Impact of E-cigarette Nicotine Concentration on Compensation, Cigarette Smoking, and Biomarkers of Exposure and Harm in Diverse Smokers
Phase: NA
Conditions: Smoking Cessation
Sponsor: University of Kansas Medical Center

KUMC – HRPP- 03/12/2015 
Page 1 of 25
University of Kansas Medical Center  
RESEARCH PROTOCOL INVOLVING HUMAN SUBJECTS 
TEMPLATE WITH GUIDANCE 
Version date: 1/26/23 
Principal Investigator: Eleanor Leavens, PhD 
Study Title: Impact of e-cigarette nicotine concentration on compensation, cigarette smoking, and 
biomarkers of exposure and harm in diverse smokers 
Co- Investigator(s): Nicole Nollen, PhD; Matthew Mayo, PhD 
I.
Purpose, Background and Rationale
A. Aim and Hypotheses
1.
E-cigarettes (ECs) are projected to exceed combustible cigarette use within two years.
Policy makers, health officials, and regulators are concerned that newer nicotine salt-
based Ecs that use high concentrations of nicotine in their e-liquids are a major reason
for this rapid growth in use. The US Food and Drug Administration (FDA) has regulatory
authority to set appropriate tobacco product standards to protect public health and has
shown interest in exploring a product standard limiting the level of nicotine in e-liquids.
While this regulatory consideration has merit, emerging research suggests it may be
misguided, leading to a product that is just as addictive but more harmful. Specifically,
among users of earlier, freebase nicotine Ecs (i.e., cig-a-like, tank systems), use of low
nicotine e-liquids was associated with a 9-fold increase in e-liquid consumption and all of
its related toxicants, likely due to compensatory puffing. The consequences of consuming
more e-liquid because of lower nicotine concentration remains an important knowledge
gap. Moreover, the National Academies of Science, Engineering, and Medicine have
concluded that completely substituting Ecs for cigarettes results in less short-term harm
than continued smoking, but the impact of low versus high nicotine concentration e-
liquids on a smokers’ ability to completely switch to Ecs (versus become ‘dual users’ or
continue smoking) is currently unknown. African American (AA) smokers, who take larger
puffs, inhale more intensely, and extract more nicotine and harmful constituents per
cigarette smoked, may be particularly impacted by nicotine product standards placed on
EC – i.e., greater compensatory puffing and more e-liquid and related toxicant
consumption at lower e-liquid concentrations. Unfortunately, the vast majority of
information on Ecs and potential product standards come from white populations and
have largely ignored African American (AA) smokers who bear a disproportionate burden
of tobacco-related morbidity and mortality. As the FDA considers regulatory action to
limit the level of nicotine in e-liquids to protect public health, it is critical that research
considers vulnerable populations and does not widen disparities.
Our long-term goal is to inform a tobacco landscape that will minimize tobacco-related
harms and downstream health inequities. The overall objective of this application is to
understand the impact of e-liquid nicotine concentration on compensatory puffing, EC
and cigarette use patterns (exclusive EC, dual EC-cig, exclusive cig), and resultant
exposure to biomarkers of harm among AA and white smokers. Adult AA and white

 
KUMC – HRPP- 03/12/2015 
 
Page 2 of 25
 
 
 
smokers will complete two study phases. In Phase 1, using a randomized crossover 
design, participants will complete two standardized, 10-puff vaping bouts over 5 mins 
followed by a 60-minute ad libitum vaping session, using two e-liquids that differ only by 
nicotine concentration (5% vs. 1.8%) to examine the effect of nicotine concentration on 
in-lab compensatory puffing, nicotine exposure, and e-liquid consumption. In Phase 2, 
the same participants will be randomized to 5% or 1.8% nicotine e-liquid and instructed 
to switch completely for 6 weeks to examine the impact of nicotine concentration on 
short-term, real-world EC use patterns and related biomarkers of exposure (e.g., exhaled 
carbon monoxide, NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol), lung 
inflammatory markers). Our central hypothesis is that, compared to the high nicotine 
concentration, while vaping the low nicotine concentration, users will engage in 
compensatory puffing, resulting in greater e-liquid consumption (Phase 1). Moreover, 
rates of dual use and continued smoking will be higher for the low (versus high) nicotine 
concentration and will result in greater exposure to toxicants (Phase 2). 
 
2. Aim 1 (Human laboratory): To examine the effect of nicotine concentration on 
compensation measured via nicotine exposure, puffing behavior, and e-liquid 
consumption. H1a: Compared to the 5% nicotine concentration, while vaping the 1.8% 
concentration, smokers will evidence greater total inhaled volume, and (H1b) greater 
consumption of e-liquid (by pod weight) (H1c) but achieve similar levels of nicotine 
exposure.  
Aim 2 (Randomized trial): To assess the comparative efficacy of 1.8% vs. 5% nicotine 
concentration on real-world EC use pattern (exclusive EC, dual EC-cig, exclusive cig). 
H2a: After a 6-week trial of EC, rates of complete substitution (i.e., percent exclusive EC) 
will be significantly greater for participants randomized to 5% (compared to 1.8%) 
nicotine e-liquid. H2b: Rates of dual EC-cig and exclusive cigarette smoking will be 
greater for participants randomized to 1.8% (compared to 5%) e-liquid.  
Aim 3 (Randomized trial): To understand the comparative exposure to non-nicotine 
constituents as a function of nicotine concentration. H3a: The degree of changes in 
exposure will be directly associated with the degree of substitution with EC—greater 
levels of substitution will confer a larger decrease in exposure. H2b: Among those who 
completely substitute Ecs, 5% users (vs. 1.8%) will have lower toxicant levels. 
B. Background and Significance 
1. Study Significance and literature review:  
 
Our study will be the first to assess the impact of nicotine concentration on compensatory 
puffing (total inhaled volume), nicotine delivery, and switch patterns (percent exclusive 
EC, dual cig-EC, and cig only users) with an explicit focus on AA and White smokers. It 
will provide the first available evidence on potential differential change in these factors 
for AA and Whites and offer rich data to the FDA that will inform evidence-based 
regulation of a nicotine standard that maximizes public health benefit and limits potential 
harm among diverse smokers. 
 
Rise of e-cigarettes (Ecs) and the impact on public health: Millions of white US 
adults and youth now use Ecs27,28 that deliver fewer carcinogens, volatile organic 

 
KUMC – HRPP- 03/12/2015 
 
Page 3 of 25
 
 
 
compounds, and other harmful toxicants than traditional cigarettes.29,30 EC data show 
lower levels of tobacco-related toxicants29,31-34 and led the National Academies of Science, 
Engineering, and Medicine to conclude in their groundbreaking report that, if used 
exclusively, Ecs are likely to pose less risk to an individual than cigarettes and, to the 
extent that adult smokers completely switch to Ecs, cause less short-term harm than 
cigarettes.35 NSBEs have again disrupted the tobacco landscape. NSBE e-liquids are 
available in high nicotine concentrations (up to 5%),36 higher than most other EC e-
liquids on the market (0.3%-2.4%).37-39 These products use protonated nicotine36, which 
make the high nicotine e-liquids palatable and reduce irritation,40 likely facilitating user 
initiation.  
 
Tobacco and EC use among African Americans (AA): AA smoke fewer days per 
month, fewer cigarettes per day (CPD)41 (1 to 10), and are less likely to be heavy 
smokers than whites.41 Despite smoking fewer cigarettes per day (CPD)41 which should 
result in reduced negative health consequences, AA smokers are exposed to greater 
levels of tobacco-related toxicants,42 have higher cardiovascular and cancer-disease risk 
at lower smoking levels and bear a disproportionate burden of smoking-related 
diseases.43,44 AA smokers take larger puffs,45 inhale more intensely,46 and extract 30% 
more nicotine and harmful constituents per cigarette compared to whites. 47 With the 
emergence of Ecs, important questions regarding the impact on AA smokers arise. 
Specifically, as more AA smokers switch to Ecs, it is not known how they will use the 
products. One possibility is that AA smokers may engage in fewer vaping sessions but 
intake more e-liquid (through increased topography), which is not harmless, compared to 
whites to reach comparable nicotine exposure. However, almost all the information on 
Ecs and potential product standards come from white populations. As the FDA considers 
regulatory action to limit the level of nicotine in e-liquids to protect public health, it is 
imperative that research be inclusive of populations who bear a disproportionate burden 
of tobacco-related morbidity and mortality. Given the dearth of preliminary data, 
subanalyses of race will be exploratory in nature. 
 
Nicotine and other EC constituents: Nicotine is the addictive component in tobacco 
products,48 including Ecs. While nicotine contributes to dependence and maintains 
tobacco product use,49 health concerns regarding nicotine primarily arise due to the type 
of delivery device and route of administration. In Ecs, nicotine is delivered in a solution of 
propylene glycol (PG), vegetable glycerin (VG), and flavorants. 50 E-liquid solutions may 
also deliver other non-nicotine constituents and harmful and potentially harmful 
constituents including heavy metals, volatile organic compounds (VOCs), and low levels 
of polycyclic aromatic hydrocarbons (PAHs).51 
 
Nicotine concentration and compensation in AA and white users: Policy makers, 
researchers, and the public have expressed concern regarding the high levels of nicotine 
in NSBEs and have suggested product standards that would place a ceiling on allowable 
nicotine concentrations to reduce public health harms52, similar to the European Union 
Tobacco Products Directive that restricts nicotine strength to ≤ 20mg/mL53 (i.e., 2%) and 
recent state-level recommendations to implement a similar rule.54-57 While such 
restrictions may have some merit, concerns regarding high nicotine concentrations and 
initially proposed product standards may be misguided and have never been tested. In a 

 
KUMC – HRPP- 03/12/2015 
 
Page 4 of 25
 
 
 
study of white tank and mod system EC users, use of low nicotine devices resulted in a 
9-fold increase in e-liquid consumption despite equivalent nicotine exposure,58 a finding 
that has been replicated in the literature.59-61 These data suggest that white users of 
older, low nicotine devices likely engage in compensatory puffing to achieve the same 
level of nicotine as high nicotine EC users,58-61 although objective measures of puff 
topography were not collected. Laboratory emissions testing research has shown that at 
low (vs. high) nicotine concentrations, a greater amount of e-liquid must be aerosolized 
to achieve cigarette-like levels of nicotine yield. Importantly, greater e-liquid 
aerosolization generated by higher temperature devices resulted in emissions of higher 
levels of carbonyl compounds, including known respiratory irritants and carcinogens in 
humans.62 If replicated in humans, EC users would likely be exposed to higher levels of 
PG, VG, flavorants, and other constituents. Given their differential puffing patterns 
(greater number of puffs45 and more intense puffing46), AA smokers may engage in even 
greater e-liquid consumption and, as a result, be exposed to greater levels of non-
nicotine constituents compared to whites. If users engage in compensatory puffing when 
using low levels of nicotine, they are being exposed to more e-liquid, and placing a 
ceiling on allowable levels of nicotine may inadvertently increase exposure to non-
nicotine constituents, particularly among AA smokers. Unlike very low nicotine 
concentration (VLNC) cigarettes,63-65 users of low nicotine Ecs have not been shown to 
reduce their use in response to the reduced levels of nicotine.58-61 Human health effects 
of exposure to larger volumes of EC aerosols remain unknown and of concern. 
 
The role of nicotine concentration in EC use trajectory in smokers: Ecs are a 
potential harm reduction tool, particularly if used exclusively by smokers who are unable 
or unwilling to quit smoking combustible cigarettes. Ecs pose less short-term risk than 
cigarettes and, particularly when used exclusively, cause less harm than cigarettes. 35 
Therefore, product standards should facilitate a transition from combustible smoking to 
exclusive EC use among adults. Only a handful of randomized trials have examined quit 
rates using Ecs and none have directly compared the impact of EC nicotine strengths on 
use trajectory. Existing studies indicate that when smokers were provided a cig-a-like 
with 7.5mg (~.75%) nicotine e-liquid, smokers achieved quit rates of only 11% at 12 
weeks.66 However, 16mg (~1.6%)67 and 18mg (~1.8%)68 e-liquids produced quit rates 
of 21.5% and 35%, respectively. Dr. Nollen’s (primary mentor) switching trial of AA and 
Latinx smokers is the only trial to examine rates of abstinence from Ecs using a NSBE 
and showed that 28% of smokers were exclusive EC users at week 6. 69 Together, these 
data suggest that rates of cigarette abstinence increase with increases in nicotine 
concentration. However, a head-to-head comparison of the impact of EC nicotine 
concentration on EC and cigarette use is a critical next step to inform nicotine product 
standards in Ecs.  
 
Relevance to tobacco regulatory science: The FDA deemed that Ecs are under their 
regulatory authority, thus allowing FDA to implement policy decisions regarding EC 
product standards, including nicotine.70 The proposed research will provide urgently 
needed data regarding nicotine product standards in Ecs and the impact on 
compensation, EC and cigarette use patterns, and resultant toxicant exposure among AA 
and white smokers. Indeed, FDA has noted that evidence-based nicotine product 
standards are a top priority, and that data are needed to inform the implementation of 

 
KUMC – HRPP- 03/12/2015 
 
Page 5 of 25
 
 
 
policy specific to nicotine product standards in Ecs. There remains an urgent need to 
understand how racially diverse smokers respond to and are impacted by potential 
product standards. 
 
2. Dr. Leavens’ recently completed randomized crossover, human laboratory pilot study (N 
= 10) of nicotine exposure of three Ecs (tank system, mod style, NSBE) and cigarettes 
showed that use of NSBEs led to shorter time to maximum plasma nicotine concentration 
than cigarettes. While the study provides initial evidence regarding nicotine delivery of 
NSBEs, participants were only provided 5% nicotine Ecs and markers of harm were not 
measured. 
 
C. Rationale 
Dr. Leavens’ recently completed randomized crossover, human laboratory pilot study (N = 
10) of nicotine exposure of three Ecs (tank system, mod style, NSBE) and cigarettes showed 
that use of NSBEs led to shorter time to maximum plasma nicotine concentration than 
cigarettes. While the study provides initial evidence regarding nicotine delivery of NSBEs, 
participants were only provided 5% nicotine Ecs and markers of harm were not measured. 
Dr. Nollen has recently completed the first EC switching study with AA adult daily smokers. 69 
Major findings include high interest in switching to EC among AA smokers, high utilization of 
NSBE, and significant reductions in cancer, respiratory, and cardiovascular markers among 
the EC group. Participants all received NSBE containing 5% nicotine. The health effect of 
1.8% versus 5% nicotine remains a critical gap that will be addressed through the proposed 
research plan. Dr. Wagener completed one of the first studies to show that use of low-
nicotine Ecs was associated with greater e-liquid consumption compared to high-nicotine 
Ecs.58 However, this study included only whites, did not include topography, and was 
conducted with devices that are now considered outdated. NSBE contain product features 
that more closely mimic the experience of smoking a cigarette (e.g., nicotine boost) 6,71,72; 
these features may impact the rate of compensation and, subsequently, the amount of e-
liquid consumed, and are gaps that will be addressed in the proposed research. The research 
will merge Dr. Leavens’ foundational knowledge of human laboratory studies of novel 
products with Dr. Nollen’s expertise in tobacco-related disparities among AA using 
randomized trial methods. Additionally, Drs. Wagener and Benowitz will supplement these 
core components by providing expertise and training in tobacco regulatory science and 
biomarkers of harm of EC use. All mentors will provide training in grantsmanship and 
professional development. 
 
 
II. 
Research Plan and Design 
 
A. Study Objectives: This study will investigate the impact of EC e-liquid nicotine 
concentration (1.8% vs. 5%) on compensatory puffing and e-liquid consumption, use 
patterns, and resultant changes in biomarkers of exposure, among AA and white smokers 
using complementary human laboratory and randomized trial methods. 
B. Study Type and Design:  
 
Adult AA (n = 24) and white (n = 24) smokers (stratified on CPD) will complete two study 
phases. Phase 1 (P1): 2-visit human laboratory trial with double-blind, randomized crossover 
design. Phase 2 (P2): 6-week, randomized substitution trial. Participants in P2 will be the 
same participants that completed P1. Both phases are necessary: Phase 1 will provide data 
on compensatory puffing and nicotine exposure, while Phase 2 will provide information on 
real-world use patterns and related short-term health effects. These two phases, combined, 

 
KUMC – HRPP- 03/12/2015 
 
Page 6 of 25
 
 
 
provide a more comprehensive picture of the impact of nicotine product standards on 
population-level health than either phase alone.  
 
C. Sample size, statistical methods, and power calculation 
1. 48 smokers will complete phase 1, a randomized crossover trial. In order to have 48 
“completers” of phase 1, we will enroll about 75 participants and stop enrollment once 48 
participants have completed phase 1. Only 48 participants will complete phases 1 and 2. 
Participants will be randomized 1:1 to the order in which they use the two nicotine 
concentrations. For the randomized trial, they will be randomized 1:1 by computer 
generated random number to switch to 1.8% or 5% nicotine e-liquid for 6 weeks. 
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 during phase 1 has been completed, the research 
assistant will select the sequential study ID number to determine the randomization 
assignment. This procedure will be conducted again at the beginning of phase 2 
(randomized trial).  
 
2. Both phases of the trial will be double blind. 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 during 
phase 1 has been completed, the research assistant will select the sequential study ID 
number to determine the randomization assignment. This procedure will be conducted 
again at the beginning of phase 2 (randomized trial). 
 
 
3. The purpose of a K01 is to build a body of preliminary evidence and determine effect 
sizes for a fully powered R01 trial. With this in mind, the proposed K01 is fully powered 
to detect differences in change in puff volume between 1.8% and 5% nicotine 
concentration e-liquids for the sample overall (Aim 1). For this aim and all subsequent 
aims, we will conduct subset analyses by race. Phase 1: The primary outcome for P1 is 
total inhaled volume. We have determined these anticipated effect sizes based on pilot 
data from Dr. Leavens’ study on puff topography among users of 5% NSBE e-liquid 
during a standard PK assessment and existing data regarding puff topography among 
users of moderate (3%) and low (1.8%) nicotine concentration e-liquid in earlier 
generation Ecs (Hiler et al., 2017).59 We are estimating topography for the lower nicotine 
concentration based on a range of values. Given that we do not have estimates for the 
NSBE, we are using the smaller, clinically meaningful difference. These estimates suggest 
an anticipated mean difference in total inhaled volume between the 1.8% and 5.0% 
nicotine concentrations of 70 mL (12% increase) and 186 mL (27% increase). We are 
basing our sample on the smaller, clinically meaningful difference (12% increase) which 
results in an effect size of 0.74. Based on this information, 48 participants we will achieve 
>90% power to detect an increase of 70mL in total inhaled volume during the PK 
assessment using two-sided tests with 0.05 alpha level, assuming a mean total volume 
of 679mL and 749mL for the high and low nicotine e-liquid, respectively, and a common 
standard deviation of 200 mL. We will subsequently conduct separate analyses by race 
(AA = 24; White = 24). Based upon the previous assumptions, this results in the ability 
to detect an effect size of 1.08 or larger within each subset. We will conduct separate 
analyses by race because, while we anticipate AA will have globally greater puff 

 
KUMC – HRPP- 03/12/2015 
 
Page 7 of 25
 
 
 
volume90, there are no data that suggest a differential change in inhaled volume between 
AA and white smokers. Based on previous research, there is potential for a main effect of 
race; however, a study of AA and white smokers stratified on baseline cigarettes per day 
has not been conducted. This study will be the first head-to-head, controlled, 
prospectively designed study to assess if there is the potential for a main effect of race. 
This sample estimate is based on our most variable outcome; therefore, we anticipate 
being overpowered to detect effects in the overall sample related to nicotine exposure 
(secondary outcome) which will show much less variability. Subsequently, after a 
standard 1-week washout period, subjects will return to be randomized to 1.8% or 5% 
nicotine e-liquid and instructed to completely substitute the EC for cigarettes. Based 
upon prior retention, we expect to randomize at least 40 subjects in P2. Further, based 
on Dr. Nollen’s past trials,25,91-93 we do not anticipate differential attrition by race. Prior 
studies conducted by the research team have retention of >90% in multi-year trials 
examining AA and white smokers. Phase 2: The primary outcome for P2 is the proportion 
of participants that achieve biochemically-verified complete substitution (i.e., exclusive 
EC use) at 6-weeks for 1.8% and 5% nicotine e-liquid. Based on Dr. Nollen’s pilot study 
examining complete substitution among AA smokers using 5% nicotine salt e-liquid69 and 
similar studies of Whites using 5% nicotine salt e-liquid in the literature, 94 we anticipate 
that ~30% of the sample overall will completely switch at 6-week follow-up in the 5% 
nicotine group and fewer in the 1.8% nicotine group. Twenty participants in each nicotine 
concentration group will allow us to estimate the rate of complete substitution (exclusive 
EC use) with a margin of error < 0.20 for each nicotine concertation group to determine 
an effect size for a larger scale study in the future. The exploratory subset analyses 
within each race will provide estimates that will determine whether a definitive trial 
comparing races is warranted. We chose the largest sample size that we could 
accommodate with the time and cost constraints. Thus, we will initially recruit 48 
subjects for P1 and expect at least 40 to return and be randomized for P2. 
 
 
D. Subject Criteria (See Vulnerable Populations appendix, if applicable):  
 
Inclusion and exclusion criteria are designed to enroll relatively healthy adult smokers who 
predominately smoke cigarettes, have little history of EC experimentation, and are 
uninterested in quitting smoking in the next 6 months. 
 
1. Inclusion criteria:  
1) identify as non-Hispanic white or non-Hispanic African American/Black 
2) willing to switch from smoking to e-cigarettes for 6 weeks 
3) speak and understand English 
4) smoke greater than or equal to 25 of the last 30 days for the past 3 months 
5) not previously used an e-cigarette for longer than 30 days 
6) exhaled carbon monoxide of greater than or equal to 6ppm at screener visit 
7) willing to abstain from marijuana for 12 hours prior to in-person lab visits 
8) willing to abstain from smoking and vaping for 12 hours prior to 3 in-person lab visits 
2. Exclusion criteria:  
1) weekly use of an EC over the last six months 
2) use of tobacco products other than cigarettes on greater than or equal to 10 days in 
the past 30 days 
3) use of EC on more than 5 of the past 30 days 
4) current use of cessation medications 

 
KUMC – HRPP- 03/12/2015 
 
Page 8 of 25
 
 
 
5) pregnant, planning to become pregnant, or breastfeeding 
6) past 30 day hospitalization/ER visit for psychiatric issue, seizure, stroke, or new heart 
problem 
7) recent history of cardiovascular or pulmonary events in the past three months 
8) treatment for alcohol or drug dependence in the past year 
9) household member currently or previously enrolled in the study 
10) current enrollment in a program aimed at changing smoking patterns 
  
1. Withdrawal/Termination criteria:  
Participants will be instructed to present to the lab nicotine deprived (12 hours abstinent) 
for the first study visit. If participants present to the first study visit with an eCO greater 
than 12 ppm or they report other nicotine use two times, they will be withdrawn from the 
study. Participants will complete a paper or online log of their practice. If they do not 
practice with each nicotine concentration prior to visit one, they will be sent home and 
again instructed to practice with each pod. After two failed practice periods, participants 
will be removed from the study.  
 
2. Participants will not be allowed to participate in another research study that aims to alter 
their tobacco use during this research study.  
 
E. Specific methods and techniques used throughout the study       
 
1. Laboratory tests:  
 
At two human laboratory visits, blood will be collected for nicotine analysis via a blood 
draw from the participant’s arm. Participants will have an intravenous catheter placed in 
their arm for collection of blood (plasma nicotine). Blood sampling for changes in nicotine 
levels will occur at -5 (baseline), 5 (post 10-puff bout), 7, 15 (beginning of ad lib 
session), 45, and 75 (post-session) minutes. No more than 7 mL of blood will be drawn 
per draw. 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. 
  
Human Laboratory Assessments (see Table 1 for timing):  

 
KUMC – HRPP- 03/12/2015 
 
Page 9 of 25
 
 
 
Topography. Puff topography will be used to objectively measure EC puffing patterns. 
Puff topography is a sensitive measure of substance self -administration.81,83 Puff 
topography will be measured throughout the EC session via a pressure flow sensor in the 
EC mouthpiece, whereby inhalation-induced pressure changes are amplified, digitized, 
and sampled. Software converts signals to airflow (ml/s) and produces measures of puff 
volume, total puff volume, puff number, and inter-puff-interval. The topography device to 
be used in this study has been successfully used by Drs. Leavens and Wagener. 1,4 During 
both phases of the study, the study e-cigarette will be equipped with an integrated puff 
topography device that allows for collection of topography data in the lab and in the 
participant’s natural environment. Participants will be provided the device and a phone 
with highly limited capabilities. Specifically, participants will only be able to change the 
brightness, connect to WIFI, and access the app for data transfer. Otherwise, the phone 
is fully locked down. Participants will be asked to open the topography app daily and 
“sync” to transfer daily topography data. The data will be utilized in an exploratory 
fashion. Only topography data and no identifiable data are transferred via the mobile 
application. 
Nicotine exposure. At both initial lab-based visits, blood samples will be collected at -5 
(baseline), 5 (post 10-puff bout), 7, 15 (beginning of ad lib session), 45, and 75 (post-
session) minutes. Seven mL of blood will be collected during each blood draw. Samples 
will be analyzed according to standardized methods84 by Dr. Na Zhang at KUMC. Blood 
will be analyzed for nicotine content to assess nicotine exposure during the session.  
Biomarkers. eCO levels will be measured at final screening and both visits. At final 
screening, eCO ≥ 6ppm will be used to verify smoking status. At study visits, eCO ≤ 12 
ppm will be used to verify tobacco abstinence.  
Other self-report assessments. The EC-adapted Tiffany-Drobes Questionnaire on 
Smoking Urges (QSU-brief)85 and Minnesota Nicotine Withdrawal Scale (MNWS)65 will 
measure smoking urges and nicotine withdrawal, respectively, during each blood draw. 
The modified Product Evaluation Scale86 (mPES) will assess satisfaction, subjective 
effects, and sensory experiences (e.g., taste) at the conclusion of each ad lib session. 
 
 
Table 1. Phase 2 assessments and timing 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
Baseline assessments and tobacco use 
 
 
 
 
 
 
 
Demographics, medical, tobacco use, substance use history 
 
 
 
 
 
 
 
Nicotine dependence 
X 
 
 
 
 
 
X 
Timeline Followback (TLFB) of EC/tobacco use 
X 
X 
X 
X 
X 
X 
X 
Puff topography 
X 
X 
X 
X 
X 
X 
X 
Assessments of nicotine exposure 
 
 
 
 
 
 
 
Plasma nicotine (acute nicotine exposure) 
 
 
 
 
 
 
 
Urinary cotinine (prolonged nicotine exposure) 
X 
 
 
 
 
 
X 
Assessment of health outcomes & biomarkers 
 
 
 
 
 
 
 
eCO (acute smoke exposure) 
X 
 
 
 
 
 
X 
NNAL (carcinogen exposure) 
X 
 
 
 
 
 
X 
Spirometry (lung function) 
X 
 
 
 
 
 
X 
Urine collection for later analysis of Acrolein & Acrylonitrile 
X 
 
 
 
 
 
X 
Blood pressure (cardiovascular effects) 
X 
 
 
 
 
 
X 
Respiratory symptoms checklist (respiratory effects) 
X 
 
 
 
 
 
X 
E-liquid consumption (by pod weight) 
X 
 
 
 
 
 
X 
Other self-report assessments 
 
 
 
 
 
 
 
Craving/Withdrawal (QSU-brief and MNWS) 
X 
 
 
 
 
 
X 

 
KUMC – HRPP- 03/12/2015 
 
Page 10 of 25
 
 
 
Randomized Trial Assessments (see Table 1 for timing):  
Nicotine exposure. Prolonged nicotine exposure will be measured using urinary cotinine 
at wks 0 & 6. Cotinine captures nicotine from all nicotine products and will allow us to 
understand whether participants maintain, reduce, or increase their nicotine exposure 
over the course of P2. Participants will bring their empty and partially used pods to each 
study visit to be weighed for measurement of e-liquid consumption.  
Health outcomes and biomarkers. eCO levels will be measured at wks 0 & 6. eCO ≤ 6 
ppm will be used to verify use trajectory at wks 0 & 6. NNAL, spirometry, blood pressure, 
and respiratory symptoms will be measured at wks 0 & 6 to assess health outcomes and 
biomarkers between users of 1.8% vs. 5% nicotine e-liquid. Specimen samples will be 
banked for later analysis of VOCs, PAHs, and other new and emerging biomarkers of 
interest, including acrolein and acrylonitrile.  
EC use trajectory (Aim 2). The 7-day Timeline Followback Interview (TLFB)87,88 will be 
used to assess the comparative effectiveness of nicotine concentration on participants EC 
use trajectory at the end of the 6-week trial of EC. The primary outcome of P2 is the 
proportion of smokers who are exclusive EC users at wk 6 for 1.8% and 5% nicotine 
concentrations. Exclusive EC users are defined as those who reported any use of ECs, no 
use of cigarettes in the past 7 days, and who have a CO < 6 ppm. 89 Dual users are 
defined as those who reported any use of ECs and any use of cigarettes in the past 7 
days. Those who reported no use of cigarettes in the past 7 days but who have a CO > 6 
at week 6 will be classified as dual users. Exclusive cigarette users are those who report 
no use of ECs and any use of cigarettes in the past 7 days. A fourth group, no use of ECs 
or combustible cigarettes, may occur.  
Other self-report assessments. The QSU-brief and MNWS will be collected at wks 0 & 
6. 
2. Study Procedures: 
i. Initial Screening: The initial screen will review inclusion/exclusion criteria. Those 
eligible will be scheduled to complete final screening within 14 days.  
ii. Final Screening and Enrollment: Participants will be instructed to smoke as 
they normally would before the final screening. Final eligibility screening will be 
conducted in-person and will consist of completing a pregnancy test on women of 
childbearing age, exhaled carbon monoxide (eCO) measurement, and obtaining 
informed consent. Participants will complete baseline measures including 
demographics, medical, tobacco use, and substance use history and measurement 
of cotinine, NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol), eCO, 
spirometry, blood pressure, lung injury panel, and respiratory symptoms. E-liquid 
Flavor Sampling and Device Practice. At the final screening and enrollment visit, 
participants will be asked to sample two e-liquid flavors (Menthol and Tobacco; 
only commercially available flavors in pod-based NSBE) with 5% nicotine to 
determine flavor preference. Consistent with established methods, at the 
conclusion of the visit, participants will be provided with the Vuse EC device and 
two pods (one each of 1.8% and 5% nicotine) both in their preferred flavor to 
take home for 48 hours and instructed to practice using each pod 2-3 times per 
day for at least 15 minutes per episode between the screener visit and the first 
study visit. Participants will complete a paper or online log of their practice. If 
they do not practice with each nicotine concentration prior to visit one, they will 
be sent home and again instructed to practice with each pod. After two failed 
practice periods, participants will be removed from the study. We considered 

 
KUMC – HRPP- 03/12/2015 
 
Page 11 of 25
 
 
 
other nicotine concentrations but chose 5% because it is the most commonly used 
NSBE concentration in market leaders like JUUL. We chose 1.8% because it 
reflects the UK nicotine standard and most likely potential regulatory decision. 
b. Phase 1 – Human Laboratory Procedures: Participants will remain abstinent from 
nicotine/tobacco and alcohol for 12 hours prior to each study visit. Abstinence will be 
verified upon arriving at the laboratory by eCO (≤ 6 ppm). Pregnancy exclusion will be 
confirmed at each visit. Self-report will be used for EC abstinence, as there is currently 
no objective, reliable measure to verify non-use of these products within the time the 
participant will be present in the lab. Participants will have an intravenous catheter 
placed in their arm for collection of blood (plasma nicotine). They will be provided the 
Vuse Alto device with one of the two e-liquid concentrations (1.8% or 5%) and will 
complete the 10-puff standardized bout (pharmacokinetic assessment) followed by a 60-
minute ad libitum vaping session. The combined 10-puff bout and ad-lib session are 
commonly used human laboratory methods for complete assessment of product 
selfadministration.21,59,75-80 For the 10-puff bout, participants will be instructed to take 
one puff every 30 seconds for five minutes. Throughout the session, puff topography will 
be measured via a pressure sensor attached to the EC device81, methods used by Dr. 
Leavens in past and ongoing studies.1,4 During the vaping session, blood sampling will 
occur at -5 (pre-session), 5 (post 10-puff bout), 7, 15 (beginning of ad lib session), 45, 
and 75 (post-session) minutes. Following a minimum 48-hour standard washout 
period1,4,59,78,82 during which they will smoke as they typically would, participants will 
repeat this procedure with the other nicotine concentration. 
Phase 2 – Randomized Trial: Participants who complete P1 (~20 AA and 20 W based on retention in 
Dr. Nollen’s trials) will undergo a 1-week washout period (week 3 in consent document) and be 
randomized (1:1) by computer-generated random numbers to 1.8% or 5% e-liquid. Randomization will 
be stratified within race on CPD. Substitution: Participants will be instructed to make a complete switch 
from cigarettes to ECs for 6 weeks. They will be provided with the Vuse EC and e-liquid and instructed 
to use it as they like but to refrain from use of other tobacco. Participants will complete in-person visits 
(wks 0 & 6) and will provide samples for biomarker assessment and complete self -report measures. 
Participants will bring all empty pods and those currently in use for weight measurement to quantify e-
liquid consumption. Phone calls will occur between in-person visits (wks 1, 2, 3, 4, & 5) to confirm 
appointments, collect data on tobacco use, and support substitution. 69 Participants will be asked to use 
the topography-equipped e-cigarette and accompanying phone/mobile application throughout phase 2 
(RCT). While participants will be instructed to completely switch to ECs during P2, research suggests 
some participants will have difficulty doing so. Therefore, we will collect information regarding use of 
other products. 
3. Due to COVID-19 and the need to keep patients and researchers safe, we may 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 
necessary.  
 
4. All procedures, tests, and visits are being performed solely for research purposes and are 
not billable to insurance.  
 
5. Samples will be labeled only with a unique study identification number and only members 
of Dr. Leavens and Zhang’s teams will have access to the samples. Samples will be 
disposed of one month after the final report is sent out to the Principal Investigator, 
unless participants agree to have their urine and/or blood stored for future testing. 

 
KUMC – HRPP- 03/12/2015 
 
Page 12 of 25
 
 
 
 
6. Timeline: The proposed study is comfortably feasible in the K01 award period, allowing time for 
project start-up and dissemination (Table 1). Refinement of assessments, database creation, and IRB 
approval will take place in the first 6 months of Year 1. We expect to recruit 10 participants in the 
second 6 months of Year 1, 18 participants in Year 2, 14 in Year 3, and 6 in Year 4. No more than 5 
participants (≤15 visits) will be recruited during each quarter of recruitment. This rate of accrual is 
commensurate with my past studies and other similar laboratory-based studies. Our final participant 
session will be in the second quarter of Year 4. Data analysis and manuscript preparation will take 
place in the 3rd and 4th quarters of Year 4 and throughout Year 5.  
Study Timeline by Year and Quarter 
 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Periods (3 months) 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Preparing research staff and  
REDCap measures 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant recruitment (N = 48) 
 
 
5 
5 
4 
5 
5 
4 
4 
4 
3 
3 
3 
3 
 
 
 
 
 
 
Phase 1 (PK assessment) 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Phase 2 (randomized trial) 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Processing/analysis of samples (P1) 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
 
 
 
 
Processing/analysis of samples (P2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
 
 
Data and manuscript preparation (P1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Data and manuscript preparation (P2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Note. P1 = Phase 1; P2 = Phase 2 
 
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 and blood draws will be conducted by an RN or LPN. 
Sterile instruments will be used for blood draws, the participants skin will be cleaned with 
an alcohol wipe at the site of the needle stick. 
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 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. If shown to be effective, our study could, in the future, minimize tobacco-related 
harms and downstream health inequities by exploring the effect of nicotine 
concentration on puffing patterns and biomarkers of harm. The data will inform 
FDA regulations that protect the public health, particularly that of smokers. 
c. The researchers hope that the information gathered from this research may be 
useful in informing regulatory decisions to benefit public health. 

 
KUMC – HRPP- 03/12/2015 
 
Page 13 of 25
 
 
 
 
G. Location where study will be performed:  
All Phase 1 visits will be run at the Clinical and Translational Science Unit-Swope (CTSU-
Swope). The CTSU offers clinical space including two smoking rooms and is staffed by 
experienced RNs and medical assistants. Biospecimens including NNAL, urinary cotinine, 
plasma nicotine, and the lung injury panel will be processed and analyzed by Dr. Na Zhang 
and her team. Blood will be collected for plasma nicotine measurement during both study 
visits during Phase 1. All biospecimen samples are deidentified and stored in a -80 degree 
freezer. Names of participants will be kept separate from participant data. Only study 
research assistants and the PI will have the information that connects participant names and 
ID numbers. All electronic data will be numerically coded and stored in a password-protected 
database, on a password-protected computer in a secure research space. Participant 
information will be accessible only to research staff, who are pledged to confidentiality and 
complete training in the ethical conduct of research (i.e., both HIPAA and CITI trainings). 
Identifying information will not be reported in any publication. No information will be stored 
locally on the laptop/tablet; all information will be stored securely in the secure data capture 
system. Research materials obtained from the participants include responses to 
questionnaires collected directly by our research team and entered directly within secure 
databases. Data will be stored in a password protected database and on password protected 
network storage. Consent forms will be stored in a separate locked filing cabinet or 
electronically on the secure database. Physiological measures include, urine, blood samples, 
and exhaled breath carbon monoxide. Research data will be obtained specifically for research 
purposes. Every effort will be made to maintain subject confidentiality, in accordance with 
HIPAA.  
H. Collaboration (with another institution, if applicable): This research is being conducted 
as part of the PI’s K01 award and is intended to provide training to establish independence. 
As such, the PI has mentors at the other institutions – The Ohio State University and UC San 
Francisco. No identifiable data will be shared with these mentors.  
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: 
Indicate, by title, who will be present during study procedure(s): Eleanor Leavens (PI), 
Nikki Nollen (co-I; mentor), Matthew Mayo (biostatistician), Tricia Snow (lead lab 
coordinator), Terri Tapp (research assistant), Leah Lambart (GRA), Stephanie Hiebert 
(GRA), Leo Byer (RA) , Dan Li (regulatory staff), CTSU staff 
 
1. Primary responsibility for the following activities, for example:  
a. Determining eligibility: Eleanor Leavens, Leah Lambart, Stephanie Hiebert, Leo 
Byer, Nikki Nollen, Terri Tapp 
b. Obtaining informed consent: Eleanor Leavens, Leah Lambart, Stephanie Hiebert, 
Leo Byer, Terri Tapp 

 
KUMC – HRPP- 03/12/2015 
 
Page 14 of 25
 
 
 
c. Providing on-going information to the study sponsor and the IRB: Eleanor 
Leavens, Dani Li, Leah Lambart, Stephanie Hiebert 
d. Maintaining participant's research records: Eleanor Leavens, Tricia Snow, Matt 
Mayo, Leah Lambart, Stephanie Hiebert, Leo Byer 
e. Completing physical examination: N/A 
f. Taking vital signs, height, weight: CTSU staff 
g. Drawing / collecting laboratory specimens: CTSU staff 
h. Performing / conducting tests, procedures, interventions, questionnaires: Eleanor 
Leavens, Tricia Snow, Leah Lambart, Stephanie Hiebert, Leo Byer, CTSU staff, 
Terri Tapp 
i. Completing study data forms: Eleanor Leavens, Leah Lambart, Stephanie Hiebert, 
Leo Byer 
j. Managing study database: Matt Mayo, Tricia Snow, Eleanor Leavens, Nikki Nollen, 
Leah Lambart, Stephanie Hiebert, Leo Byer 
 
L. Assessment of Subject Safety and Development of a Data and Safety Monitoring 
Plan 
 
1. Elements of the plan include: 
The current study does not pose more than minimal risk; however, we are extremely 
sensitive to the history of 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. In addition, we will have firm stopping rules to protect the safety 
of study participants. The Vuse Alto EC will be used for the proposed study. The Vuse 
Alto device is a commercially available pod-based device and is compatible with nicotine 
salt and freebase nicotine e-liquid. We will use commercially available nicotine salt e-
liquid in 5% and 1.8% nicotine concentrations. 
 
2. All adverse events (AEs) occurring during the study will be assessed (e.g., symptoms 
checklist, NCI’s Common Toxicity Criteria (CTC) version 5.0), documented, and reported 
to Drs. Leavens (Principal Investigator) and Nollen (Primary Mentor). The occurrence of 
AEs will be assessed each study visit throughout phase 1 and 2 of the study. Drs. 
Leavens and Nollen will review the AE logs at least weekly for all patients on the trial. 
The study investigators will follow all AEs to the point of a satisfactory resolution. All AEs 
will be assessed to determine if they meet criteria for an SAE. Serious adverse events 
(SAEs), as defined by the FDA, will be systematically evaluated at each visit. Any SAE, 
whether or not related to study, will be reported to the KUMC IRB, DSMC, and the FDA. 
The initial SAE report will be followed by submission of a completed SAE report to all 
three institutions.  
 
3. In the event that a participant discontinues study treatment due to an SAE, the 
participant will continue to have appropriate follow-up and assessment. Outcome of SAEs 

 
KUMC – HRPP- 03/12/2015 
 
Page 15 of 25
 
 
 
will be periodically reported to NIH. A summary of the SAEs that occurred during the 
previous year will be included in the annual progress report to NIH.  
 
 
III. 
Subject Participation 
 
A. Recruitment: 
1. African American and White current daily smokers will be recruited from the local 
community using standard media outlets, combination of flyers, referrals, social media, 
and radio/TV ads, and in collaboration with Swope Health Center, which serves a large 
proportion of AAs and has been a recruitment site for all of Dr. Nollen’s previous trials. 
We will also use the Frontiers registry, SlicerDicer, C3OD, and HERON databases to 
identify adult smokers who have agreed to be contacted for research. Consistent with 
past trials, we will send the patient a letter informing them of the study. We will then 
follow-up via phone the week after the letter was sent and offer screening. 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 opportunity to be 
screened.   
2. Recruitment methods are described above. Recruitment will be conducted by members of 
the study team. Recruitment will be overseen by Dr. Leavens. Screening will be 
conducted over the phone and by redcap survey.  
3. Advertisements and flyers that will be used for recruitment will be submitted prior to 
study recruitment efforts begin. Advertisements and flyers will be handed out to potential 
participants by the study team and will be placed in clinics at KUMC/TUKHS and in the 
community.  
4. Letters will be mailed directly to patients to inform them of the study. Within one week of 
mailing letters, study staff will make follow-up calls to patients and offer initial screening. 
Letters will be submitted prior to study recruitment efforts begin.  
B. Screening Interview/questionnaire: The initial screen will review inclusion/exclusion 
criteria aside from exhaled carbon monoxide (eCO) measurement. Participants who are 
deemed to be eligible at the initial screening will report to the lab for in-person final 
screening within 14 days of the initial screening. During the final screening visit, participants 
will complete informed consent procedures, including HIPAA documentation. Only those 
participants who provide consent will complete the additional screening questionnaires. 
Additional screening measures include questionnaires, an expired carbon monoxide sample 
to confirm smoking status, and (if female) a urine pregnancy test. At the final screening and 
enrollment visit, participants will be asked to sample two Vuse EC flavors to determine flavor 
preference. Participants will complete baseline measures including demographics, medical, 
tobacco use, and substance use history and measurement of cotinine, NNAL, eCO, 
spirometry, blood pressure, lung injury panel, and respiratory symptoms. 
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 and deemed to be initially eligible will meet 
the research assistant at the Clinical and Translational Science Unit (CTSU) at KUMC. 
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 

 
KUMC – HRPP- 03/12/2015 
 
Page 16 of 25
 
 
 
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 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, Dr. Leavens will determine whether the subject is able to give 
informed consent. 
D. Alternatives to Participation: The alternative to participation is not participating, 
continuing to smoke cigarettes as usual, obtaining an EC on their own, attempting to quit 
using FDA-approved pharmacotherapy, attempting to quit cold turkey.  
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: In Phase 1, participants will receive 
$60 for each of the human laboratory visits. If they complete both human laboratory visits, 
they will receive a $20 bonus. Therefore, participants who attend screening and both study 
visits will earn $140. In Phase 2, participants will receive $20 for attending each randomized 
trial study visit/phone call which will be paid at the next in-person visit. In addition, they will 
receive $80 for providing samples and bringing their used and current e-cigarette pods for 
measurement. Participants who complete all Phase 2 procedures will earn $220. Participants 
who complete all study procedures can earn up to $360. Participants may also receive $20 
for each referral who is eligible and enrolls in the study. They may complete up to 3 different 
referrals for an additional total of $60. 
H. Payment for a research-related injury: N/A 
IV. 
Data Collection and Protection 
A. Data Management and Security:  
1. 
We will use the participant’s name only on the screening and informed consent/HIPPA 
documents and these will be kept in a locked file cabinet, to be kept in our study office. 
Protection against loss of confidentiality and privacy will be maintained by numerically 
coding all data, disguising identifying information, and keeping data locked in file drawers 
or in a secure, password-protected database. All biospecimen samples are deidentified 
and stored in a freezer at the CTSU. Names of participants will be kept separate from 
participant data. Only study research assistants and the PI will have the information that 
connects participant names and ID numbers. All electronic data will be numerically coded 
and stored in a password-protected database, on a password-protected computer in a 
secure research space. Participant information will be accessible only to research staff, 
who are pledged to confidentiality and complete training in the ethical conduct of 
research (i.e., both HIPAA and CITI trainings). Identifying information will not be 
reported in any publication. No information will be stored locally on the laptop/tablet; all 
information will be stored securely in the secure data capture system. Only summaries of 

 
KUMC – HRPP- 03/12/2015 
 
Page 17 of 25
 
 
 
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: Blood will be collected for plasma nicotine measurement 
during both study visits during Phase 1. Six blood draws (one needle stick) per participant 
per visit will occur and be processed and analyzed. At both visits, blood samples will be 
collected at -5 (baseline), 5 (post 10-puff bout), 7, 15 (beginning of ad lib session), 45, and 
75 (post-session) minutes. Seven mL of blood will be collected during each blood draw (7 mL 
per draw x 6 draws per visit x 2 visits = 44 mL total during study). Samples will be analyzed 
according to standardized methods84 by Dr. Na Zhang at KUMC. Blood will be analyzed for 
nicotine content to assess nicotine exposure during the session. 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. Samples will be 
stored at the Bioanalytical Laboratory at the Clinical and Translational Science Unit (CTSU) at 
KUMC. 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 (blood/plasma and urine) 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, urine 
and blood (i.e., plasma) 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, EC, and carcinogen exposure 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.    
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 Dr. Leavens 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.  

 
KUMC – HRPP- 03/12/2015 
 
Page 18 of 25
 
 
 
 
V. 
Data Analysis and Reporting 
A. Statistical and Data Analysis: Data will be summarized using means and standard 
deviations, both overall and stratified (by race). To assess aim 1, we will conduct a 2x2 
crossover study and utilize linear mixed effects models to assess differences in total inhaled 
volume between 1.8% and 5% nicotine concentration globally and by race. This technique 
allows us to handle repeated measures that are inherently correlated. Similar analyses will 
be done on consumption of e-liquid, plasma nicotine levels, craving and withdrawal. Period 
and carryover effects will be considered in the models. If warranted, based upon results from 
aim 1, we will examine race and its interaction with nicotine concentration in the linear 
mixed effects models for all outcomes. However, we have limited power to detect an 
interaction and do not anticipate a differential change between AAs and whites, thus we 
must see a differential effect (e.g., one race responds to one dose and the other race 
responds to the other dose). If the interaction term is significant, the interaction will be 
probed. For aim 2, we will obtain the number of participants who have completely 
substituted ECs for combustible cigarettes for each group (1.8% vs. 5%) and by race, 
calculate the corresponding proportion, assuming that if they fail to return, they did not have 
complete substitution, and calculate the 95% confidence interval for this proportion for each 
group independently. Given the small sample size, we do not expect to have the ability to 
obtain statistical difference, but we will have solid estimates on these proportions for each 
nicotine concentration group and will be able to calculate an effect size for future studies 
which can be designed to test a difference. Similarly, we will have estimates on proportion of 
dual cig-EC and cigarette only use. Finally, for aim 3, we will estimate the mean, standard 
deviation, and median for the change in e-liquid consumption and biomarkers for each 
nicotine concentration group. Given the sample size and distribution of the mean, we will 
either utilize the two-sample t-test or Wilcoxon rank sum test to test if there are differences 
between nicotine concentration groups. Primarily, we will calculate the potential effect size 
on these variables globally and by race. We will examine the rate of adverse events globally 
(experience any adverse event) and by event type for each nicotine concentration group and 
by race. Data will be transformed as appropriate. While we do not make any specific 
hypotheses regarding sex differences, we will consider sex as a covariate in all analyses. We 
expect to recruit equal numbers of males and females to explore sex as a moderator of our 
study outcomes in exploratory analyses. All analyses will be conducted at the 0.05 Type I 
error level. We will not adjust for multiplicity; Bonferroni or other adjustments would be too 
restrictive in this pilot study. 
B. Outcome: The primary study endpoint is identifying the impact of e-liquid nicotine 
concentration on compensatory puffing, EC and cigarette use patterns, and resultant 
exposure to biomarkers of harm among AA and white smokers. Our central hypothesis is 
that, compared to the high nicotine concentration, while vaping the low nicotine 
concentration, users will engage in compensatory puffing, resulting in greater e-liquid 
consumption (Phase 1). Moreover, rates of dual use and continued smoking will be higher for 
the low (versus high) nicotine concentration and will result in greater exposure to toxicants 
(Phase 2). 
C. Study results to participants: Study results will not be shared with research participants.  

 
KUMC – HRPP- 03/12/2015 
 
Page 19 of 25
 
 
 
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.  
 

 
KUMC – HRPP- 03/12/2015 
 
Page 20 of 25
 
 
 
VI. 
Bibliography / References / Literature Cited  
 
1. Leavens EL, Driskill LM, Molina N, et al. Comparison of a preferred versus non-preferred 
waterpipe tobacco flavour: subjective experience, smoking behaviour and toxicant exposure. 
Tobacco control. 2018;27(3):319-324. PMID: 28381414 
2. Wagener TL, Leavens EL, Mehta T, et al. Impact of flavors and humectants on waterpipe tobacco 
smoking topography, subjective effects, toxicant exposure and intentions for continued use. 
Tobacco Control. 2020. PMID: 32404518 
3. Keller-Hamilton B, Mehta T, Hale J, et al. Effects of flavorants and humectants on waterpipe 
tobacco puffing behavior, biomarkers of exposure, and subjective effects among adults with high 
vs. low nicotine dependence. Tobacco control. In Press. 
4. Leavens EL, Morgan TL, Brett EI, et al. Concurrent alcohol use and waterpipe tobacco smoking: 
smoking topography, toxicant exposure, and abuse liability. Nicotine & Tobacco Research. 2019. 
PMID: 30820567; PMCID: PMC7297088 
5. Leavens E, Smith T, Natale N, Carpenter M. Electronic cigarette dependence and demand among 
pod mod users as a function of smoking status. Psychology of Addictive Behaviors: Journal of 
the Society of Psychologists in Addictive Behaviors. 2020. PMID: 32297753; PMCID: 
PMC7572426 (available on 2021-11-01) 
6. Brett EI, Stevens EM, Wagener TL, et al. A content analysis of JUUL discussions on social media: 
Using Reddit to understand patterns and perceptions of JUUL use. Drug and alcohol dependence. 
2019;194:358-362. 
7. Leavens EL, Stevens EM, Brett EI, et al. JUUL electronic cigarette use patterns, other tobacco 
product use, and reasons for use among ever users: Results from a convenience sample. 
Addictive behaviors. 2019;95:178-183. PMID: 30933713 
8. Leavens EL, Stevens EM, Brett EI, Leffingwell TR, Wagener TL. JUUL in school: JUUL electronic 
cigarette use patterns, reasons for use, and social normative perceptions among college student 
ever users. Addictive behaviors. 2019;99:106047. PMID: 31442788; PMCID: PMC7153300 
9. Leavens EL, Mehta T, Shihadeh A, Halquist M, Hale J, Wagener TL. Nicotine delivery and abuse 
liability of pod-mods, second- and third-generation electronic cigarettes, and cigarettes. Society 
for Research on Nicotine and Tobacco; 2020, March; New Orleans, LA. 
10. Wagener TL, Avery JA, Leavens EL, Simmons WK. Associated Changes in E-cigarette Puff 
Duration and Cigarettes Smoked Per Day. Nicotine & Tobacco Research. 2020. PMID: 33049064 
11. Stevens EM, Hébert ET, Tackett AP, Leavens EL, Wagener TL. Harm perceptions of the JUUL 
ecigarette in a sample of ever users. International Journal of Environmental Research and Public 
Health. 2020;17(13):4755. PMID: 32630647; PMCID: PMC7369803 
12. Stevens EM, Johnson AL, Leshner G, et al. People in E-Cigarette Ads Attract More Attention: An 
Eyetracking Study. Tobacco Regulatory Science. 2020;6(2):105-117. 
13. Stevens EM, Kim S, Leshner G, et al. The Attitudinal and Motivational Effects of Anti-waterpipe 
Messages. American journal of health behavior. 2019;43(3):478-489. 
14. Wedel AV, Stevens EM, Molina N, Leavens EL, Roberts C, Wagener TL. Examining pregnant 
smokers’ attitudes toward cessation aids and electronic nicotine delivery systems. The Journal of 
the Oklahoma State Medical Association. 2018;111(8):812. PMID: 31404418; PMCID: 
PMC6688761 
15. Leavens ELS, Stevens EM, Brett EI, Molina N, Leffingwell TR, Wagener TL. Use of Rideshare 
Services to Increase Participant Recruitment and Retention in Research: Participant 
Perspectives. Journal of Medical Internet research. 2019;21(4):e11166. PMID: 30958269; 
PMCID: PMC6475818 

 
KUMC – HRPP- 03/12/2015 
 
Page 21 of 25
 
 
 
16. Leavens EL, Lechner WV, Stevens EM, et al. Electronic cigarette and combustible cigarette use 
following a campus-wide ban: prevalence of use and harm perceptions. Journal of American 
College Health. 2020;68(4):332-335. PMID: 30681933 
17. Leavens EL, Meier E, Brett EI, et al. Polytobacco use and risk perceptions among young adults: 
The potential role of habituation to risk. Addictive behaviors. 2019;90:278-284. PMID: 
30472536 
18. Tackett AP, Leavens EL, Wiedenmann A, et al. Preliminary exploration of secondhand smoke 
exposure in youth with Sickle Cell Disease: biochemical verification, pulmonary functioning, and 
health care utilization. Psychology, health & medicine. 2019;24(1):35-42. PMID: 30203658; 
PMCID: PMC6262893 
19. Leavens EL, Brett EI, Morgan TL, et al. Descriptive and injunctive norms of waterpipe smoking 
among college students. Addictive behaviors. 2018;77:59-62. PMID: 28963891 
20. Leavens EL, Meier E, Tackett AP, et al. The impact of a brief cessation induction intervention for  
waterpipe tobacco smoking: a pilot randomized clinical trial. Addictive behaviors. 2018;78:94- 
100. PMID: 29128712; PMCID: PMC5801765 
21. Wagener TL, Floyd EL, Stepanov I, et al. Have combustible cigarettes met their match? The 
nicotine delivery profiles and harmful constituent exposures of second-generation and third-
generation electronic cigarette users. Tobacco control. 2017;26(e1):e23-e28. 
22. Leavens EL, Brett EI, Frank S, et al. Association between breath alcohol concentration and 
waterpipe lounge patrons’ carbon monoxide exposure: A field investigation. Drug and alcohol 
dependence. 2017;170:152-155. PMID: 27918950 
23. Busch AM, Leavens EL, Wagener TL, Buckley ML, Tooley EM. Prevalence, Reasons for Use, and 
Risk Perception of Electronic Cigarettes Among Post-Acute Coronary Syndrome Smokers. J 
Cardiopulm Rehabil Prev. 2016;36(5):352-357. PMID: 27120039; PMCID: PMC5001913 
24. Wagener TL, Shaikh RA, Meier E, et al. Examining the smoking and vaping behaviors and 
preferences of vape shop customers. Tob Prev Cessation. 2016;2(Supplement):5. 
25. Nollen NL, Mayo MS, Sanderson Cox L, et al. Factors that explain differences in abstinence 
between black and white smokers: a prospective intervention study. JNCI: Journal of the 
National Cancer Institute. 2019;111(10):1078-1087. 
26. Brett EI, Miller MB, Leavens EL, Lopez SV, Wagener TL, Leffingwell TR. Electronic cigarette use 
and sleep health in young adults. Journal of Sleep Research. 2020;29(3):e12902. PMID: 
31486154; PMCID: PMC7299171 
27. Wang TW, Asman K, Gentzke AS, et al. Tobacco product use among adults—United States, 
2017. Morbidity and Mortality Weekly Report. 2018;67(44):1225. 
28. Wang TW, Gentzke A, Sharapova S, Cullen KA, Ambrose BK, Jamal A. Tobacco Product Use 
Among Middle and High School Students - United States, 2011-2017. MMWR Morb Mortal Wkly 
Rep. 2018;67(22):629-633. 
29. Goniewicz ML, Knysak J, Gawron M, et al. Levels of selected carcinogens and toxicants in vapour 
from electronic cigarettes. Tobacco control. 2014;23(2):133-139. 
30. Geiss O, Bianchi I, Barrero-Moreno J. Correlation of volatile carbonyl yields emitted by e-
cigarettes with the temperature of the heating coil and the perceived sensorial quality of the 
generated vapours. International journal of hygiene and environmental health. 
2016;219(3):268-277. 
31. Uchiyama S, Ohta K, Inaba Y, Kunugita N. Determination of carbonyl compounds generated 
from the E-cigarette using coupled silica cartridges impregnated with hydroquinone and 2, 4-
dinitrophenylhydrazine, followed by high-performance liquid chromatography. Analytical 
Sciences.2013;29(12):1219-1222. 

 
KUMC – HRPP- 03/12/2015 
 
Page 22 of 25
 
 
 
32. Kosmider L, Sobczak A, Fik M, et al. Carbonyl compounds in electronic cigarette vapors: effects 
of nicotine solvent and battery output voltage. Nicotine & Tobacco Research. 2014;16(10):1319-
1326. 
33. Papoušek R, Pataj Z, Nováková P, Lemr K, Barták P. Determination of acrylamide and acrolein in 
smoke from tobacco and e-cigarettes. Chromatographia. 2014;77(17-18):1145-1151. 
34. Tayyarah R, Long GA. Comparison of select analytes in aerosol from e-cigarettes with smoke 
from conventional cigarettes and with ambient air. Regulatory Toxicology and Pharmacology. 
2014;70(3):704-710. 
35. National Academies of Sciences E, Medicine. Public health consequences of e-cigarettes. National 
Academies Press; 2018.  
36. Labs J. JUULpod Basics. Accessed September 16, 2019, 2019. 
37. Goniewicz ML, Kuma T, Gawron M, Knysak J, Kosmider L. Nicotine levels in electronic cigarettes. 
Nicotine & Tobacco Research. 2013;15(1):158-166. 
38. Trehy ML, Ye W, Hadwiger ME, et al. Analysis of electronic cigarette cartridges, refill solutions, 
and smoke for nicotine and nicotine related impurities. Journal of Liquid Chromatography & 
Related Technologies. 2011;34(14):1442-1458. 
39. Cameron JM, Howell DN, White JR, Andrenyak DM, Layton ME, Roll JM. Variable and potentially 
fatal amounts of nicotine in e-cigarette nicotine solutions. Tobacco control. 2014;23(1):77-78. 
40. Bowen A, Xing C. Nicotine salt formulations for aerosol devices and methods thereof. In: Google 
Patents; 2015. 
41. Kabat GC, Morabia A, Wynder EL. Comparison of smoking habits of blacks and whites in a case 
control study. American Journal of Public Health. 1991;81(11):1483-1486. 
42. Ahijevych K, Gillespie J, Demirci M, Jagadeesh J. Menthol and nonmenthol cigarettes and smoke 
exposure in black and white women. Pharmacology Biochemistry and Behavior. 
1996;53(2):355-360. 
43. Haiman CA, Stram DO, Wilkens LR, et al. Ethnic and racial differences in the smoking-related 
risk of lung cancer. New England Journal of Medicine. 2006;354(4):333-342. 
44. Society AC. Cancer facts & figures. American Cancer Society. 2016. 
45. Gunawan T. Differences in Smoking Topography, Subjective Responses, and Short-term 
Abstinence between African American and White Menthol and Non-menthol Smokers, American 
University; 2018. 
46. Jarvik M, Tashkin D, Caskey N, McCarthy W, Rosenblatt M. Mentholated cigarettes decrease puff  
volume of smoke and increase carbon monoxide absorption. Physiology & behavior. 
1994;56(3):563-570. 
47. Perez-Stable EJ, Herrera B, Jacob III P, Benowitz NL. Nicotine metabolism and intake in black 
and white smokers. Jama. 1998;280(2):152-156. 
48. Surgeon General U. Department of Health and Human Services, The Health Consequences of  
Smoking: Nicotine Addiction, A Report of the Surgeon General (DHHS Publication Number CDC 
88-8406). Public Health Service Office on Smoking and Health, Rockville, MD. 1988. 
49. Benowitz NL. Nicotine addiction. New England Journal of Medicine. 2010;362(24):2295-2303. 
50. Hutzler C, Paschke M, Kruschinski S, Henkler F, Hahn J, Luch A. Chemical hazards present in 
liquids and vapors of electronic cigarettes. Archives of toxicology. 2014;88(7):1295-1308. 
51. Goniewicz ML, Smith DM, Edwards KC, et al. Comparison of nicotine and toxicant exposure in 
users of electronic cigarettes and combustible cigarettes. JAMA network open. 
2018;1(8):e185937-e185937. 
52. US Food and Drug Administration. FDA announces comprehensive regulatory plan to shift 
trajectory of tobacco-related disease, death [press release]. July. 2017;28:2017. 

 
KUMC – HRPP- 03/12/2015 
 
Page 23 of 25
 
 
 
53. European Tobacco Products Directive. Electronic Cigarettes and Herbal Products for Smoking; 
Article 20. https://eur-lex.europa.eu/legal 
content/EN/TXT/HTML/?uri=CELEX:32014L0040&rid=6#d1e2288-1- 
54. Utah Administrative Code, Rule R384-415-5. https://rules.utah.gov/publicat/code/r384/r384-
415.htm. 
55. Utah Department of Health. E-cigarette Standards. https://utahtobaccolaws.org/ecigarette-
sales/ Accessed February 1, 2021. 
56. US Congress. H.R.4624 - Ending Nicotine Dependence from Electronic Nicotine Delivery Sys-
tems Act of 2019. 2019. Available: https://www.congress.gov/bill/116th-congress/house-
bill/4624/text?r=8&s=1  
57. E-cigarette Policy Options for States. Association of State and Territorial Health Officials. 
58. Wagener TL, Floyd EL, Stepanov I, et al. Have combustible cigarettes met their match? The 
nicotine delivery profiles and harmful constituent exposures of second-generation and third-
generation electronic cigarette users. Tob Control. 2017;26(e1):e23-e28. 
59. Hiler M, Breland A, Spindle T, et al. Electronic cigarette user plasma nicotine concentration, puff  
topography, heart rate, and subjective effects: Influence of liquid nicotine concentration and 
user experience. Experimental and clinical psychopharmacology. 2017;25(5):380. 
60. Kośmider L, Kimber CF, Kurek J, Corcoran O, Dawkins LE. Compensatory puffing with lower 
nicotine concentration e-liquids increases carbonyl exposure in e-cigarette aerosols. Nicotine and 
Tobacco Research. 2017;20(8):998-1003. 
61. Dawkins LE, Kimber CF, Doig M, Feyerabend C, Corcoran O. Self-titration by experienced e-
cigarette users: blood nicotine delivery and subjective effects. Psychopharmacology. 
2016;233(15-16):2933-2941. 
62. Talih S, Salman R, El-Hage R, et al. Might limiting liquid nicotine concentration result in more 
toxic electronic cigarette aerosols? Tobacco Control. 2020. 
63. Donny EC, Denlinger RL, Tidey JW, et al. Randomized trial of reduced-nicotine standards for 
cigarettes. New England Journal of Medicine. 2015;373(14):1340-1349. 
64. Donny EC, Houtsmuller E, Stitzer ML. Smoking in the absence of nicotine: behavioral, subjective 
and physiological effects over 11 days. Addiction. 2007;102(2):324-334. 
65. Hatsukami DK, Kotlyar M, Hertsgaard LA, et al. Reduced nicotine content cigarettes: effects on 
toxicant exposure, dependence and cessation. Addiction. 2010;105(2):343-355. 
66. Caponnetto P, Campagna D, Cibella F, et al. EffiCiency and Safety of an eLectronic cigAreTte 
(ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized control design 
study. PloS one. 2013;8(6):e66317. 
67. Bullen C, Howe C, Laugesen M, et al. Electronic cigarettes for smoking cessation: a randomised 
controlled trial. The Lancet. 2013;382(9905):1629-1637. 
68. Hajek P, Phillips-Waller A, Przulj D, et al. A randomized trial of e-cigarettes versus nicotine 
replacement therapy. New England Journal of Medicine. 2019;380(7):629-637. 
69. Pulvers K, Nollen NL, Rice M, et al. Effect of Pod e-Cigarettes vs Cigarettes on Carcinogen 
Exposure Among African American and Latinx Smokers: A Randomized Clinical Trial. JAMA 
network open. 2020;3(11):e2026324-e2026324. 
70. US Food and Drug Administration. Deeming tobacco products to be subject to the Federal Food, 
Drug, and Cosmetic Act, as amended by the Family Smoking Prevention and Tobacco Control 
Act; restrictions on the sale and distribution of tobacco products and required warning 
statements for tobacco products. Final rule. Federal register. 2016;81(90):28973. 
71. Keamy-Minor E, McQuoid J, Ling PM. Young adult perceptions of JUUL and other pod electronic 
cigarette devices in California: a qualitative study. BMJ open. 2019;9(4):e026306. 

 
KUMC – HRPP- 03/12/2015 
 
Page 24 of 25
 
 
 
72. Nardone N, Helen GS, Addo N, Meighan S, Benowitz NL. JUUL electronic cigarettes: Nicotine 
exposure and the user experience. Drug and alcohol dependence. 2019;203:83-87. 
73. US Food and Drug Administration Center for Tobacco Products. Research Priorities. Published 
2018. Accessed September 16, 2019. 
74. Deveci SE, Deveci F, Açik Y, Ozan AT. The measurement of exhaled carbon monoxide in healthy 
smokers and non-smokers. Respiratory medicine. 2004;98(6):551-556. 
75. Carter LP, Stitzer ML, Henningfield JE, O'Connor RJ, Cummings KM, Hatsukami DK. Abuse 
liability assessment of tobacco products including potential reduced exposure products. Cancer 
Epidemiology and Prevention Biomarkers. 2009;18(12):3241-3262. 
76. Yingst JM, Hrabovsky S, Hobkirk A, Trushin N, Richie JP, Foulds J. Nicotine absorption profile 
among regular users of a Pod-Based electronic nicotine delivery system. JAMA network open. 
2019;2(11):e1915494-e1915494. 
77. Maloney S, Eversole A, Crabtree M, Soule E, Eissenberg T, Breland A. Acute effects of JUUL and 
IQOS in cigarette smokers. Tobacco Control. 2020. 
78. Ramôa CP, Hiler MM, Spindle TR, et al. Electronic cigarette nicotine delivery can exceed that of  
combustible cigarettes: a preliminary report. Tobacco control. 2016;25(e1):e6-e9. 
79. Spindle TR, Talih S, Hiler MM, et al. Effects of electronic cigarette liquid solvents propylene 
glycol and vegetable glycerin on user nicotine delivery, heart rate, subjective effects, and puff 
topography. Drug and alcohol dependence. 2018;188:193-199. 
80. Dawkins L, Corcoran O. Acute electronic cigarette use: nicotine delivery and subjective effects in 
regular users. Psychopharmacology. 2014;231(2):401-407. 
81. Shihadeh A. Investigation of mainstream smoke aerosol of the argileh water pipe. Food and 
Chemical Toxicology. 2003;41(1):143-152. 
82. Breland AB, Kleykamp BA, Eissenberg T. Clinical laboratory evaluation of potential reduced 
exposure products for smokers. Nicotine & Tobacco Research. 2006;8(6):727-738. 
83. Maziak W, Rastam S, Shihadeh AL, et al. Nicotine exposure in daily waterpipe smokers and its 
relation to puff topography. Addictive behaviors. 2011;36(4):397-399. 
84. Jacob III P, Wu S, Yu L, Benowitz NL. Simultaneous determination of mecamylamine, nicotine, 
and cotinine in plasma by gas chromatography-mass spectrometry. Journal of pharmaceutical 
and biomedical analysis. 2000;23(4):653-661. 
85. Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges (QSU-
brief) in laboratory and clinical settings. Nicotine & Tobacco Research. 2001;3(1):7-16. 
86. Hatsukami DK, Zhang Y, O’Connor RJ, Severson HH. Subjective responses to oral tobacco 
products: scale validation. nicotine & tobacco research. 2013;15(7):1259-1264. 
87. Brown RA, Burgess ES, Sales SD, Whiteley JA, Evans DM, Miller IW. Reliability and validity of a 
smoking timeline follow-back interview. Psychology of Addictive Behaviors. 1998;12(2):101. 
88. Robinson SM, Sobell LC, Sobell MB, Leo GI. Reliability of the Timeline Followback for cocaine, 
cannabis, and cigarette use. Psychology of addictive behaviors. 2014;28(1):154. 
89. Benowitz NL, Bernert JT, Foulds J, et al. Biochemical Verification of Tobacco Use and Abstinence: 
2019 Update. Nicotine Tob Res. 2019. 
90. Ahijevych K, Parsley LA. Smoke constituent exposure and stage of change in black and white 
women cigarette smokers. Addictive behaviors. 1999;24(1):115-120. 
91. Ahluwalia J, Pulvers K, Nollen N, et al. A Randomized Trial of E-cigarettes to Reduce Harm in 
Smokers. The E-Cigarette Summit; 2019; London. 
92. Nollen NL, Cox LS, Mayo MS, Ellerbeck EF, Madhusudhana S, Ahluwalia JS. A randomized clinical 
trial of counseling and nicotine replacement therapy for treatment of African American non-daily 

 
KUMC – HRPP- 03/12/2015 
 
Page 25 of 25
 
 
 
smokers: Design, accrual, and baseline characteristics. Contemporary clinical trials. 
2018;70:72-82. 
93. Nollen NL, Cox LS, Yu Q, et al. A clinical trial to examine disparities in quitting between African 
American and White adult smokers: Design, accrual, and baseline characteristics. Contemporary 
clinical trials. 2016;47:12-21. 
94. Eisenberg MJ, Hébert-Losier A, Windle SB, et al. Effect of e-Cigarettes Plus Counseling vs 
Counseling Alone on Smoking Cessation: A Randomized Clinical Trial. Jama. 
2020;324(18):1844-1854. 
95. Chow S-C, Wang H, Shao J. Sample size calculations in clinical research. CRC press; 2007. 
96. Senn SS. Cross-over trials in clinical research. Vol 5: John Wiley & Sons; 2002.