Comparative Acceptability of Tobacco and Menthol Flavored E-cigarettes Among Menthol Cigarette Smokers
Phase: NA
Conditions: Tobacco Use Disorder
Sponsor: University of Kansas Medical Center

University of Kansas Medical Center  
RESEARCH PROTOCOL INVOLVING HUMAN SUBJECTS  
TEMPLATE WITH GUIDANCE 
 
Version date: January 11,2023 
Principal Investigator: Nikki Nollen  
Study Title: The Impact of Menthol Flavoring on Switching in Adult Menthol Smokers 
Co- Investigator(s): Lisa Sanderson Cox, Eleanor Leavens, Matthew Mayo 
 
I. 
Purpose, Background and Rationale 
A. Aims and Hypotheses  
 
Nearly 12 of the 34 million adult smokers in the US smoke menthol cigarettes. When added to cigarettes, 
menthol increases addictive potential and dependence, and decreases the likelihood of cessation. These 
effects are particularly felt in the African American (AA) community where targeted marketing has resulted 
in ≈85% of AA versus ≈20% of White smokers using menthol cigarettes. The FDA’s decision to advance 
the rulemaking process to ban menthol cigarettes is an important step toward closing the gap in tobacco-
related disease and death disproportionately experienced by AA smokers. The agency’s regulatory action 
stopped short of including menthol-flavored e-cigarettes (ECs) and debate continues about whether more 
comprehensive enforcement priorities inclusive of menthol flavored e-liquids should be enacted. While a 
ban on menthol flavored EC liquids may reduce youth and young adult initiation, it may also discourage 
adult menthol smokers to switch from tobacco cigarettes to EC. This could slow harm reduction and result 
in a negative public health impact that would be concentrated in racial/ethnic minority communities 
already disproportionately burdened by tobacco. FDA has identified the impact of EC flavoring on smoking 
patterns as a research priority area, and there is an urgent need for studies that examine tobacco 
regulatory actions with a specific focus on possible unintended consequences that may increase tobacco-
related health disparities. To date, a prospectively designed randomized clinical trial (RCT) has not been 
conducted; therefore, the efficacy of menthol-flavored versus tobacco-flavored EC to facilitate switching 
from combustible cigarettes to EC in adult menthol smokers is not known. Our experienced, multi-
disciplinary team is one of the only groups in the country exclusively focused on tobacco-related health 
disparities intervention research in the AA community. Our recently completed RCT provided menthol EC 
or tobacco EC to AA and Latinx adult smokers. Among menthol smokers, post-hoc analyses found 
equivalent rates of switching from tobacco cigarettes to EC, tobacco harm reduction, EC product use, and 
acceptability between those who used tobacco EC versus menthol EC, although the study was not 
prospectively designed for this purpose and is limited by a small sample size for these comparisons. These 
data are consistent with observational studies that have found that nicotine – not flavor – drive use in 
adult EC users and provide strong preliminary evidence to support restrictions on menthol flavored EC 
given potential benefit to youth and lack of evidence of harm to smokers. However, to empirically answer 
this question, a fully powered RCT is needed.  
The objective of this application is to provide much needed data to the FDA to guide regulatory action 
on EC flavoring. Menthol smokers (n=800), stratified by race and gender, will be randomized 1:1 into a 
12-week open label, non-inferiority trial comparing a 4th generation nicotine salt-based pod-system EC in 
menthol- versus tobacco-flavored e-liquid. Follow-up will continue through week 26. The central 
hypothesis is that tobacco EC are not inferior to menthol EC at facilitating a switch to EC in menthol 
cigarette smokers. 
 
Our specific aims are: 
1) Compare the effectiveness of menthol versus tobacco EC at facilitating switching at week 
12. Hypothesis 1: Participants randomized to tobacco EC (versus menthol EC) will demonstrate 
non-inferior rates of complete and predominant switching to EC (primary outcome). Complete 
switching is defined as exclusive use of EC, confirmed with CO < 6 ppm, and predominant 
switching is defined as use of EC with > 50% reduction in CPD. Rates of complete and predominant 
switching will also be compared separately by group.  

2)  Compare tobacco harm reduction of menthol versus tobacco EC at week 12. Participants 
randomized to tobacco EC (versus menthol EC) will demonstrate comparable (i.e., no statistically 
significant differences) change in CO, respiratory symptoms, lung function, blood pressure, and 
tobacco-related quality of life from baseline to week 12. 
3) Compare the acceptability of menthol versus tobacco EC at week 12. Hypothesis 3: 
Participants randomized to tobacco EC (versus menthol EC) will consume comparable amounts of 
study provided e-liquid (measured in grams) and demonstrate comparable reductions in cigarette-
related withdrawal, craving, and dependence. Subjective effects of vaping will also be compared 
between groups. 
4) Examine the long-term effectiveness of menthol versus tobacco EC at week 26. Switching 
patterns at week 26 will be compared to examine long-term maintenance of EC and smoking 
patterns under naturalistic conditions (EC only provided up to week 12).  Hypothesis 4: There will 
be no statistically significant difference in rates of complete or predominant switching at week 26 
between those randomized to menthol versus tobacco EC.   
 
B. Background and Significance 
 
Electronic cigarettes as a harm reduction strategy for adult cigarette smokers. Tobacco, but 
primarily cigarettes, remains the leading cause of preventable disease in the US, claiming 480,000 lives 
per year and affecting an additional 16 million smokers who suffer from smoking-related chronic 
diseases.(1) Eliminating tobacco use in adult cigarette smokers remains the primary end-game for reducing 
tobacco’s public health burden,(2) but tobacco harm reduction has emerged as an important complement 
to these efforts.(3) Specifically, the availability of potentially less harmful products has led to increased 
focus on replacing all forms of combustible tobacco with noncombustible nicotine products that deliver 
nicotine but fewer tobacco toxicants to adults who cannot or are not ready to quit cigarettes. Central to 
harm reduction is the fact that nicotine contributes relatively little harm compared to the deleterious 
effects of combustible tobacco.(4)  
 
Electronic cigarettes (ECs) have emerged as an effective harm reduction strategy for individuals who 
smoke cigarettes who cannot or will not quit using FDA-approved cessation methods.(5) EC are used by 
one in six US adult cigarette smokers(2, 6) and are now the most common assisted method of quitting 
cigarettes.(7) Exclusively switching from cigarettes to ECs optimizes harm reduction relative to continued 
smoking(8-12) and growing evidence indicates that partially switching to EC reduces cigarette consumption, 
is a marker of EC acceptability, and might also be associated with reduced harm, particularly for cancer 
and COPD.(10, 13, 14) In our RCT that directly informs the current study, partial switchers replaced > 75% of 
their cigarettes with EC, resulting in a decrease of 70 cigarettes per week from baseline and significant 
reductions in the potent lung carcinogen, NNAL, carbon monoxide, and respiratory symptoms.(15) Current 
estimates indicate that 6.6 million premature deaths could be prevented over the next decade in the US 
and 86.7 million fewer years of life lost if adult cigarette smokers switched to EC.(5) 
Menthol flavoring in cigarettes. Menthol is a flavor additive with a minty taste and aroma that, when 
added to cigarettes, increases appeal and addictive potential, reduces the irritation and harshness of 
smoking, leads to greater depth of inhalation of tobacco smoke and its harmful constituents, facilitates 
dependence, and decreases the likelihood of cessation.(16) Targeted tobacco industry marketing of menthol 
cigarettes to African American (AA) communities since the 1940s has led to disproportionately higher 
rates of menthol cigarette use.(17-19) Today, 85% of all AA smokers smoke menthol cigarettes compared to 
20% of Whites.(20) Despite similar smoking prevalence, smoking on fewer days, and lower overall levels of 
daily cigarette consumption,(21-23) AAs are two to three-times more likely to die of tobacco-related 
illnesses, including cancer and heart disease, than other racial/ethnic groups; (24-26) menthol cigarettes are 
believed to be a major reason for this disproportionate suffering among AA smokers. Simulation modeling 
estimated that if the US had implemented a menthol cigarette ban in 2011, 190,000 Black lives and 
633,000 deaths, overall, would have been averted by 2050.(27) The FDA’s monumental decision to advance 
the rulemaking process to ban menthol cigarettes is an important step toward closing the gap in tobacco-
related disease and death disproportionately experienced by AA smokers. 
Menthol flavoring in EC. The FDA’s regulatory action on April 29, 2021 stopped short of including 
menthol-flavored ECs and debate continues about whether more comprehensive enforcement priorities 
inclusive of menthol flavored e-liquids should be enacted. At present, FDA is calling for research that 
examines the impact of EC flavoring on tobacco use behaviors with a particular focus on possible 
unintended consequences of tobacco regulatory actions on populations disproportionately burdened with 
tobacco-related health disparities. The current proposal directly responds to this call and, to our 
knowledge, will be the first prospectively designed study to directly compare the efficacy of menthol 

versus tobacco EC at facilitating switching from tobacco cigarettes to EC in adult menthol smokers 
transitioning to EC. We anticipate enrolling > 80% racial/ethnic minorities (primarily AA and Latinx) into 
the current study, thereby focusing on the populations who will be most impacted by regulatory action on 
menthol.  
 
C. Rationale 
Innovation in this application lies in the methods applied to the research question and the population 
studied. The status quo as it pertains to understanding the role of EC flavoring in adult smoker’s tobacco use 
behaviors is to conduct observational and lab-based studies. (35, 37, 38, 40, 41, 45, 46) (42) These designs contribute 
important information about the association between EC flavors and switching, but they cannot determine 
causality and are limited by self-selection bias. To definitively answer the question about the efficacy and 
acceptability of menthol EC versus tobacco EC at facilitating switching in adult smokers, an RCT is needed to 
establish if the observed associations are due to self-selection or are truly causal.  In that regard, the 
research proposed in this application is innovative, because it represents a departure from the status quo by 
being the first RCT to directly compare EC flavoring in adult menthol smokers interested in switching. 
Results from our preliminary studies (see C3) suggest comparable rates of switching from tobacco 
cigarettes to EC, tobacco harm reduction, EC product use, and acceptability between adult menthol 
smokers who used tobacco EC versus menthol EC and, in doing so, provide compelling evidence for 
conducting a fully powered RCT comparing menthol and tobacco EC. In addition, racial/ethnic minorities in 
the US are more likely to smoke menthol cigarettes and will be most impacted by regulatory action on 
menthol as a characterizing EC flavor, yet these groups are underrepresented in existing observational and 
lab-based studies examining the role of EC flavoring on adult smoker’s tobacco use behaviors. The research 
proposed in this application is further innovative, as it represents a departure from the status quo in that we 
will conduct the largest intervention trial of racial/ethnic minority menthol smokers ever done. We anticipate 
> 80% representation from racial/ethnic minority groups, primarily AA and Latinx. Results have the 
potential to shift paradigms. Specifically, based on our strong preliminary data, we expect that both menthol 
and tobacco EC will be acceptable and result in high rates of switching and improvements in tobacco-related 
health effects. The study will provide critical data to the FDA to inform regulatory action of menthol EC that 
could slow youth and young adult initiation with no resulting negative impact on switching in adult 
combustible cigarette smokers transitioning to EC and no unintended consequences in a priority 
population of predominately AA and Latinx smokers. 
 
II. 
Research Plan and Design 
 
A. Study Objectives 
This study will examine the short- and long-term effectiveness, tobacco harm reduction, and acceptability 
of menthol versus tobacco EC in adult menthol smokers not interested in quitting nicotine but interested in 
switching from cigarettes to EC.  
 
B. Study Type and Design 
 
Menthol smokers (n=800), stratified by race and gender, who are not interested in quitting nicotine will be 
randomized 1:1 into a 12-week open label, non-inferiority trial comparing a 4th generation nicotine salt-
based pod-system EC in menthol or tobacco flavoring. Each group will be provided a 12-week supply of EC 
5% nicotine concentration in either menthol or Virginia tobacco and will complete 4 check-in sessions to 
facilitate switching to EC.  The primary outcome is the proportion who make a complete or predominant 
switch to EC at week 12, where complete switching is defined as exclusive use of EC, biochemically 
confirmed with CO < 6, and predominant switching is defined as use of EC with > 50% reduction in CPD.  
Secondary outcomes include acceptability and long-term effectiveness. Follow-up will continue through 
week 26 to examine long-term maintenance of EC product use and smoking behavior under naturalistic 
conditions. Participants will be recruited and enrolled in collaboration with The University of Kansas Health 
System and Swope Health Central (Swope), a federally qualified health center serving a predominately AA 
population, that has been the site for our previous trials. 
 
Why a non-inferiority trial? Non-inferiority trials are executed when one product is anticipated to be 
‘not unacceptably worse than’ a comparator product and have value when it is feasible to sacrifice some 
degree of benefit to gain advantages provided by another product. 53,54 In the case of EC flavoring, the 
tradeoff of lower efficacy and acceptability of tobacco EC to adult menthol smokers may be well worth the 
advantages gained in youth and young adult initiation so long as the difference between tobacco and 

menthol EC is not so large that adult menthol smokers are unwilling to use tobacco EC. The alternative 
would be a superiority study, but these are used to conclude that one product is better than the other, 
and at the time of this proposal there is no data supporting this approach that menthol EC are more 
effective than tobacco EC at facilitating a switch from tobacco cigarettes to EC or vice versa. Rather, data 
from our RCT and other studies suggest that tobacco EC are non-inferior to menthol EC in terms of 
effectiveness and acceptability to adult users, but a fully powered RCT is needed.  
 
 
C. Sample size, statistical methods, and power calculation 
Sample size calculation. The aim of this non-inferiority trial is to establish that tobacco EC are not inferior 
to menthol EC in terms of the primary outcome, which is the proportion of menthol smokers who make a 
complete or predominant switch to EC, defined as use of EC along with a > 50% reduction in cigarettes from 
baseline to week 12. We assume 1) based on our RCT, that 73% in the menthol EC group will be complete 
or predominant switchers at week 12. We arrived at the 73% estimate at week 12 by examining the trend in 
switching from week 2 to week 6 in our RCT. Specifically, we noted a 12% reduction in switching from week 
2 to week 6 and assumed that a similar trend would continue through week 12. Given an 85% switch rate in 
the menthol EC group at week 6 in our RCT and assuming a 12% reduction in switching from week 6 to 12, 
gives us a 73% switch rate at week 12. We also assume 2) to prove non-inferiority, the proportion in the 
tobacco EC group that are complete and partial switchers at week 12 will be similar to the menthol EC as 
long as it is greater than 64%. So, we can assume that P1=the proportion in the tobacco EC group that will 
be complete or predominant switchers at week 12=0.64 and that P2=the proportion in the menthol EC 
group that will be complete or predominant switchers at week 12=0.73. Then to test for noninferiority we 
have the following hypotheses: H0 (null hypothesis): P1-P2 < -0.09 and H1 (alternative hypothesis): P1-P2 
> -0.09. Following these assumptions 400 per group gives us 82% power with a Type 1 error rate of 2.5% 
using a normal approximation test for non-inferiority. Sample size calculations were done with PASS 16.0.4. 
Basis for sample size calculations. Estimates for non-inferiority trials are guided by an effectiveness ratio 
that indicates how effective one product is relative to another product and is determined from estimates on 
the outcome of interest and the a priori difference threshold. The FDA and other regulatory bodies have 
established an effectiveness ratio of > 80% to indicate bioequivalence (i.e., non-inferiority).132 This is the 
criterion that we used in determining sample size for this study. Recent tobacco non-inferiority studies, 
including a tobacco harm reduction study comparing EC to heat-not-burn, have used a difference threshold 
of 15%.133 134 Using this 15% threshold and our estimate of a 73% complete or predominant switch rate in 
the menthol EC group gives us an effectiveness ratio of 79% (.58/.73), which is under the criteria set by 
FDA.  Raising the difference threshold to 14% would give us an effectiveness ratio of 81% (.59/.73). While 
this meets FDA criteria for non-inferiority, we felt that a difference of 14% was too large. Rather, we have 
gone with a more stringent difference threshold of 9%; at this threshold the proposed effectiveness ratio for 
our study is 88% (.64/.73), meaning that tobacco EC will be assumed to not be inferior to menthol EC if 
they are at least 88% as effective at facilitating a complete or predominant switch as menthol EC. This 
criterion places us well above the equivalence threshold set by the FDA and is more conservative than 
similar tobacco harm reduction non-inferiority studies, which we believe is a strength of this study. Missing 
data.  We expect minimal (<5%) lost to follow-up at week 12 based on our recent studies, however those 
lost will be considered as non-complete or predominant switcher and will be imputed as such. 
 
Statistical evaluation of study aims 
 
Aim 1. Compare the effectiveness of menthol versus tobacco EC at facilitating switching at week 
12. Primary hypothesis. Participants randomized to tobacco EC (versus menthol EC) will demonstrate 
non-inferior rates of complete and predominant switching to EC (primary outcome). Complete switching is 
defined as exclusive use of EC, biochemically confirmed with CO < 6 ppm, and predominant switching is 
defined as use of EC with > 50% reduction in CPD. We will test this hypothesis by calculating the 95% 
confidence interval for the difference in P1-P2, as defined above. To show noninferiority the upper limit of 
the confidence interval must be greater than or equal to 0.00 and lower limit of the confidence interval must 
be larger than -0.09. If the upper limit of the confidence interval is less than 0.00 then we cannot conclude 
noninferiority. If the upper limit is greater than or equal to 0.00 and the lower limit is less than or equal to -
0.09 then the results would be inconclusive.   
Rates of complete and predominant switching will also be compared separately by group using the chi-
square test. Note, that we have not specified an a priori difference threshold for these analyses and, 
therefore, they are not testing noninferiority and should be considered exploratory. What these analyses will 
provide is an estimate of the proportion of complete switchers in the tobacco EC versus menthol EC group 

and, separately, an estimate of the proportion of predominant switchers in the tobacco EC versus menthol 
EC group.  
 
Aim 2. Compare tobacco harm reduction of menthol versus tobacco EC at week 12. Hypothesis 2. 
Participants randomized to tobacco EC (versus menthol EC) will demonstrate comparable (i.e., no 
statistically significant differences) change in CO, respiratory symptoms, lung function, blood pressure, and 
tobacco-related quality of life from baseline to week 12. Each of these measures are on a quantitative scale 
and, given the sample size, we can assume the central limit theorem will hold. Thus, we will calculate the 
mean change and standard deviation of the change for each of these measures from baseline to week 12 by 
group.  We will then conduct the two-sample t-test comparing the means between the groups while also 
reporting the corresponding 95% confidence intervals. Given that we expect to show noninferiority and 
comparable effects between groups, we except to fail to reject each of these tests and thus each confidence 
interval for the difference between groups will contain 0.00.  However, if any of these variables are different 
when noninferiority is seen – i.e., Aim 1 is supported, meaning tobacco EC are found to be non-inferior to 
menthol EC on rate of switching –  we will then utilize logistic regression analyzes to identify any phenotypic 
or consumption patterns that may predict why these variables differ in the face of noninferiority. For 
example, we may find that tobacco-related quality of life differs by group even though tobacco EC were 
found to be noninferior to menthol EC on rate of switching.  In this case, factors such as gender, age, 
socioeconomic status, study-related side effects, adverse events, change in CPD, cigarette-related 
withdrawal, craving, dependence, EC usage and grams of e-liquid consumed, subjective effects of vaping, 
baseline smoking history, or psychosocial factors may explain this difference and the regression analyses 
undertaken will illuminate the potential reasons for the difference. If noninferiority is not seen – i.e., Aim 1 is 
not supported -- then we expect to see a difference in one or more of these measures. 
 
Aim 3. Compare the acceptability of menthol versus tobacco EC at week 12. Hypothesis 3. 
Participants randomized to tobacco EC (versus menthol EC) will consume comparable amounts of study 
provided e-liquid (measured in grams) and demonstrate comparable reductions in cigarette-related 
withdrawal, craving, and dependence. Subjective effects of vaping will also be compared between groups. 
Each of these measures are on a quantitative scale and, given the sample size, we can assume the central 
limit theorem will hold. Thus, we will calculate the mean e-liquid consumption over 12 weeks and its 
corresponding standard deviation by group. We will then compare the difference in these means between 
the groups using a two-sample t-test and calculate the corresponding 95% confidence interval. Given that 
we expect to show noninferiority in tobacco EC versus menthol EC, we expect to find no difference in e-liquid 
consumption and, therefore, the confidence interval for the difference between groups will contain 0.00. If 
noninferiority is not seen, then we may see a difference in the e-liquid consumption by group. For change in 
cigarette-related withdrawal, craving, dependence, and subjective effects of vaping, we will calculate the 
mean change and corresponding standard deviation for each of these measures by group.  We will then 
conduct the two-sample t-test comparing the means between the groups while also reporting the 
corresponding 95% confidence intervals. Given that we expect to show noninferiority in tobacco EC versus 
menthol EC, we expect to find no difference in cigarette-related withdrawal, craving, dependence, or 
subjective effects of vaping. This means that we expect to fail to reject each of the t-tests and expect that 
each confidence interval for the difference between groups will contain 0.00. However, as described in Aim 
2, if any of these variables are different when noninferiority is seen, we will then utilize logistic regression to 
identify any phenotypic or consumption patterns – e.g., gender, age, socioeconomic status, study-related 
side effects, adverse events, change in CPD, cigarette-related withdrawal, craving, dependence, EC usage 
and grams of e-liquid consumed, subjective effects of vaping, baseline smoking history, or psychosocial 
factors -- may explain this difference and the regression analyses undertaken will illuminate reasons for the 
difference. 
If noninferiority is not seen, then we would expect to see a difference in one or more of these measures. 
 
Aim 4. Examine the long-term effectiveness of menthol versus tobacco EC at week 26.  We will 
compare switching patterns at week 26 to examine long-term maintenance of EC and smoking patterns 
under naturalistic conditions (EC only provided up to week 12).  Hypothesis 4. There will be no statistically 
significant difference in rates of complete or predominant switching at week 26 between those randomized 
to menthol versus tobacco EC.  For this aim we will calculate the proportion of complete and predominant 
switchers as defined above but at week 26.  We will then calculate the corresponding 95% confidence 
interval on the difference in these proportions. The lost to follow-up rate at month 6 in the RCT that forms 
the basis for this proposal was < 10%.  We do not expect the lost to follow-up rate to exceed 20% at month 
6; however, given that we are not sure of our loss to follow-up rate we will report complete and 

predominant switching at month 6 assuming those lost are not complete or predominant switchers and 
subsequently report on completers only.   
 
 
D. Subject Criteria (See Vulnerable Populations appendix, if applicable) 
Participants will be adults 21 years or older who smoked at least 5 cigarettes daily at enrollment and have 
smoked menthol cigarettes for > 6 months. The study will be open to both men and women.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
Inclusion criteria are displayed in the adjoining table.  Eligible individuals must be at least 21 years, 
interested in switching to EC, smoked >5 cpd, smoke menthol cigarettes for >6 months, be a verified 
smoker (CO > 5PPM), be willing to complete all visits, and have a functioning telephone number. 
 
Exclusion criteria 
Exclusion criteria are also displayed in the adjoining table. Individuals who are interested in quitting 
smoking will be excluded and referred to smoking cessation resources. Other exclusions include individuals 
who have used EC on at least 4 of the past 30 days, uncontrolled hypertension (BP > 180 (systolic) or > 
105 (diastolic)), anticipated or current pregnancy (as measured by over-the-counter pregnancy test kit for 
women of childbearing age only), breast feeding. Other exclusions include use of stop smoking 
medications in the past 30 days, daily use of other nicotine or tobacco products, plan to move from the 
Kansas City area in the next year, or other smoker in household enrolled in the study. 
 
Withdrawal/Termination Criteria  
There are no expected circumstances in which the subject’s participation will be terminated by the 
investigator. 
 
Clarify whether a study subject may participate in another research study while participating in 
this research study 
Subjects are not able to participate in a smoking cessation research study while they are enrolled in the 
current study.  
 
E.  Specific methods and techniques used throughout the study       
 
Laboratory tests 
Not more than 20 ml of urine and saliva will be collected at Weeks 0, 12 and 262.  The urine and saliva will 
be banked for future analyses.   
 
Study Procedures:  
Intervention 
All eligible participants who provide written informed consent and complete the baseline survey will be 
randomized in a 1:1 fashion to either menthol or Virginia tobacco EC. 
Eligibility Criteria 
Inclusion Criteria 
Exclusion Criteria 
• ≥ 21 years of age 
• Smoke >5 CPD 
• Smoked menthol 
cigarettes for > 6 months 
• Verified smoker (CO > 5 
ppm) 
• Functioning telephone 
• Interested in switching to 
EC 
• Interested in quitting smoking 
• Use of other tobacco products in past 30 days (i.e., cigarillos, cigars, 
hookah, smokeless tobacco, pipes) 
• EC use on > 4 of the past 30 days 
• Uncontrolled hypertension: BP > 180 (systolic) or > 105 (diastolic) 
• Use of smoking cessation pharmacotherapy in the month prior to 
enrollment 
• Pregnant, contemplating getting pregnant, or breastfeeding 
• Plans to move from KC during the treatment or follow-up phase 
• Another household member enrolled in the study 

 
Treatment Overview.  
 
Randomization. All eligible participants who provide written informed consent and complete the baseline 
survey will be stratified by race and gender and randomized 1:1 to either menthol or Virginia tobacco EC. 
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. 
EC (Weeks 0-12). Participants will be provided a 12-week supply of VUSE 5% nicotine concentration in 
either menthol or Virginia tobacco that will be dispensed at the weeks 0, 4, and 8 in-person visits (4-week 
supply @ each visit).  One pod delivers the equivalent of one pack of cigarettes, with variability of 13-30 
cigarettes based on user, 77 and therefore allocation will be based on 1 pod per pack of cigarettes at week 0 
and on current use patterns at weeks 4 and 8. 
 
EC use. Participants will be instructed to use only the study EC in the flavor provided but to report all 
ECs by timeline follow-back at follow-up visits. To aid in recall and assessment of fidelity to protocol, 
participants will be given dated bags to collect all EC. Bags will be returned at each visit during the 
intervention phase to confirm use of EC (i.e., grams of e-liquid consumed and count of pods) as well as 
protocol adherence (i.e., the number of pods/grams vaped in the study provided versus non-study provided 
flavor) (see Measures). Those not attending EC dispensing visits will be reached by phone and delivered 
enough to get them to the next dispensing time point. Participants will be compensated for returned pods, 
but earnings will not be tied to protocol adherence. Participants will be paid for returned pods even if they 
return non-study provided EC to increase honest reporting.   
 
EC Check-in: Participants will be provided brief education and advice on benefits of switching to EC at 
baseline (week 0), followed by in person check-ins at weeks 4, 8, and 12 to monitor EC use. They will also 
complete weekly calls during the first month to encourage adoption of the EC and ensure that participants 
have sufficient supply.  Check-in sessions will be conducted by our experienced staff, who are certified 
tobacco treatment specialists, have extensive experience treating racially/ethnically diverse smokers within 
clinical trials, and are active members of the community. Drs. Cox and Leavens, co-Is and clinical 
psychologists, will be responsible for staff training and supervision, as they have done over the past 20 
years for over 6 clinical trials. Each session will last approximately 15-30 minutes. 
 
Procedures and Methods 
 
An overview of major study events is provided in the adjoining table. 
 
 
 
 
 
 
Screen* 
Enroll 
 
 
 
 
 
Primary 
Outcome 
 
 
 
▫Wk 0 
Wk 1* 
Wk 2* 
Wk 3* 
Wk 4 
Week 8 
Wk 12 
Wk 18 
Week 26 
Remuneration 
 
$40 
 
 
 
$60 
$60 
$60 
$40 
$40 
EC Check-ins 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense EC 
 
X 
 
 
 
X 
X 
X 
 
 
Screening 
X 
X 
 
 
 
 
 
 
 
 
Consent 
 
X 
 
 
 
 
 
 
 
 
Assessments 
 
X 
 
 
 
X 
X 
X 
X 
X 
Spirometer 
 
X 
 
 
 
 
 
X 
 
X 
CO 
 
X 
 
 
 
X 
X 
X 
X 
X 
Blood Pressure 
 
X 
 
 
 
 
 
X 
 
X 
Exhaled Breath 
Condensates 
 
X 
 
 
 
X 
X 
X 
 
 
Urine and Saliva 
 
X 
 
 
 
 
 
X 
 
X 
* Over the phone 
 
Initial Screening. The initial screen will review inclusion/exclusion criteria. Those eligible will be 
scheduled to complete final eligibility screening within 21 days. All ineligible smokers will be 
referred to local resources when applicable. 
 

Final Screening and Enrollment (Wk 0). Final eligibility screening will be conducted in person 
and will consist of a pregnancy test on women of childbearing age and obtaining informed consent.  
 
Electronic cigarettes (Wk 0, 4, 8, 12). Participants will be provided a 12-week supply of VUSE 
5% nicotine concentration in either menthol or Virginia tobacco that will be dispensed at the weeks 
0, 4, and 8 in-person visits (4-week supply @ each visit).  To aid in recall and assessment of 
fidelity to protocol, participants will be given dated bags to collect all EC. Bags will be returned at 
each visit during the intervention phase to confirm use of EC (i.e., grams of e-liquid consumed and 
count of pods) as well as protocol adherence.  
 
EC Check-in Visits (Wks 0, 4, 8, and 12). Check-in sessions, each lasting approximately 20 
minutes, will be completed in person at Wks 0, 4, 8, and 12 and by phone at Weeks 1, 2, and 3. 
The number of sessions is consistent with our previous studies where we have achieved visit 
completion rates of ~ 80%.12,14,15,19 
 
Spirometer. Lung function will be assessed via spirometry.  We will carefully monitor respiratory 
symptoms over time using standardized measures. Spirometry will be completed at Wks 0, , 12, 
and 26. 
 
Carbon Monoxide.  Exhaled air carbon monoxide (CO) is an immediate, non-invasive method of 
biochemically verifying smoking status. At Wks 0, 4, 8, 12, 18, and 26, all participants will breathe 
into a Micro-3 Smokerlyzer (Bedfont Scientific) for the purpose of determining smoking levels.  
 
Blood Pressure.  Systolic and diastolic blood pressure will be measured with an Welch Allyn blood 
pressure cuff at Wks 0, 12, and 26.   
 
Exhaled breath condensates (EBC).  EBC will be used as another mean to assess airway 
inflammation. EBCs will be collected using the RTube (Respiratory Research, Inc.). Subjects will 
breathe in and out through a mouthpiece at tidal volume. A one-way valve will direct the exhaled 
air through the cooling sleeve where the samples are collected. The collection time will be 10 
minutes. Typical condensate fluid yield is 300 µl/minute for an adult at normal tidal breathing 
effort. The EBC will be stored in 1 ml aliquots at -80˚C for subsequent analysis. Samples will be 
standardized by total collected volume. EBC will be used to measure inflammatory patterns using 
nanobiosensors.  
 
Retention. Retention is enhanced by having participants meet with the same study team member 
each time. We have also developed a system of reminders and compensation for participant efforts 
that have resulted in impressive retention rates in our previous clinical trials. Reminders. Five days 
prior to each visit a reminder postcard, email, and/or text noting the scheduled appointment date 
and time will be sent. Participants will also be called, texted, or emailed (based on preference) up 
to 6 times to remind them of their upcoming visit. A detailed tracking database, with an automated 
reminder system, will notify study staff of when to send reminder messages. Compensation. 
Participants will be compensated in the form of a ClinCard, which works like a debit card.  They will 
receive $40 at Wks 0, 4, 8, 18, and 26 and $50 at Week 12 as compensation for their time/travel. 
To encourage use of the study provided EC, an additional $20 will be provided at weeks 4, 8, and 
12 for returning EC pods, regardless of the flavor returned.   
 
Clearly indicate which procedures, tests, visits, etc., are parts of usual standard therapy 
and which are performed solely for research purposes.  
 
All tests, procedures, and visits are being performed solely for research purposes and are not 
billable to insurance companies. 
 
Describe the fate of any body component (blood, CSF, bone marrow, etc.) used in the 
study, emphasizing confidentiality of labeling of the sample and the sample’s destruction 
or storage.  
 
Samples will be labeled only with a unique study identification number and only members of Dr. 

Nollen and Toren’s team will have access to the samples. For participants who have agreed to have 
their biospecimens stored for future testing, samples will be stored indefinitely.  
 
 
F. Risk/benefit assessment 
 
Physical risk 
The most common side effects related to EC include cough, dry mouth, shortness of 
breath, mouth and throat irritation, headache, dizziness, nausea or vomiting, and increased heart 
rate/palpitations. In rare instances, severe pulmonary disease associated with EC use and death have 
been noted, but these incidents have primarily occurred in a black-market product that contained 
tetrahydrocannabinol, or THC, in combination with vitamin E acetate. These additives are not present in 
the EC used in this study.  
 
Psychological risk 
Risks for participants also include those associated with the inconvenience of participation including 
answering surveys, providing saliva, urine, and participating in follow-up visits and assessments. 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 offering study visits in the evening and on weekends and offering 
patients a choice of where they will be seen (KUMC or Swope). Another risk is feeling pressured to be in 
the study, which we will track in order to monitor and will report this as an adverse event.   
 
Social risk 
None 
 
Economic risk 
None 
 
Potential benefit of participating in the study 
There are also no direct benefits to participating in this study except that researchers hope that the 
information from this research study may be useful in informing the FDA’s regulatory action on menthol 
flavoring in EC. 
G. Location where study will be performed:  
The study will take place at The University of Kansas Tobacco Treatment Center at Swope, 4001 Dr. 
Martin Luther King Jr. Blvd, in Kansas City, Missouri (hereafter referred to as Swope) or at the KUMC 
CRU in Fairway, Kansas based on the preference of each participant.  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 at Swope.  Only 
study staff will have access to the locked records at Swope 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: 
Indicate, by title, who will be present during study procedure(s) 
Personnel on the project include:  Nicole L. Nollen (PI), Lisa Cox (Co-I), Eleanor Leavens (Co-I), 
Matt Mayo (co-I, lead biostatistician), Tricia Snow (project director), Alexandra Brown (senior 
research analyst), Dinesh Pal Mudaranthakam, (clinical information specialist), Leah Lambart 
(Graduate Research Assistant), Drennon ‘Kris’ Leverette (Graduate Research Assistant), and Terri 
Tapp (research assistant). 

 
1. Primary responsibility for the following activities, for example:  
a. Determining eligibility: Tricia Snow, Terri Tapp, Leah Lambart,  Olivia Funk, Anetra 
Hunter, Brian Hernandez, Sophia Jumani 
b. Obtaining informed consent: Tricia Snow, Terri Tapp, Leah Lambart, , Olivia Funk, 
Anetra Hunter, Brian Hernandez, Sophia Jumani 
c. Providing on-going information to the study sponsor and the IRB: Nicole Nollen, 
Tricia Snow 
 
d. Maintaining participant's research records: Tricia Snow, Terri Tapp, Leah Lambart, , 
Alexandra Brown, Dinesh Pal Mudaranthakam, Matt Mayo 
 
e. Completing physical examination: Not applicable 
f. Taking vital signs, height, weight: Height and weight will be the only vital signs taken.  They will be 
performed by Tricia Snow, Terri Tapp, Leah Lambart, Olivia Funk, Anetra Hunter, Brian Hernandez, 
Sophia Jumani.  
g. Drawing / collecting laboratory specimens: Tricia Snow, Terri Tapp, Leah Lambart, 
Olivia Funk, Anetra Hunter, Brian Hernandez. KUMC Study staff will be handling and 
storing the samples. 
 
h. Performing / conducting tests, procedures, interventions, questionnaires: Tricia 
Snow, Terri Tapp, Leah Lambart, Olivia Funk, Anetra Hunter, Brian Hernandez, 
Sophia Jumani  
 
i. 
Completing study data forms: Tricia Snow, Terri Tapp, Leah Lambart, Olivia Funk, 
Anetra Hunter, Brian Hernandez, Sophia Jumani  
j. 
Managing study database: Matt Mayo, Alexandra Brown, Dinesh Pal Mudaranthakam, 
Tricia Snow 
 
 
L. Assessment of Subject Safety and Development of a Data and Safety Monitoring Plan 
 
The current study involves an EC that is publicly marketed and commercially available for purchase 
to anyone over the age of 21.  ECs are a tobacco product and are being provided for non-therapeutic 
purposes. ECs are no more harmful than conventional cigarettes, and various studies suggest that 
they may offer reduced harm. 
 
This study does not involve more than minimal risk. We will protect participants and minimize risks 
by using the strict exclusion criteria and careful monitoring of adverse events (AEs). AEs will be 
tracked during regularly scheduled visits or through spontaneous reports made by participants. Dr. 
Nollen 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 Dr. Nollen. SAEs will be reported to the KUMC 
IRB, FDA, and NIDA within 24 hours of first awareness of the event. Unexpected adverse events that 
are related to the study medication will be reported to KUMC IRB, FDA, and NIDA within 5 working 
days of first awareness of the event if the event is not serious fatal and within 24 hours of first 
awareness if the event is serious. Unexpected adverse events that are unrelated to the study 
medication will be reported to the KUMC HSC during yearly routine event reporting. IRB actions 
taken in this study will be reported to NIDA.  Dr. Greiner (or the treating provider) will determine 
relatedness for each reported AE. SAEs will be defined as any event experienced by a study subject 
while on the study medication 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, is a congenital anomaly in the offspring of a subject who received the study 
medication, or required intervention to prevent permanent impairment or damage.  
 
 
III. 
Subject Participation 
 
A. Recruitment: 
 

Participants will be recruited through clinic and community-based efforts. Flyers will be placed 
around Swope and KUMC for patients to take and providers will be asked to refer patients by 
providing them with the study line information. We will use the KUMC HERON database and the 
Swope 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 use radio, TV, bus and Facebook ads 
and word of mouth, as needed, to recruit participants. Finally, smokers are currently being screened 
for other research studies being conducted by our team (i.e., active studies being conducted Drs. 
Nollen, Cox, or Leavens). Those who are found to be ineligible for these studies will be informed 
about the current study and offered the 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.   
 
B. Screening Interview/questionnaire 
 
The screening interview will take place over the phone or in person and be conducted by a member 
of the study team. The screening questionnaire will address the general inclusion/exclusion criteria in 
the Eligibility Criteria table above. Only participants who have expressed interest will be screened. 
  
C. Informed consent process and timing of obtaining of consent 
 
Consent will be obtained prior to participant involvement. Individuals interested in the proposed 
study will meet the research assistant at Swope or the 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 and their decision to participate will not affect their 
current or future medical care at the treating facility. The consenting process will take place in a 
private location. 
D. Alternatives to Participation 
Alternatives to participating in the study are continue to smoke cigarettes as usual or switch to other 
alternative sources of nicotine, including purchasing nicotine gum or patches from the pharmacy or 
obtaining a prescription for nicotine inhaler, nicotine nasal spray, or nicotine lozenge. 
 
E. Costs to Subjects 
There are no costs to subjects. 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 participants.   
 
G. Payment, including a prorated plan for payment 
Participants will be given a $40 electronically loaded ClinCard at Wks 0, 4, 8, 12,18, and 26 as 
compensation for their time/travel.  To encourage use of the study provided EC, an additional $20 will 
be provided at weeks 4, 8, 12 visits for returning EC pods, regardless of the flavor returned.  
Participants must complete the visit to receive the reimbursement associated with that time point. 
Participants may receive $20 for each referral who is eligible and enrolls in the study.  Participants 
may complete up to 3 different referrals for the study for a total of $60.  Travel costs will not be 
reimbursed.   
 
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 20 ml of urine and saliva will be collected at Weeks 0, 12 and 26. Samples will be 
stored at the Bioanalytical Laboratory at the Fairway Clinical Research Center under the direction of 
Paul Toren, PhD.  Samples will be accessible only to members the study team. Results from 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. 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 biomarkers of 
tobacco-related harm and 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.    
 
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 II.C. above (Sample Size, Statistical Methods, and Power Calculations) 
 
B. Outcome 
EFFECTIVENESS (Aims 1 & 4).   
Switching (Primary Outcome). The primary outcome is the proportion of menthol smokers who make 
a complete or predominant switch to EC, defined as use of EC along with a > 50% reduction in cigarettes 
from baseline to week 12. The 7-day Timeline Follow Back Interview (TLFB) will be used to assess 
participants cigarette and EC use patterns each day for the past 7 days at each visit (weeks 0, 4, 8, 12, 
18, 26). The primary endpoint is, however, fixed at week 12. The TLFB is a reliable and valid way of 
collecting information about substance use quantity and frequency and, in tobacco research, has been 
corroborated against interactive voice response, butt counts (storing and returning the butts of 
cigarettes smoked), and biological measures for cigarettes smoked and puff topography for EC, 
supporting the strong validity of this self-report measure compared to other ‘gold standard’ measures. 
For each of the last 7 days participants will be asked to recall the number of cigarettes smoked and EC 
sessions vaped; following standard practice, an EC session is defined as at least 15 puffs or lasting 
around 10 minutes. For each EC session, participants will be asked to specify the device used (i.e., study 
provided versus something else) and the flavor (i.e., menthol, Virginia tobacco, something else).* For 
non-study provided EC, detailed information will be collected about the type of EC (e.g., brand, pod-
based, disposable, refillable), flavor, nicotine concentration and, if available, whether the product is 
nicotine salt-based. To aid in recall and corroborate self-report, participants will be given dated bags to 
collect all EC. Bags will be returned at each visit during the intervention phase and used to confirm use 
of study provided EC (i.e., grams of e-liquid consumed) and protocol adherence (i.e., the number of 
pods vaped in the study provided versus non-study provided flavor). Complete switching is defined as 
any use of EC and no use of cigarettes in the past 7 days (i.e., 100% reduction in CPD from baseline), 
biochemically confirmed with an expired breath CO < 6 parts per million (ppm). CO is used for 
verification because cigarettes produce carbon monoxide as a byproduct of combustion, while heating an 
e-liquid does not generate CO. The < 6 ppm CO cutoff is more conservative than the < 10 ppm cutoff 
that is commonly used and reflects the current state of knowledge for detecting recent cigarette 
smoking. Predominant switching is defined as those who report any use of EC along with a > 50% 
reduction from baseline in CPD.  A > 50% reduction has been selected because it is a measure of 
acceptability of the EC products and is associated with substantial reductions in biomarkers of harm 
and exposure relative to continued smoking and is a common endpoint used in tobacco harm reduction 
studies. Partial switching will be defined as those who report any use of EC along with a < 50% 
reduction from baseline in CPD.  No switching (i.e., exclusive cigarette user) will be defined as those 
who reported no use of ECs and any use of cigarettes in the past 7 days. A potential fourth group, no 
use of e-cigarettes or combustible cigarettes, may occur. For all switching trajectories, use of EC will 
be corroborated with pod counts and objectively measured EC pod weights during the intervention 
phase.  
 
Other outcomes of interest include tobacco harm reduction and EC acceptability. These constructs may 
be measured by the following:  
 
TOBACCO HARM REDUCTION (Aim 2). Tobacco harm reduction is a global topic of interest among 
those transitioning from cigarettes to EC and is largely driven by reduction in CPD. We expect 
comparable rates of switching between groups and, therefore, comparable rates of tobacco harm 
reduction, defined as change in each of the following constructs from baseline to week 12. 
• 
Tobacco Quality of Life Impact Tool (TQOLIT™v1) will be used to assess was used to assess the 
impact of smoking/vaping on health-related quality of life.  
• 
Carbon Monoxide. Carbon monoxide will be measured in parts per million (PPM) using a coVita 
Bedfont Micro+ Smokerlyzer at each study visit.  
• 
Blood Pressure. Systolic and diastolic blood pressure will be measures with an Welch-Allyn blood 
pressure cuff. 
• 
Respiratory symptoms have emerged as a primary concern among EC users and, therefore, we will 
carefully monitor respiratory symptoms over time using the following standardized measures:  

• 
Lung function will be assessed via spirometry.  We will summarize all values returned from the 
spirometer (i.e., FVC, FEV1, FEV1/FVC%, PEF) but will focus our attention on FEF 25-75%, the 
pulmonary function test of small airway disease that is most sensitive to effects of cigarette smoking.  
• 
American Thoracic Society Questionnaire (ATSQ) will be used to assess common respiratory 
symptoms (e.g., cough first thing in the morning, wheezing, shortness of breath, etc.). This measure 
was selected because it contains items relevant to acute respiratory effects experienced by some 
cigarette smokers when they initiate EC. 
• 
Leicester Cough Questionnaire (LCQ) is a valid, repeatable measure of chronic cough which is 
responsive to change, especially the onset of cough in established cigarette smokers when they initiate 
EC.  
It is not within the scope or budget of this study to examine additional biomarkers of exposure or 
potential harm, but we will collect urine and saliva samples from all participants at weeks 0 and 12 and 
bank them for future analyses. Potential biomarkers of interest have been selected to align with other 
studies and because they represent categories of toxicants commonly found in tobacco products and 
tobacco smoke that have been classified by the FDA as contributing to respiratory, cardiovascular, and 
cancer-related diseases associated with smoking.  
Biomarkers of interest include:  
• 
cotinine 
• 
total NNAL (for nicotine-derived nitrosamine ketone - 
NNK); 
• 
2-hydroxyethylmercapturic acid (HEMA) (for ethylene 
oxide); 
• 
2-hydroxy-3-butenyl-mercapturic acid and isomers 
(MHBMA) (for 1,3-butadiene); 
• 
3-hydroxy-1-methyl propyl-mercapturic acid (HMPMA) 
(for crotonaldehyde); 
• 
3-hydroxypropylmercapturic acid (3-HPMA) (for 
acrolein); 
• 
S-phenylmercapturic acid (S-PMA) (for benzene); 
• 
2-cyanoethylmercapturic acid (CEMA) (for 
acrylonitrile); 
• 
2-hydroxypropylmercapturic acid (2-HPMA) (for 
propylene oxide) 
• 
pyrene (1-OHP) 
• 
matrix metalloproteinaise-8 (MMP8) and interleukin-9 
(IL9) for airway epithelial cell inflammation 
• 
8-Epi-prostaglandin F2α (oxidative stress) 
• 
11-Dehydrothromboxane B2 (platelet activation) 
• 
soluble intercellular adhesion molecule-1 (sICAM) 

 
 
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ACCEPTABILITY (Aim 3). Detailed assessment of EC product use, effects on withdrawal, craving, 
and dependence, and subjective and sensorial effects will be evaluated at all study visits to compare 
acceptability by group (menthol versus tobacco EC). 
Grams of study e-liquid consumed (weeks 4, 8, 12). Use of the study EC in the flavor provided 
will be objectively measured by asking participants to bring all used, unused, or partially used pods to 
the weeks 4, 8, and 12 study visits. Pods will be weighed prior to their distribution and then upon 
return to derive total grams of study e-liquid in the flavor provided consumed from weeks 0-12. In 
our RCT, 95%, 92%, and 98% of participants returned their pods at weeks 2, 4, and 6, respectively, 
and there was no evidence of cheating – i.e., returned pods were in the flavor provided by the study -
- suggesting that participants used only the study provided pods throughout the intervention phase. 
For unreturned pods, we will conservatively assume 0 grams of e-liquid consumed. Objective 
measurement of pod weights was strongly correlated with number of e-cigarette sessions per day 
measured by TLFB in our RCT (r=0.58, p < .001). 
Flavor usage (all visits). Based on our RCT, we expect low rates of non-study EC product use, but 
we will conduct rigorous assessments of adherence to EC flavoring during the intervention phase and 
continued use during the long-term follow-up phase. From the TLFB, we will summarize the 
proportion of total EC that were in the study provided versus a non-study provided flavor. From pod 
counts, we will summarize the number of pods returned by flavor (i.e., menthol, Virginia tobacco, 
other) and derive an estimate of the proportion of total pods returned that were in the study provided 
flavor (versus non-study provided flavor).   
Craving (all visits). Craving for cigarettes will be assessed using the Questionnaire on Smoking 
Urges-Brief (QSU) and its companion, the Questionnaire on Vaping Craving-Brief (QVC) will be 
assessed at each visit and compared between groups. Both measures yield a total score and two 
factor scores: desire to smoke/vape and intention to smoke/vape. The QVC yields a third factor, 
positive outcome of vaping. 
Withdrawal (all visits).The Minnesota Tobacco Withdrawal Scalewill be used to rate eight 
withdrawal symptoms in the past 24 hours: anger, anxiety, concentration, craving, hunger, sadness, 
and sleep.  Items are rated from 1 (strongly disagree) to 5 (strongly agree). Scores will be 
summarized overall and for each construct.  
Dependence (all visits). Following guidance from the TCORS dependence workgroup, we will 
include a compendium of dependence measures, validated for use in assessing both cigarette and EC 
related dependence, to cover all components of dependence (i.e., quantity and frequency of use, 
tolerance, perceived benefits, withdrawal symptoms, cravings/urges to use, use despite harm, 
impaired control, automaticity, preferred over competing rewards, and sensory dependence.) We 
have intentionally selected cigarette dependence measures that have parallel EC dependence 
measures to allow for direct comparison in dependence across products by group. These measures 
include:  
• 
Patient Reported Outcomes Measurement Information System (PROMIS) Nicotine Dependence 
Item Bank 107-109 and its companion the E-Cigarette Dependence Scale.  
• 
Penn State Cigarette Dependence Index (PS CDI) and its companion the Penn State Electronic 
Cigarette Dependence Index PS ECDI)  
• 
Wisconsin Inventory of Smoking Dependence Motives (WISDM) and its companion the E-Cigarette 
Wisconsin Inventory of Smoking Dependence Motives (eWISDM). Dependence will be summarized for 
the WISDM total score as well as the average score on the Primary Dependence Motives (i.e., 
Automaticity, Loss of Control, Craving, and Tolerance. 
• 
Time to First Cigarette and Time to First EC of the Day. This single item from the Fagerstrom 
Cigarette Dependence Scale is the best indicator of dependence in a sample of mostly light smokers 
(< 10 CPD).  
Subjective effects of vaping (all visits). The 12-item Modified Cigarette Evaluation Scale adapted 
for e-cigarettes will be administered at all time points to access product satisfaction and subjective 
and sensorial effects of vaping by group (menthol versus tobacco EC). Questions are answered on 7-
point scale from 1 (not at all) to 7 (extremely) and assess vaping satisfaction (was vaping 

 
 
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satisfying, did the e-cigarette taste good, did you enjoy vaping), enjoyment of respiratory tract 
sensations (did you enjoy the sensations in your throat and chest), psychological reward (did 
vaping calm you down, did vaping make you feel more awake, did vaping make you feel less 
irritable, did vaping help you concentrate), craving reduction (did vaping immediately relieve your 
craving for a cigarette), and aversion (did vaping make you dizzy, did vaping make you nauseous). 
The single item, “Did the e-cigarette taste good?” will be used as a proxy for flavor liking as has 
been done in previous studies. The 23-item Sensory E-cigarette Expectancies Scale, particularly the 
subscales related to taste/smell (‘I like the taste of vaping’, ‘I like the smell of vaping,’ ‘I like the 
flavor of vaping’) and  pleasure/satisfaction (‘I like how vaping makes me feel good physically,’ ‘I like 
the feeling of satisfaction that I get from vaping’) will be administered for secondary assessment of 
product satisfaction and acceptability.  
OTHER CONSTRUCTS OF INTEREST 
Safety and tolerability 
• 
Side Effects. A symptoms checklist will be used to assess participants experience (yes/no) of 
common smoking/vaping related side effects, including cough, dry mouth, shortness of breath, mouth 
and throat irritation, headache, dizziness, nausea or vomiting, and increased heart rate/palpitations. 
For each side effect reported, participants will be asked whether they attribute the side effect to 
cigarettes, EC, or both. 
• 
Safety. Adverse events observed or reported will be recorded at each in-person visit. Assessments 
as to seriousness, severity, and the relationship to treatment and other causes will be made. Serious 
adverse events will also be captured in the centralized database. AEs and SAEs will be reported to the 
appropriate regulatory agencies.  
Descriptive measures (Week 0) 
• 
Demographic variables include gender, age, marital/cohabitation status, socioeconomic status, 
psychiatric history, depressive symptoms (PHQ-9), and symptoms of generalized anxiety (GAD-7). 
• 
Psychosocial variables include individual- (federal poverty level, financial strain, home 
ownership, housing stability) and area-level socioeconomic disadvantage (neighborhood social 
cohesion and trust, safety, and incivilities), race consciousness, experiences of discrimination, 
perceived stress, resilience, and history of trauma (i.e., adverse childhood experiences). These 
factors influence differences in smoking outcomes in racial/ethnic minority and socioeconomically 
disadvantaged smokers and were chosen for that reason.  
• 
Cigarette use history will include cigarettes per day, age when started smoking regularly, length of 
time as a smoker, number of 24 hour quit attempts in the last year, length of the longest quit 
attempt, other smokers/vapers in the home, smoking/vaping status of partner and five best 
friends/family members.  
 
C. Study results to participants  
Study results will not be shared with participants. 
 
D. Publication Plan 
We plan to publish results in appropriate tobacco journals – e.g., JAMA, JNCI, Journal of General 
Internal Medicine, Addiction, Annals of Behavioral Medicine, Nicotine & Tobacco Research, Cancer 
Epidemiology, Biomarkers, & Prevention.  
 
VI. 
Bibliography / References / Literature Cited  
 
1. 
American Cancer Society. Cancer Facts & Figures for African Americans 2016-2018. 2016; 
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer-facts-and-figures-for-african-
americans/cancer-facts-and-figures-for-african-americans-2016-2018.pdf. 

 
 
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2. 
NCI. A Socioecological Approach to Addressing Tobacco-Related Health Disparities. . In: Services. USDoHaH, ed. 
National Cancer Institute Tobacco Control Monograph 22. Vol NIH Publication No. 17-CA-8035A. Bethesda, Maryland: 
National Cancer Institute; 2017. 
3. 
Stead LF, Koilpillai P, Fanshawe T, Lancaster T. Combined pharmacotherapy and behavioural interventions for smoking 
cessation. . Cochrane Database of Systematic Reviews 2016(3). 
4. 
Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. 
In: Services DoHaH, ed. Rockville, MD: U.S. Department of Health and Human Services; 2008. 
5. 
Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine 
patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled 
clinical trial. Lancet (London, England). 2016;387(10037):2507-2520. 
6. 
Jamal A, King B, Neff L, Whitmill J, Babb S, Graffunder C. Current Cigarette Smoking Among Adults — United States, 
2005–2015. MMWR Morb Mortal Wkly Rep 2016;65(44):1205-1211. 
7. 
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. 
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