers in order to inform regulatory decisions and maximize public health. 
2. Overall Literature Review: The current study will utilize a nicotine salt-based 
e-cigarette from JUUL. Research from JUUL shows that it can deliver 
cigarette-like levels of nicotine to the user. 1 One independent study showed 
that JUUL delivered a higher and faster boost in nicotine compared to other e-
cigarette devices and showed that the boost and rate of nicotine deliver was 
comparable to smoking one cigarette when used by established e-cigarette 
users.2 One recent study reports on nicotine delivery among smokers and 
indicates that JUUL approached but did not reach cigarette-like levels of 
nicotine delivery.3 Unpublished data from our laboratory suggest that some 
smokers are able to effectively extract nicotine from JUUL while others may 
necessitate significant practice in order to achieve cigarette-like serum 
nicotine levels.4 In regards to HNB, we will be using the IQOS device created 
by Philip Morris International (PMI). Until recently, the only data on the abuse 
liability and nicotine delivery of this product were from PMI. To our 
knowledge, only one recently published independent study has been 
conducted and showed that while IQOS significantly increased nicotine levels 

 
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following the 10-puff PK assessment and ad lib use, it did not reach cigarette-
like levels of nicotine delivery.3 Data from PMI on the pharmacokinetics (PK) 
of IQOS suggest that the device is capable of delivering cigarette-like levels of 
nicotine in a regimented PK study as well as when users engage in ad lib 
smoking.5,6 However, we are unaware of any independent studies comparing 
the IQOS HNB product, popular e-cigarettes, and combustible cigarettes in 
terms of nicotine deliver, overall abuse liability, or acceptability for 
substitution. Moreover, we are unaware of any studies examining these 
concepts in AA smokers, a population particularly vulnerable to tobacco-
related harms. 
3. Detailed review:  
Does brief exposure to e-cigarettes and HNB devices increase risk to 
smokers? 
- 
No, there is no evidence to suggest that brief use of e-cigarette or HNB 
products increases risk to current cigarette smokers above that provided 
by cigarettes alone. Lab studies of toxin exposure suggest that e-
cigarettes incur no greater risk to health than do conventional 
cigarettes.7-9 Indeed, e-cigarettes generally show lower levels of harmful 
and potentially harmful constituents.7-9 The evidence is so strong 
regarding the reduced harm of e-cigarettes compared to cigarettes, that 
the National Academies of Sciences, Engineering, and Medicine has 
concluded that there is “conclusive evidence” that e-cigarettes are 
associated with reduced harm compared to cigarettes.8 To date, e-
cigarette studies discussing adverse events report mild and tolerable side 
effects that generally resolved completely over time with continued use; 
the most predominant of which were mouth/throat irritation, cough, and 
headache.10-12 In four randomized clinical trials, no serious adverse 
events were reported and the e-cigarette group and the nicotine patch 
group had comparable levels of adverse events in two studies.13 The most 
common were mouth irritation, throat irritation, dry cough and 
headache.13 Fewer studies exist on HNB products but those that do, 
mimic results from studies on e-cigarettes and show that HNB products 
have lower toxicant levels compared to combustible cigarettes and have 
lower levels of harmful and potentially harmful constituents.14 In fact, 
studies in which smokers are asked to switch to exclusive HNB use, levels 
of harmful and potentially harmful constituents approach those observed 
in non-smokers.15,16 Similar to the e-cigarette literature, research 
discussing adverse events with HNB products report no serious adverse 
events and only mild and tolerable side effects that resolve completely 
over time. The most common adverse effect was cough.17  
What are the effects of dual e-cigarette and conventional cigarette 
use? 
- 
Research shows that when smokers begin using e-cigarettes, they reduce 
the number of cigarettes they smoke per day and show decreases in 
tobacco-related toxins.7-9 In a study conducted by Dr. Nollen and her 
team,18 smokers were asked to completely substitute with e-cigarettes. 
Approximately 30% were successful in completely substituting.18 
Moreover, those that did not successfully substitute but instead used both 
cigarettes and e-cigarettes, significantly reduced their cigarettes per day 
and showed significant reductions in NNAL, a potent lung carcinogen at 6-
week follow-up.19 While those that switch to these products and those 
that go on to dual use them show reductions in harm, cigarette smokers 

 
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continue smoking at their usual rate and show no reductions in toxicant 
exposure.18,19 
What are the effects of dual HNB and conventional cigarette use? 
- 
Less information is known regarding dual HNB and conventional cigarette 
use because the product has only been on the US market for a short 
time. However, the existing studies show that when randomized to switch 
completely to HNB products, 64% switched completely. Moreover, users’ 
levels of NNAL dropped significantly from baseline to follow-up and were 
significantly lower than NNAL levels in the traditional cigarette group at 
follow-up.20 While our study is not a switching or cessation trial, these 
data suggest that brief use of HNB devices by current smoker swill not 
increase their harm. It is also unlikely that they will become dual users of 
HNB products as this has not been documented in the literature.  
Does use of e-cigarettes and HNB devices increase conventional 
cigarette smoking? 
- 
No, e-cigarette and HNB devices do not increase conventional cigarette 
smoking. As mentioned above, studies conducted by our team show that 
when provided an e-cigarette, users reduce their cigarette smoking.18,19 
While the HNB literature remains in its infancy, no studies suggest that 
brief exposure to HNB products increase cigarette smoking. 
Is the proposed pharmacokinetic evaluation method common? 
- 
Yes, this method of evaluation is the gold standard for evaluating nicotine 
delivery and abuse liability.3,21-27 In addition, studies on relatively newer 
products almost always recruit smokers because cigarette smoking is the 
most harmful form of tobacco use in the world. Therefore, it is generally 
agreed that inviting smokers to use a product with potentially reduced 
harm for a brief period of time incurs no elevated risk to the participant. 
To date, this method has been successfully applied to assess e-
cigarettes,3,21-24 HNB products,3 and waterpipes.25-27 In fact, a recent 
publication mimicked this study almost exactly but with white smokers 
and was published in the highest impact journal in the field of tobacco 
regulatory science.3 Researchers on this team have been PI and co-I on 
five such pharmacokinetic studies.4,23,25-27  
 
C. Rationale 
1. Industry-funded studies suggest that HNB devices and popular e-cigarettes 
can deliver cigarette-like levels of nicotine and therefore have comparable 
abuse liability profiles to combustible cigarettes. If this is the case and 
research continues to show that these products expose users to less harm 
compared to traditional cigarettes, they may be an acceptable product for use 
by current smokers who are unwilling or unable to quite to reduce tobacco-
related harm. However, industry-funded studies are open to bias and 
therefore independent studies are urgently needed to inform appropriate 
regulations.  
2. The current study will provide objective data on the nicotine delivery and 
overall abuse liability (craving, reductions in nicotine-related withdrawal 
symptoms), and acceptability of emerging and popular products (HNB and e-
cigarettes) among AA smokers, a population particularly vulnerable to 
tobacco-related harms and who has been underrepresented to date in data 
aimed at informing regulations to improve public health. Moreover, we will 
investigate how flavors in e-cigarettes impact product acceptability and abuse 
liability (i.e., interest in future use, puff patterns/topography, subjective 

 
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experience) among menthol cigarette smokers. These data will be used by the 
FDA to inform appropriate regulation of these products.  
3. Tobacco remains the leading cause of preventable death in the US and each 
year close to half a million people die due to tobacco-related diseases. 
Therefore, for smokers that are unable or unwilling to quit, products such as 
e-cigarettes and HNB devices may present less harm and improve public 
health.  
 
II. 
Research Plan and Design 
 
A. Study Objectives: The objective of this study is to understand the abuse liability 
and resultant toxicant exposure of new and emerging tobacco products in 
comparison to smokers’ usual brand cigarette and to further understand how 
flavors in e-cigarette products impact abuse liability among menthol cigarette 
smokers. The current study is not a cessation study and does not aim to induce 
long-term uptake of the study products. The objective of the study is to test the 
acute pharmacokinetic profile and acceptability of these products during a 65-
minute use period with each product across three to four study visits. African 
American and white smokers (N = 20) will be recruited and complete three to 
four in-laboratory sessions in a randomized crossover design. 
B. Study Type and Design: The proposed study is a randomized crossover trial. 
Current smokers will be randomized to session order and complete a 
standardized 10-puff bout (5 minutes) followed by a 60-minute ad libitum session 
with each product (usual brand cigarette, e-cigarette, heat-not-burn). 
Throughout each visit, blood will be collected for nicotine analysis via an IV 
catheter placed in the patient’s arm. Blood samples will be aliquoted into two 
separate vials. One will be analyzed for the current study and one will be placed 
in a biospecimen repository if participant provides consent for biorepository. Puff 
topography will be collected passively throughout the session to measure puffing 
patterns. Participants will complete self-report measures of nicotine withdrawal 
and craving. Finally, breath samples will be collected to measure changes in 
exhaled carbon monoxide, a potent lung toxicant, pre- and post-product use. At 
the final visit, participants will complete a behavioral economics concurrent 
choice task (see below for description) to behaviorally measure their decisions 
regarding use of e-cigarettes or HNB products in place of cigarettes. Finally, 
participants will be contacted by phone 6 months following the conclusion of visit 
3 (or study discontinuation) to complete a phone survey. The objective of this 
survey is to assess for ongoing use of study products and is part of safety 
monitoring. We have no hypotheses related to the follow-up.  
 
Participants who report typically smoking menthol cigarettes will be invited to 
complete a fourth session. Participants will undergo overnight tobacco/nicotine 
abstinence before the visit (eCO<12ppm). Participants will then be randomized 
1:1 to e-cigarette flavor order (tobacco e-cigarette, menthol e-cigarette) and will 
complete sessions in a counterbalanced fashion to control for order effects. They 
will complete a 30-minute ad libitum session with the first product, based on 
randomization, followed by a 1.5-hour standard washout period, followed by a 
30-minute ad libitum vaping session with the second product (menthol or tobacco 
flavor). Throughout each session, puff topography will be measured via a 
pressure sensor attached to the e-cigarette device. Participants will complete 
self-report measures of smoking urges and withdrawal symptoms pre- and post-

 
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vaping session. In addition, they will complete measures of subjective vaping 
experience, perceptions of flavor, product demand, and intentions for future use.  
 
C. Sample size, statistical methods, and power calculation 
1. 20 eligible AA and white smokers will be randomized. We will use a 1:1 
fashion randomization to product order (combustible cigarette, e-cigarette, 
heat-not-burn device vs. combustible cigarette, heat-not-burn device, e-
cigarette). Randomization will be determined by computer-generated random 
numbers. Randomization assignments will be placed in sealed envelopes with 
sequential study ID numbers. After baseline data collection has been 
completed, the research assistant will select the sequential study ID number 
to determine the randomization assignment 
2. No blinding is involved in the first three study visits. For participants who 
complete the fourth visit (flavor assessment), participants and research 
assistants that interact with participants will be blind to flavor (double blind 
design). 
3. Due to the pilot nature of the current study, a primary aim of the study is to 
collect data for power calculations for a fully powered trial. Therefore, formal 
power calculations were not conducted. ANOVAs will be conducted to detect 
within-subject differences between products for all outcomes. A Bonferroni 
correction will be applied to adjust for multiple comparisons. A paired samples 
t-test will be conducted to detect differences in outcomes in the e-cigarette 
flavor assessment.  
 
D. Subject Criteria (See Vulnerable Populations appendix, if applicable): 
Participants will be AA and white adult smokers ≥21 years old. The study will be 
open to both men and women. We have chosen to focus on AA because their 
unique smoking profile places them at potentially greater risk for tobacco-related 
disease and death and because AA smokers are understudied in terms of the 
potential differential effect of tobacco-related policy among this population. 
Women who are pregnant, plan to become pregnant, or are breastfeeding will be 
excluded from the study because tobacco products will be provided and smoking 
is associated with low birth weight and premature labor. Children and those <21 
years old will be excluded because the minimum age for purchasing tobacco 
products is 21 years old.  
1. Inclusion criteria: Non-Hispanic African American or white/Caucasian, ≥21 
years old, smoke 5-30 cigarettes per day, daily cigarette smoker, smoked at 
current rate for at least 6 months, interested in trying e-cigarettes and HNB 
products, not interested in or unable/unwilling to quit cigarette smoking, 
willing to complete three in-person study visits, willing to have IV catheter 
placed.  
2. Exclusion criteria: Interested in quitting cigarettes in the next 30 days, use of 
smoking cessation pharmacotherapy in the past 30 days, use of non-cigarette 
tobacco products in the past 30 days, use of e-cigarettes >5x in lifetime, use 
of e-cigarettes ≥4 of the past 30 days use of HNB products >5x in lifetime, 
use of HNB products ≥4 of the past 30 days, weight < 110 lbs, uncontrolled 
hypertension (systolic BP ≥ 180 or diastolic BP ≥ 105), pregnant, plans to 
become pregnant, or breastfeeding, live >10 miles from study site (Fairway 
CRU), current enrollment is a research study or program that aims to alter 
tobacco use.  
3. Withdrawal/Termination criteria: Participants will be instructed to practice 
with (and attempt to switch to) each device prior to attending study visits 2 
and 3. Participants may be removed from the study if they fail to complete 

 
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sufficient practice prior to each study visit. Additionally, participants will 
present to the lab nicotine deprived (12 hours abstinent) for study visits 1, 2, 
and 3. If participants present to study visit 1 and eCO is greater than 12 ppm 
or they report other nicotine use two times, they will be removed from the 
study.    
4. Participants will not be allowed to participate in another research study that 
aims to alter their tobacco use during this research study.  
 
A. E.  Specific methods and techniques used throughout the study  
 
1. Laboratory tests: Throughout each visit, blood will be collected for nicotine 
analysis via an IV catheter placed in the patient’s arm. Blood draws will occur 
during the PK phase of each visit and will be taken at baseline (0 minutes), 5 
minutes, 7 minutes, 15 minutes, and post-ad lib portion (may vary by 
participant depending on how long they choose to use the product). No more 
than 7 mL of blood will be drawn per draw (≤35 mL per visit). Blood will be 
processed and analyzed for nicotine and cotinine levels. If consent is provided 
for banking, samples will be banked for possible future analysis. 
2. Study Procedures:  
a. Initial screening: The initial screening will review inclusion/exclusion 
criteria. Those eligible will be scheduled to completely visit within 14 
days. 
b. Visit one: At visit one, participants will be re-screened according to 
inclusion/exclusion criteria. They will be instructed to remain nicotine 
abstinent for 12 hours prior to the visit. Participants will complete 
carbon monoxide (CO) measurement to confirm abstinence (CO ≤ 12 
ppm). CO is collected by a simple, non-invasive breath test that 
involves the participant holding their breath for ~15 seconds and then 
exhaling into a straw connected to the CO monitor. Participants will be 
provided with an overview of the study, will provide informed consent, 
and complete baseline self-report measures. Participants will then 
complete the PK phase of the study. Participants will have an 
intravenous catheter placed in their arm. They will complete a 10-puff 
standardized puffing bout followed by a 60-minute ad-lib smoking 
session with their usual brand cigarette. Specifically, a research 
assistant with a stopwatch will instruct the participant to take a puff 
every 30 seconds, resulting in 10 puffs over 5 minutes. Throughout 
the session, puff topography will be measured via a pressure sensor 
attached to the device/product. This will not require anything 
additional of the participant. Blood draws will occur during the 10-puff 
bout at -5, 5, 7, 15, and at the end of the ad-lib smoking period (~60 
minutes after the 10-puff bout). Following the smoking period, the 
participant will be instructed to make notes regarding their preferences 
related to the product (e.g., liking, satisfaction, craving, 
intentions/willingness for future use). Participants will complete self-
report measures of nicotine craving and withdrawal at each blood draw 
during the 10-puff bout and every 10 minutes throughout the ad-lib 
smoking period. At the end of the session, participants will complete a 
measure of product liking/evaluation. At the end of visit one, 
participants will be randomized to product order (e-cigarettes followed 
by HNB device vs. HNB device followed by e-cigarette). Participants 
will be shown how to use the device, puff on it, charge it, replace the 
pod/heat stick. Participants will be compensated $50 for this visit. In 

 
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addition, participants will be asked to bring an unopened back of their 
usual brand cigarettes to this visit. They will be compensated an 
additional $6 for this, bringing their total compensation to $56 for this 
visit. We anticipate the visit to last no more than 3 hours. 
c. Between visits one and two: Participants will be provided with the 
product to be used at the next visit (determined by randomization 
completed at the end of visit one) and asked to take it home for 48 
hours (+3 days) and instructed to, at minimum, practice using it 2-3 
times per day between visits. However, they will be encouraged to full 
substitute the study product for their cigarettes to ensure they conduct 
sufficient practice. They will be provided with e-liquid or heat sticks 
and the device for practice. Participants will complete and return a 
practice log at the following visit. 
d. Visit two: Aside from the product being used, visit two will closely 
mirror visit one. Participants will complete baseline self-report 
measures regarding their practice period (product liking/evaluation 
and preferences). Participants will again complete CO measurement to 
confirm tobacco/nicotine abstinence. They will complete a PK and ad-
lib session identical to visit one. At the end of the session, they will be 
oriented to the final device and again instructed to practice with (and 
attempt to fully substitute) it at home. Participants will be 
compensated $75 for this visit. We anticipate the visit to last no more 
than 2.5 hours. 
e. Between visits two and three: Participants will be provided with the 
product to be used at the next visit (determined by randomization 
completed at the end of visit one) and asked to take it home for 48 
hours (+3 days) and instructed to, at minimum, practice using it 2-3 
times per day between visits. However, they will be encouraged to full 
substitute the study product for their cigarettes to ensure they conduct 
sufficient practice.  They will be provided with e-liquid or heat sticks 
and the device for practice. Participants will complete and return a 
practice log at the following visit. 
f. 
Visit three: Aside from the product being used, the first portion of 
visit three will closely mirror visits one and two. Participants will 
complete baseline self-report measures regarding their practice period 
(product liking/evaluation and preferences). Participants will again 
complete CO measurement to confirm tobacco/nicotine abstinence. 
They will complete a PK and ad-lib session identical to visits one and 
two. Following the PK and ad-lib sessions, participants will have a 1.5-
hour washout/rest period in order to bring them to a state of nicotine 
deprivation. During the washout period, participants will be allowed to 
watch a movie or listen to music. Participants will then complete a 
concurrent choice task with their usual brand cigarette, e-cigarette, 
and HNB device. In the task, participants will earn puffs of the various 
products by clicking a mouse/keyboard a set number of times. The 
participants will be free to choose how they allocate the puffs between 
the available products. For each task, participants can earn up to 20 
puffs and the task will last up to 1.5 hours. Puff topography will be 
measured throughout the task. The objective of the task is to 
behaviorally measure whether or not participants see the e-cigarette 
and/or HNB device as an acceptable or preferable substitute for their 
usual brand cigarette. Participants will be compensated $100 for visit 

 
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three. In addition, participants will earn up to $50 for completing all 
study visits (see section III.G.). We anticipate that visit three will last 
no more than 4.5 hours.   
i. Computer task: The usual brand cigarette, e-cigarette, and 
HNB product are all available. Participants will earn puffs of the 
products by clicking boxes on a computer screen that represent 
the products. To earn 1 puff of a product, the participant will be 
instructed that they must click the corresponding box. In order 
to earn puffs of the e-cigarette or HNB product, they will click 
the corresponding box 10 times. To test relative demand for 
their usual brand cigarette, it will be placed on a variable ratio, 
meaning the number of clicks necessary to earn puffs of the 
usual brand cigarette will increase with each trial of the task. 
Once participants earn a puff, they will be given two minutes to 
have the puff before the next trial begins.  
 
Computer screen simulation for task:  
 
 
g. Visit four (menthol smokers only): Participants who report typically 
smoking menthol cigarettes will be invited to complete a fourth 
session. Participants will undergo overnight tobacco/nicotine 
abstinence before the visit (eCO<12ppm). Participants will then be 
randomized 1:1 to e-cigarette flavor order (tobacco e-cigarette, 
menthol e-cigarette). They will complete a 30-minute ad libitum 
session with the first product, based on randomization, followed by a 
1.5 hour standard washout period, followed by a 30-minute ad libitum 
vaping session with the second product. Throughout each session, puff 
topography will be measured via a pressure sensor attached to the e-
cigarette device. Participants will complete self-report measures of 
smoking urges and withdrawal symptoms pre- and post-vaping 
session. In addition, they will complete measures of subjective vaping 
experience, perceptions of flavor, product demand, and intentions for 

 
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future use. We anticipate that the session will last ~3 hours. 
Participants will earn $50 for attending the study visit. 
h. Six-month follow-up: Six months after completion of visit 3 (or 
study discontinuation), participants will be contacted by phone to 
assess ongoing use of study products. Three attempts will be made to 
contact the participant for this follow-up. If they endorse ongoing use, 
they will be advised to quit all tobacco use and offered a referral to the 
Quitline. We anticipate this phone follow-up to last no more than 10 
minutes. This follow-up assessment is for safety monitoring only.  
3. Due to COVID-19 and the need to keep patients and researchers safe, we will 
use Zoom, a HIPAA compliant, university approved video conferencing 
software, during the visit. This will allow the participant to smoke freely 
(unmasked) while the researcher can watch and communicate with the 
participant via video conferencing from outside the clinic room. We will utilize 
Zoom as much as possible and only enter the room when absolutely 
necessary.  
4. All tests, procedures, and visits are being performed solely for research 
purposes and are not billable to insurance companies. 
5. Samples will be labeled only with a unique study identification number and 
only members of the research team will have access to the samples. Samples 
will be disposed of one month after the final report is sent to the Principal 
Investigator, unless participants agree to have their samples stored for future 
testing. 
6. Timeline/project flow:  
 
Note. +CO ≤ 12 ppm; *blood draws, topography, self-report measures of craving, withdrawal, and 
product liking. 6 month follow-up not depicted. 
 
F. Risk/benefit assessment:   
1. Physical risk: The potential risks for this study are minimal. There is a slight 
risk of discomfort, bruising and infection with blood draw. Blood will be drawn 
by trained research staff. IVs will be placed by an RN or LPN. Sterile 
instruments will be used and for blood draws, the participants skin will be 
cleaned with an alcohol wipe at the site of the needle stick. Participants will 
complete no more than two study visits in a seven-day period.  
2. Psychological risk: Risks for participants include those associated with the 
inconvenience of participation including answering surveys, providing blood 
samples, and completing multiple visits. To minimize the inconveniences 
associated with study participation we will review all data collection 
instruments and study procedures to minimize the number of items in our 
instruments and improve the accessibility and convenience of our study 
procedures.  We anticipate using several methods to enhance convenience to 
participants, including providing rideshare services to and from all study visits 
and offering study visits throughout the day. Another risk is feeling pressured 
to be in the study, which we will track in order to monitor and will report as 
Visit Four 
-Present nicotine 
deprived 
-30 min ad lib 
vaping session 
-1.5 hour 
washout period 
-30 min ad lib 
vaping session 

 
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an adverse event. Finally, although very unlikely, some questions may make 
participants uncomfortable; participants are not required to answer questions 
they do not wish to. 
3. Social risk: None 
4. Economic risk: None 
5. Potential benefit of participating in the study  
a. There are no direct benefits to participants for participating in this 
study 
b. The researchers hope that the information gathered from this research 
may be useful in informing regulations to maximize public health 
G. Location where study will be performed: The screener visit will take place at 
Swope Health Central, 3801 Blue Parkway, in Kansas, Missouri or at the KUMC 
CRU in Fairway, Kansas based on the preference of each participant. Study visits 
1, 2, and 3 will take place at the KUMC CRU in Fairway, Kansas. All data will be 
directly entered into an electronic data capture system (i.e., RedCap or CRIS), 
therefore minimizing the use of paper records.  If paper records are generated, 
they will be stored in locked file cabinets.  Only study staff will have access to the 
locked records and the secure online electronic data capture system.   
H. Collaboration (with another institution, if applicable): N/A 
I. Single IRB Review for a Multi-site study (if applicable): N/A 
 
J. Community-Based Participatory Research (if applicable): N/A 
 
K. Personnel who will conduct the study, including: 
1. Indicate, by title, who will be present during study procedure(s): Personnel on 
the project include Nikki L. Nollen (PI), Eleanor L. S. Leavens (co-
investigator), Matt Mayo (co-investigator and biostatistician), Matthias 
Salathe (co-investigator), Tricia Snow (program coordinator director), TBD 
(GRA), CRU staff 
2. Primary responsibility for the following activities, for example:  
a. Determining eligibility: Eleanor Leavens, Nikki Nollen, Tricia Snow, 
Matthias Salathe, and GRA 
b. Obtaining informed consent: Eleanor leavens, GRA 
c. Providing on-going information to the study sponsor and the IRB: 
Eleanor Leavens, Nikki Nollen, Tricia Snow 
d. Maintaining participant's research records: Eleanor Leavens, Nikki 
Nollen, Tricia Snow, Matt Mayo, GRA 
e. Completing physical examination: N/A 
f. Taking vital signs, height, weight: CRU staff, Eleanor Leavens, GRA, 
Tricia Snow 
g. Drawing / collecting laboratory specimens: CRU staff 
h. Performing / conducting tests, procedures, interventions, 
questionnaires: Eleanor Leavens, GRA, Tricia Snow 
i. Completing study data forms: Eleanor Leavens, GRA, Tricia Snow, CRU 
staff 
j. Managing study database: Matt Mayo, Tricia Snow, Eleanor Leavens, 
Nikki Nollen 
 
L. Assessment of Subject Safety and Development of a Data and Safety 
Monitoring Plan 

 
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1. The current study does not pose more than minimal risk; however, we are 
extremely sensitive to the recent cases of acute lung injury associated with e-
cigarette products and the CDCs warnings. We continue to closely monitor the 
situation. To address this concern, we will obtain informed consent, closely 
monitor AEs and SAEs and promptly report any that occur. Dr. Salathe will 
provide medical oversight. In addition, we will have firm stopping rules to 
protect the safety of study participants. Further, we will purchase our supply 
directly from JUUL and will advise participants to not modify the e-liquid in 
any way – e.g., adding THC or vitamin E – which has been the case in the 
majority of reported cases. Altering the e-liquid would be difficult as 
participants will be provided JUUL pods which are closed systems, not easily 
tampered with. We also include a 6-month follow-up to assess for any on-
going study product use and again offer a referral to the Quitline.    
2. We will protect participants and minimize risks by using the strict exclusion 
criteria and careful monitoring of AEs. AEs will be tracked during regularly 
scheduled visits (including 6-month phone follow-up) or through spontaneous 
reports made by participants. Drs. Leavens, Nollen, and Salathe will be made 
aware of unexpected or serious AEs within 24 hours of the first report by 
participants; all other AEs will be reviewed weekly by Drs. Leavens Nollen and 
discussed at regular meetings with Dr. Salathe. SAEs will be reported to the 
KUMC IRB within 24 hours of first awareness of the event. Unexpected 
adverse events that are related to the study products will be reported to 
KUMC IRB within 5 working days of first awareness of the event if the event is 
not serious and within 24 hours of first awareness if the event is serious. 
Unexpected adverse events that are unrelated to the study products will be 
reported to the KUMC HSC during yearly routine event reporting. Dr. Salathe 
will determine relatedness for each reported AE. SAEs will be defined as any 
event experienced by a study subject while using the study device that is 
fatal, life-threatening (subject was at risk of death from the event as it 
occurred), disabling or incapacitating, requires inpatient hospitalization or 
prolongs a current hospitalization, or required intervention to prevent 
permanent impairment or damage.   
3. In the case of AEs, participants will be reminded of the voluntary nature of 
the study and be allowed to discontinue participation without negative 
consequences. In the case of SAEs related to use of study products, 
participation will be discontinued. 
 
 
III. 
Subject Participation 
 
A. Recruitment: 
1. Participants will be recruited through clinic, community-based efforts, and 
social media platforms. Flyers will be placed around Swope and KUMC for 
patients to take.  We will use the KUMC HERON database and the TMC 
electronic medical records to identify smokers and will ask their physician to 
send their patient a letter informing them of the study.  We will also use the 
Frontiers registry to identify adult smokers who have agreed to be contacted 
for research. We will also use radio ads, word of mouth, and our existing pool 
of participants from prior studies. We will post the study to the KUMC Intranet 
list of current studies for KUMC employees. Additionally, participants are 
currently being screened for other research studies conducted by our team. 
Those who have completed studies or who are ineligible for other studies 
being conducted will be informed about the current study and offered the 

 
KUMC – HRPP- 03/12/2015 
 
Page 13 of 17 
 
 
opportunity to be screened. Recruitment letters, advertisements, and flyers 
are in the process of being developed. They will be submitted to the IRB for 
approval before any participants are enrolled.  
2. Recruitment methods are described above. Recruitment will be conducted by 
members of the study team. Recruitment will be overseen by Drs. Nollen and 
Leavens. Screening will be conducted over the phone.  
3. Advertisements and flyers that will be used for recruitment are attached. 
Advertisements and flyers will be handed out to potential participants by the 
study team and will be placed in clinics at Swope and KUMC. 
 
B. Screening Interview/questionnaire: The screening will be conducted over the 
phone. The screening questionnaire will address the general inclusion/exclusion 
criteria as listed above. Only participants who have expressed interest will be 
screened. Prior to screening, participants will be given a brief overview of the 
study and informed that we need to collect some information to learn whether 
they may be eligible for the research. They will be informed that completion of 
the screening interview is voluntary, and they can discontinue screening at any 
time. Participants will be asked to provide verbal consent for screening.  
C. Informed consent process and timing of obtaining of consent 
1 
Consent procedures will be conducted by trained members of the research 
team. Prior to consent, participants will be provided a detailed and 
comprehensive overview of study procedures.  
2 
Individuals interested in the proposed study will meet the research assistant 
at the Fairway CRU. Each individual will be given a copy of the consent form 
and as much time as they need to review its contents. After the consent form 
is read, both the individual and the research assistant will review the consent 
form together and the potential participant will be encouraged to ask 
questions. Each individual will be reminded that participation in the study is 
completely voluntary. The consenting process will take place in a private 
location. 
3 
We are recruiting otherwise healthy smokers and do not anticipate 
recruitment of subjects with compromised cognitive abilities and/or decisional 
impairment. However, if questions regarding a participant’s ability to provide 
informed consent arise, Drs. Nollen and Leavens will determine whether the 
subject is able to give informed consent. 
D. Alternatives to Participation: The alternative to participation is not 
participating. 
E. Costs to Subjects: There are no costs to participants. All tests, procedures, and 
visits are being performed solely for research purposes and are not billable to 
insurance companies.  
F. How new information will be conveyed to the study subject and how it 
will be documented: We have plans to publish data from this study in 
aggregate but will not provide any individualized feedback to patients. 
G. Payment, including a prorated plan for payment: Participants who screen 
fail at visit one will be compensated $20 and will not be allowed to continue with 
the study. Eligible participants who complete study procedures will receive $50 
for visit one, $75 for visit two, $100 for visit three, and $50 for visit four (if 

 
KUMC – HRPP- 03/12/2015 
 
Page 14 of 17 
 
 
participant qualifies) in appreciation for their time and participation. Participants 
may receive an addition $50 at visit three if they attend all visits, return 
completed practice logs, and have CO ≤ 12 ppm  at all visits. For each visit that 
must be rescheduled due to CO > 12 ppm or an incomplete practice log, 
participants will have $10 deducted from their bonus. Finally, participants will be 
provided transportation via a rideshare service to and from each visit. 
H. Payment for a research-related injury: N/A 
IV. 
Data Collection and Protection 
A. Data Management and Security: Confidentiality will be maintained by 
assigning each participant a study identification number and numerically coding 
all data. The association of the ID-code and the participant’s name will be kept by 
Tricia Snow in a locked file cabinet. The screening questionnaire and all survey 
data will be directly entered into RedCap or CRIS and accessible only by study 
staff. Any paper copies of records will be kept in a locked filing cabinet in offices 
that are kept locked when unoccupied.  Only summaries of group data will be 
reported in any publications or presentations, with no identification of individuals.  
Because identifiable information will be collected, participant privacy will be 
maintained throughout the duration of the study by adhering to the regulations 
set forth by the HIPAA Privacy Rule.  More specifically, identifiable information 
will not be released without written authorization of the participant.  Mobile 
devices will not be used for data collection or storage. Identifiable data will not be 
sent outside of KUMC. 
 
B. Sample / Specimen Collection: No more than 7 mL of blood will be collected 
per blood draw (7 mL per draw x 5 draws per visit x 3 visits = 105 mL total 
during study). All samples will be de-identified and labeled with a study 
identification number. Blood samples will be aliquoted into two separate vials. 
One will be analyzed for the current study and one will be placed in a 
biospecimen repository if participant provides consent for biorepository. 
Participants will complete no more than two study visits in a seven-day period. 
Samples will be stored at the Bioanalytical Laboratory at the Fairway Clinical 
Research Center under the direction of Greg Reed, PhD. Samples will be 
accessible only to members of the study team. Results from biomarker analyses 
will be de-identified and shared only with members of the research team. Any 
resulting publications will present the data in aggregate; individual participants 
will not be identified. Samples will be disposed of one month after the final report 
is sent out to the Principal Investigator, unless participants agree to have their 
samples stored for future testing. For participants who agree to future testing, 
samples will be stored indefinitely. 
C. Tissue Banking Considerations: For participants who agree to future testing, 
samples will be stored indefinitely. New markers of nicotine and carcinogen 
exposure and genetic differences in nicotine metabolism are being discovered and 
the stored biological samples would be used for analysis of these new markers.  
All samples stored for future biomarker analyses will be de-identified and 
accessible only to members of the study team. Results from these analyses will 
be de-identified and shared only with members of the research team. Any 
resulting publications will present the data in aggregate; individual participants 
will not be identified.    

 
KUMC – HRPP- 03/12/2015 
 
Page 15 of 17 
 
 
D. Procedures to protect subject confidentiality: Confidentiality will be 
maintained by assigning each participant a study identification number and 
numerically coding all data.  All biological samples and survey data will be labeled 
with the study identification number and never with the participants name or 
other identifiable information.  The association of the ID-code and the 
participant’s name will be kept by Tricia Snow in a locked file cabinet and will 
only be accessible to members of the study team. 
E. Quality Assurance / Monitoring: All data will be directly entered into our 
electronic data capture system (i.e., RedCap or CRIS) that contains edit checks to 
control the quality and completeness of data entry. Completeness of data entry 
will be automatically verified before each assessment is completed. The electronic 
data capture system is behind the KUMC secure firewall with role-based access 
that is HIPAA and human subjects compliant. There are no plans for ongoing 
third-party monitoring. 
 
V.Data Analysis and Reporting 
A. Statistical and Data Analysis:  See section II.C. above for sample size and 
power calculations. To determine differences on self-report measures between 
products, an analysis of variance (ANOVA) will be conducted. Differences in 
nicotine delivery will be compared across products at each timepoint using similar 
procedures. Mean differences in puff allocation will be investigated for the 
computer task.  
B. Outcome: The primary study endpoint is nicotine delivery. We hypothesize that 
combustible cigarettes will show the fastest and greatest nicotine delivery, 
followed by e-cigarettes, and heat-not-burn devices. Further, topography 
measures will be greatest for cigarettes, followed by e-cigarettes, and heat-not-
burn devices. In terms of self report measures of abuse liability, use of cigarettes 
will be associated with the greatest reduction in symptoms of nicotine withdrawal 
and craving. Exhaled carbon monoxide will be greatest for cigarettes, followed, 
by heat-not-burn devices and e-cigarettes (no exposure). The primary endpoint 
of the computerized concurrent choice task is the proportion of puffs allocated to 
each product. The third aim is exploratory, and we therefore do not have specific 
hypotheses related to aim three.  
C. Study results to participants: Study results will not be shared with research 
participants. 
D. Publication Plan: We plan to publish results in appropriate tobacco and public 
health journals such as Addiction, Tobacco Control, Nicotine and Tobacco 
Research, etc. In addition, results will be presented at regional, national, and 
international conferences. 
 
APPENDIX I: VULNERABLE POPULATIONS 
 
N/A 
 
VI. 
Bibliography / References / Literature Cited  
 
 

 
KUMC – HRPP- 03/12/2015 
 
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