Effects of Electronic Nicotine Delivery System Flavor Regulations on Tobacco Behavior, Toxicity, and Abuse Liability Among African American Menthol Smokers (RVA Flavors)
Phase: NA
Conditions: Electronic Nicotine Delivery System Flavors
Sponsor: Virginia Commonwealth University

RVA-Flavors | Protocol | Page 1 
RVA-Flavors Protocol 
Title: Predicting Effects of ENDS Flavor Regulations on Tobacco 
Behavior, Toxicity, and Abuse Liability among African American 
Menthol Smokers 
Version 12 
04.17.2024 
NCT05023096

RVA-Flavors | Protocol | Page 2 
 
1. Background: Black/African Americans (AA) have the highest tobacco-related cancer incidence 
and mortality rates of any racial/ethnic group. Over 70% of AA smokers smoke menthol as their 
usual brand, compared to 20% for White smokers. Menthol is the only characterizing flavor 
allowed in cigarettes under current federal regulations, and menthol use is associated with 
progression to established cigarette smoking as well as more difficulty quitting. Evidence 
regarding the effects of electronic nicotine delivery systems (ENDS, i.e., e-cigarettes) suggests 
these products may be a less harmful alternative to cigarettes. Little work has examined how 
ENDS uptake affects tobacco use and associated toxicity among AA smokers, particularly those 
who smoke menthol. Recently, FDA began regulating closed-system devices like JUUL, which 
have captured over 70% of the ENDS market and contributed to dramatic increases in youth 
ENDS use. As of early 2020, flavored ENDS cartridges (small, enclosed unit used as part of an 
ENDS) other than menthol/tobacco are banned in the US. However, to achieve its public health 
mission, the FDA must balance restricting access to ENDS flavors that appeal to youth with the 
need for evidence on “whether and how certain flavors may help adult cigarette smokers reduce 
cigarette use and switch to potentially less harmful products” (FDA, 2018). Understanding the 
potential of ENDS to reduce the public health burden of combusted tobacco use equitably 
requires a targeted study to predict how future ENDS flavor regulations will impact AA menthol 
smokers.  
The current study will evaluate whether ENDS menthol flavor availability affects measures of 
tobacco use, biomarkers of cigarette/ENDS exposure, and addiction among AA menthol 
smokers (N=210) by performing a 3-arm, parallel-group, 6-week clinical trial of ENDS provision 
with follow-up to 30 days. JUUL devices with compatible cartridges at 5% nicotine, which our 
team has extensively evaluated, will be provided. Study arms will differ by potential FDA 
regulations on ENDS flavor availability: 1) the current market where only menthol and tobacco 
flavored ENDS cartridges are available; 2) a market where only tobacco flavor is available, and 
3) a market with only unflavored cartridges. Study visits will occur weekly beginning 1 week prior 
to randomization with daily tobacco use monitoring throughout and biomarker/self-report data 
collection at each weekly visit. AA menthol smokers are disproportionately harmed by tobacco 
products and could experience significant health benefits from increased availability of well-
regulated ENDS.  
Results of this work will help FDA make predictions about the impact on AA menthol smokers of 
moving from the current regulatory market for cartridge-based ENDS where menthol and 
tobacco are available, to one where only tobacco or no flavors are available. Answers to these 
questions will address FDA's priorities in behavior, toxicity, and addiction, and will provide new 
data regarding the consequences of potential FDA regulatory actions on menthol flavor ENDS 
to help maximize health-promoting effects and minimize unintended consequences among AA 
menthol smokers. 
2. Objectives:  
The specific aims of our study are to: 
1) Compare the effect of ENDS flavor availability on patterns of tobacco use behavior. H1: 
Cigarettes per day will be lowest and ENDS use (puffs per day) will be highest in the 
M+T_Reg condition relative to other conditions. 
a. Primary outcome: Change in average daily cigarette use from Week 0 (prior to 
randomization) vs. Week 6 (defined as number of cigarettes smoked in the past 
day, collected via daily text survey, averaged over the previous 7 days) 
b. Secondary outcome: Change in average daily ENDS use from Week 1 (following 
randomization) vs. Week 6 (defined as number of ENDS puffs in the past day 
[daily times used * average puffs per time used], collected via daily text survey, 
averaged over the previous 7 days) 

RVA-Flavors | Protocol | Page 3 
 
2) Quantify the effect of ENDS flavor availability on biomarkers of cigarette/ENDS exposure 
(expired air carbon monoxide [CO], urine cotinine/NNAL, and urine propylene glycol 
[PG]). H2: Biomarkers of exposure to cigarettes (NNAL/CO) will decrease and from 
ENDS (PG) will increase most in the M+T_Reg condition.   
a. Primary outcome: Change in CO exposure from Week 0 (prior to randomization) 
vs. Week 6 
b. Secondary outcomes: Change in NNAL exposure from Week 0 (prior to 
randomization) vs. Week 6; Change in PG exposure from Week 0 (prior to 
randomization) vs. Week 6. 
3) Test the effect of ENDS flavor availability on addiction/abuse liability using validated 
behavioral economic instruments at multiple time points during the trial. H3: Smokers will 
be (a) willing to pay more money for ENDS in the M+T_Reg condition and (b) willing to 
substitute from cigarettes to ENDS earlier in the M+T_Reg condition. 
a. Primary outcome: Willingness to substitute from cigarettes to ENDS (at Week 6)  
b. Secondary outcome: Willingness to pay for ENDS (at Week 6).  
 
3. Overview of Design. This is a 3-arm, parallel group, 6-week clinical lab study of ENDS 
provision with a 30-day follow-up post-intervention among AA menthol smokers. We aim to have 
equal allocation by study arm. Study arms will differ by potential FDA regulations (Reg) on 
ENDS flavor availability as follows, with nicotine concentration and ENDS device held constant: 
1) the current market for cartridge-based ENDS where only menthol and tobacco flavors are 
available for consumers to choose from (M+T_Reg); 2) a market where only tobacco flavor is 
available (T_Reg), and 3) an unflavored control condition (U_Reg), representing a market where 
all characterizing ENDS flavors are banned. 
 
4. Participants. A total of 210 AA community volunteers who currently use menthol cigarettes will 
be randomized in this study. We will attempt to recruit an equal number of men and women and 
equal numbers above and below 100% of the Federal Poverty Level to explore differences in 
condition effects across gender and income. To achieve this number of participants, the VCU 
Wright Center informatics team will provide contact information sourced from the EMR for ~5000 
patients who fit the study criteria. These patients will be invited to participate in the study. 
 
a. Inclusion criteria:  
i. ≥21 years of age (id-verified) 
ii. identify as AA (single or multi-race) 
iii. have used ≥5 CPD for ≥1 year 
iv. biochemically confirmed cigarette smoking status  
1. expired air CO >5 ppm 
2. positive urine cotinine result at screening (defined at least 200 ng/ml; 
NicAlert cassette test) 
v. regular cigarette brand is flavored to taste like menthol or mint  
vi. ENDS use in the past 3 months 
vii. report no intent to quit smoking in the next 6 months (unwilling to quit) 
viii. previous quit attempt using an evidence-based quit method (unable to quit) 
ix. have a working mobile phone with a texting/data plan  
x. are willing receive phone calls/text messages and complete internet-based/online 
surveys related to the study.  
xi. read and write in English 
 
b. Exclusion criteria:  

RVA-Flavors | Protocol | Page 4 
 
i. are unwilling to use JUUL/pod-based ENDS as part of the trial 
ii. unstable or significant medical condition in the past 12 months (e.g., recent heart 
attack, stroke, severe angina including high blood pressure if systolic >159 or 
diastolic >99 observed during screening; inpatient psychiatric treatment; 
uncontrolled seizures) 
iii. report any other illegal drug use in past 30 days, not including marijuana 
iv. report intent to become pregnant or current pregnancy/breastfeeding (pregnancy 
confirmed via urinalysis) 
v. report any other condition that may affect participant safety or not allow them to 
fully participate in the study (e.g., contraindication to spirometry; allergy to 
propylene glycol/vegetable glycerin). 
 
5. Products. Randomized participants will receive an ENDS supply consistent with their condition 
throughout the 6-week intervention period. 
a. ENDS. For all conditions, ENDS batteries will be purchased directly from JUUL Labs. 
Inc. Across ENDS regulatory conditions, ~5% nicotine pods will be used to control for 
nicotine delivery and due to availability of pharmacokinetic data from similar products 
(Hajek, Pittaccio et al., 2020; Maloney, Crabtree et al., 2020). As unflavored pods are 
unavailable for purchase from JUUL and to ensure all conditions have the same ENDS 
operating characteristics/nicotine delivery, for all conditions we plan to purchase unfilled 
JUUL compatible pods and verify the similarity of heating element and other product 
characteristics to JUUL products using resources at the CSTP (Project 1 Investigator: 
Dr. Talih). We will purchase tobacco, menthol, and unflavored ENDS liquid at 5% 
nicotine from a reputable supplier. We will verify the equivalence of the liquid 
characteristics (protonated vs. unprotonated nicotine; PG/VG ratio) relative to currently 
marketed menthol and tobacco-flavored JUUL pods. We have experience purchasing 
and independently testing unflavored/flavored liquid (Barnes, Bono et al., 2017; Cobb, 
Lopez et al., 2019). 
i. If supply-chain/access issues occur, we may substitute our JUUL compatible 
pods with actual JUUL Labs. Inc. pods in menthol and tobacco flavor. These 
substitutions can only occur for the M+T_Reg and T_Reg conditions. If 
unflavored pods become unavailable, individuals randomized to U_Reg will have 
either their product supply stopped (if already randomized) or be randomized to 
either the M+T_Reg and T_Reg condition. 
b. Product Instructions. At each in-person visit during the intervention period we will instruct 
participants: “We are providing you with an e-cigarette in [condition-specific flavors] over 
the next [X] weeks to be used as a substitute or complete replacement for your own 
brand cigarettes. We want to understand how you use these specific e-cigarettes as well 
as your own brand cigarettes when they are the only products available to you. 
Therefore, please refrain from using all other nicotine/tobacco products and other e-
cigarette flavors for the duration of the study. If you use anything else, it is important that 
you tell us what you used.” 
c. Product Distribution. Following randomization, participants will be provided with two pre-
charged JUUL batteries with a USB-compatible charger and USB-power outlet adapter. 
All pods will be provided in sealed single-use containers. A 2018 convenience survey of 
adult JUUL users indicated that daily users consume on average 10 pods per month 
(i.e., <1 pod/day; Leavens, Stevens et al., 2019). This data and our experience with 
distributing ENDS to smokers (P50DA036105-Project 3) led to us estimate individuals 
may use up to 1 pod/day. At randomization and week 3 visit participants will receive ~3 

RVA-Flavors | Protocol | Page 5 
 
weeks worth of pods (21 pods) plus 11 additional pods to allow for product loss and/or 
malfunction (~32 pods total). All participants will receive brief instructions on how to use 
their ENDS device and taste-test their assigned flavor(s; at least 4 directed puffs per 
flavor). Individuals randomized to the M+T_Reg condition will choose how many pods of 
each flavor they prefer to receive. To minimize sharing, we will emphasize that these 
products are investigational and provide an incentive for returning used/unused pods 
($30 for returning >70% of the supplied ENDS product at each visit). We may 
incorporate returned products into each new week’s supply for that participant. This 
strategy has been used successfully by our Co-I Dr. Donny at Wake Forest University 
(not engaged with study). At the conclusion of the Week 6 visit, all participants will be 
provided with tobacco prevention/cessation resources, and they will be able to keep their 
ENDS devices/charging materials and up to 4 unused pods in their condition-specific 
flavors. 
d. Product Labeling. Distributed products for all conditions will be labeled with the following. 
-Participant ID (PID: ) 
-Date of visit 
-Visit Number (Visit: ) 
For JUUL-compatible pods that are filled by the study staff, each pod once filled with 
liquid will be stored in a single use sealable bag labeled with an additional label: 
-VCU Lot Number (VCU Lot: ) 
-VCU Liquid Lot Number (LIQ Lot: ) 
-Pod preparation date (PREP: ) 
When distributed to participants, up to 4 single pod bags will be placed inside a larger 
bag with the same two labels included. 
e. Other Product Information: E-cigarette companies have to apply to the Food and Drug 
Administration (FDA) and be approved for sale in U.S. markets. In June 2022, the FDA 
denied the marketing application from JUUL, the manufacturer of the e-cigarettes used 
in this study. The FDA determined that JUUL did not provide enough evidence about the 
toxicity of its e-cigarette device and pods in its application. However, the FDA has not 
received clinical information to suggest an immediate hazard associated with the use of 
JUUL devices or JUUL pods. The FDA decision to ban the sale of JUUL is not final yet 
due to ongoing legal disputes. When and if the FDA’s decision to ban JUUL is final, it will 
be illegal to sell JUUL products. However, it will still be legal for researchers to study 
these products and for participants to use them. 
i. The above text has been added to the informed consent form for this study under 
Most Common Risks and Discomforts to address recent developments 
regarding JUUL products from the FDA. 
ii. An investigational tobacco product application describing the products provided 
and procedures used in this study was submitted for review to the FDA Center 
for Tobacco Products on 7/22/2022. 
 
6. Recruitment and Enrollment. Participants will be recruited by institutional review board-
approved advertisements as in previous studies conducted at the VCU BHRL/CSTP and by 
word of mouth. The BHRL and CSTP Tobacco User Registries are available to aid recruitment 
efforts (>6000 records). Interested individuals will either 1) complete a pre-screener specific to 
this study (see Pre-Screener measures) or 2) access the BHRL/CSTP website and/or complete 
a screening survey (pre-screen) specific to these registry protocols online or via phone to 
determine initial eligibility. 
 

RVA-Flavors | Protocol | Page 6 
 
We also will recruit from a list of VCU Medical Center patients who meet study eligibility criteria 
as determined by the Cerner EMR and/or Massey Cancer Center Informatics Team. Tobacco 
use history is recorded in each patient’s social history. Additionally, a text data mining algorithm 
may be used to search for key terms in provider notes (e.g., tobacco, smoking, quitting smoking, 
e-cigarette) to identify potential participants. Once we have this list of potential participants we 
will proactively recruit. 
 
Proactive recruitment strategies will include the following: 
- From the EMR-generated list of potential participants, our research personnel will call 
individuals and/or leave up to 2 voice-mail messages introducing them to the study and the pre-
screener. 
- From the EMR-generated list of potential participants, our research personnel will mail 
individuals a letter (see Mail Invitation), introducing them to the study, as well as information 
about how to complete the pre-screener.  
- After the initial pull of potential participants for this study, we will ask to re-run this EMR-
generated list about 1x/month to learn if there are any new potential participants. 
- No data from the list will be stored in the project. The list will be used to contact potential 
participants and then destroyed after the contacts above have been completed. 
 
7. Consent process. Informed consent for the prescreening will be obtained prior to completing 
any questions and informed consent for the full study will be obtained at the in-person screening 
visit prior to completing any research activities. At the in-person visit, the informed consent 
document will be either be played via a pre-recorded powerpoint tool or read aloud by a trained 
research staff. Prior to participant signature, research staff will ensure all questions and 
concerns about the study are answered fully. This process will be documented via 
administrative forms in REDCap and with signed paper documents which will be kept in a 
locked file cabinet separate from other research data during and after data collection. 
 
8. Study Procedures. Study participation will consist of three primary phases (see table below): 1) 
screening/baseline, 2) experimental/intervention period, and 3) 30-day follow-up during which 
participants will not be provided with study product nor will be given explicit recommendations to 
change their tobacco use behavior.   
a. Screening and baseline. Once the participant is deemed potentially eligible from the 
online/phone-based screening survey (pre-screen; via one of the pre-screener measures 
included in the current protocol or BHRL/CSTP Tobacco User Registry survey), an in-
person screening/baseline assessment will be scheduled. Then, an informed consent 
will be obtained for the full study, and participants will be asked to complete baseline 
forms and measures (e.g., urinalysis/expired air CO) to assess/confirm eligibility.  
i. During the informed consent procedure, all participants will be provided 
information regarding an optional project (funded within Virginia Youth Tobacco 
Projects Program (VYTP), sponsored by the Virginia Foundation for Healthy 
Youth; PI: Dr. Shawn Jones, VCU Psychology Department).  
ii. The VYTP part of the study focuses on the impact of racial socialization, identity, 
media perceptions, and racial discrimination on tobacco use. More specifically, 
this project aims to understand how race-related factors during adolescence 
impact tobacco use in adulthood. Participants are eligible to participate in this 
part of the study they are aged 21 or older. The only additional participant 
activities related to the VYTP part of the study are the completion of additional 
questions (~25 min) at the screening/baseline session. Engagement in this part 

RVA-Flavors | Protocol | Page 7 
 
of the study is completely optional and will have no bearing on full study 
participation. Participant payments for the VTYP part of the study will be sourced 
from a separate fund/index.  
iii. Participants who meet all eligibility criteria at the in-person screening/baseline 
assessment, will be instructed to smoke their usual brand of cigarettes normally 
for the next 7 days, avoid using any other tobacco products, and complete daily 
text surveys to report their CPD. The primary purpose of this baseline period is to 
familiarize participants with the data collection procedures/system, reduce 
dropout prior to randomization, and collect a baseline measure of CPD. 
Participants will also be provided with contraception resources at this point in the 
study to help prevent pregnancy during the study. 
iv. Participants who are asked to complete the baseline period will be eligible for 
randomization if they: 
1. average CPD > 4  on the 7 prior daily surveys responded to 
OR 
average CPD > 4 on the 7-day timeline follow back questionnaire asked 
at randomization 
2. attend randomization visit in the study window 
v. Participants who are ineligible to participate in the main study (at 
screening/baseline or prior to randomization) will be informed that based on 
their responses: 
1. the current study is not a good fit for them 
2. a screening payment (and if applicable daily survey and/or randomization 
visit payment) for their time and effort will be provided 
3. tobacco prevention/cessation resources will be provided. 
 
b. Experimental/intervention period.  
i. Approximately 1 week after consent/baseline (Week 0), participants will return to 
the study site to be randomized to 1 of 3 conditions with equal probability using a 
computer-generated sequence. Condition assignment will be unblinded due to 
the nature of study conditions, but allocation concealment will be used to limit 
biased assignment.  
ii. At Week 3 and 6, participants will return used/unused product and at Week 3 
make selections for product dispensation for the subsequent weeks (could occur 
at the study site or in-person at their home).  
iii. Daily text surveys to measure tobacco/study product use will also continue 
throughout the intervention period.  
iv. Participants will complete self-report/behavioral measures at the end of each 
study week (sent via email/text for remote visits or completed in-person at the 
study site). These surveys will also record changes in concomitant medications, 
and assess any adverse events. If indicated, study staff will follow-up with 
participants via phone or in-person regarding responses provided. 
v. Physiological measures and expired air CO and spirometry will be measured and 
urine will be collected for biomarker assessment (NNAL, cotinine, propylene 
glycol) at the end of Weeks 0, 3, and 6. Heart rate, blood pressure, and 
spirometry will only be measured if participants attend subsequent visits at the 
study site.  

RVA-Flavors | Protocol | Page 8 
 
vi. To capture ENDS and other study product-related experiences that are not well-
assessed by current behavioral and self-report measures, a brief recorded semi-
structured interview will be conducted via phone/Zoom at Weeks 2 and 5.  
vii. Of note – For at home visits (Week 3 and 6; per participant preference), study 
staff will remain outside the participants’ home and provide/receive study-related 
materials (cooler containing urine sample materials; bag containing CO 
monitor/END-related materials) at the building door/main entrance. For these at 
home visits, participants will receive an online survey to containing weekly self-
report measures.  
viii. At the conclusion of the Week 6 visit, all participants will be provided with 
tobacco prevention/cessation resources. Participants will be able to keep their 
ENDS devices/charging materials and up to 4 unused pods in their condition-
specific flavors.  
ix. Following randomization and at the conclusion of the study period (two unique 
times), all participants will be sent a greeting card (see approved scripts).  
c. 30-day Follow-up. Participants will be asked to complete a reduced set of self-report 
measures via an online survey. 
 
9. Measures. Participants will complete the measures listed on the measures timeline below. 
 
Screening 
/Baseline 
Rand 
Weekly study visits 
30-d 
FU 
Study Week 
-1 
0 
1 
2 
3 
4 
5 
6 
~10 
Study Visit Window 
NA 
-1/+7 
-3/+3 
-3/+3 
-3/+3 
-3/+3 
-3/+3 
-3/+3 
-7/+7 
Approximate visit length (min) 
60-120 
60-120 
<60 
<60 
60-120 
<60 
<60 
60-120 
<60 
Mode: InPS=in-person at study 
site, IPH=in-person at home, 
Rem=phone/online 
InPS 
InPS  
Rem 
Rem 
InPS or 
InPH+Rem 
Rem 
Rem 
InPS or 
InPH+Rem 
Rem 
Tobacco use behavior (Aim 1) 
 
 
 
 
 
 
 
 
 
Daily Tobacco Use (daily text 
surveys) 
 
x 
x 
x 
x 
x 
x 
x 
  
7-day Tobacco Use TLFB 
 
x 
x 
x 
x 
x 
x 
x 
x 
ENDS liquid consumed (weight 
via products returned) 
 
 
 
 
x 
 
 
x 
 
Cigarette/ENDS (Aim 2) 
 
 
  
  
  
  
  
  
 
Expired air CO 
x* 
x 
 
 
x 
 
 
x 
 
Urinary cotinine, NNAL, PG 
x* 
x 
  
  
x 
  
  
x 
 
Abuse liability/addiction (Aim 3) 
  
 
 
 
 
 
 
 
  
Cigarette/ENDS purchase tasks 
(n=3) 
  
x (cigarette-
only) 
 
 
x 
 
 
x 
 
Other self-report measures 
  
  
  
  
  
  
  
  
  
Demographics, tobacco use 
history, medical history 
x 
 
  
  
  
  
  
  
 
Drug/alcohol use 
x 
  
  
  
  
  
  
 
  
Tobacco perceptions/attitudes  
x 
  
  
  
  
  
  
 
  
Stage of change/quit confidence 
 
x  
  
 
x 
 
  
x 
x 
Environmental smoke exposure 
x 
  
  
 
x 
 
  
x 
 
Cigarette/ENDS dependence 
 
x (cigarette-
only) 
 
 
x 
 
 
x 
x 
Withdrawal/stress 
 
x 
x 
x 
x 
x 
x 
x 
x 
Respiratory measure 
 
x 
  
  
x 
  
  
x 
x 

RVA-Flavors | Protocol | Page 9 
 
ENDS evaluation 
 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
End of intervention 
 
 
 
 
 
 
 
x 
 
Follow-up form 
 
 
 
 
 
 
 
 
x 
Semi-structured interview 
  
 
  
x 
 
  
 x 
 
  
Other physiological measures 
  
  
  
  
  
  
  
  
  
Spirometry  
 
x 
 
 
x# 
 
 
x# 
 
Height 
x 
 
 
 
 
 
 
 
 
Heart rate, blood pressure, weight  
x 
x 
 
 
x# 
 
 
x# 
 
Pregnancy test 
x 
  
  
  
  
  
  
  
  
VYTP Measures: Racial 
socialization, identity, media 
perception, discrimination and 
tobacco use 
x^ 
 
 
 
 
 
 
 
 
*Semi-quantitative cotinine and CO are collected at in-person screening to confirm eligibility by confirming exposure 
to nicotine and cigarettes 
^Only individuals who opt-in to the VTYP project and are eligible to participate in this optional ancillary study (based 
on self-reported age) will be asked to provide self-reported data about the impact of racial socialization, identity, 
media perception, and racial discrimination on tobacco use during the screening/baseline session. 
#Spirometry, heart rate, blood pressure, and weight will only be collected at in-person visits but not if participant 
chooses the remote option to complete this visit) 
 
a. Screening and baseline assessment: We will assess DEMOGRAPHICS, TOBACCO USE 
HISTORY/QUIT ATTEMPTS, MEDICAL HISTORY including health/psychiatric conditions (e.g., 
Medical History Form used in P50DA036105-Project 3), DRUG/ALCOHOL USE (e.g., NIDA 
Quick Screen; NIDA, 2012), TOBACCO PERCEPTIONS/ATTITUDES (see Bono et al., 2019), 
and ENVIRONMENTAL SMOKE EXPOSURE (e.g., Nondahl et al., 2005) using standardized 
items from PhenX, national surveys (e.g., PATH; BRFSS; TUS-CPS) and 
items/measures adapted specifically for ENDS (Dawkins et al., 2013). Several of these 
measures are repeated during the intervention and follow-up period to assess change 
over time. 
 
b. Experimental/intervention period:  
i. Participants complete TEXT SURVEYS once per day for the week prior to and 
throughout the 6 weeks where study product is provided. Please note, these 
texts include limited items in order to increase compliance and decrease burden 
as in (Donny et al., 2015). The survey assesses previous day cigarette smoking, 
ENDS use, and other tobacco/nicotine use. This information can be used to 
better characterize study product use patterns as JUUL batteries do not have an 
integrated automatic puff counter (unlike the device used in P50DA036105-
Project 3).  
ii. At weekly visits (0-6), a more intensive 7-DAY TIMELINE FOLLOW-BACK PROCEDURE 
(TLFB; Sobell & Sobell, 1992) will be performed to measure these same 
outcomes as well as use of other tobacco products, alcohol, and cannabis.  
iii. We will also weigh ENDS products returned at Weeks 3 and 6 to determine the 
volume of ENDS LIQUID CONSUMED (as in Cobb et al., 2020; Ohaus Model 
PA163C; 0.000 g detection limit).   
iv. Immediately following randomization, participants will be asked to complete ~4 
directed puffs of each of assigned ENDS available for their condition (order 
randomized for those with two flavors). Prior to testing, a brief video will be 
played by staff members describing how to use the device and associated 

RVA-Flavors | Protocol | Page 10 
 
materials. BRIEF SUBJECTIVE MEASURES OF ACCEPTABILITY/FLAVOR LIKING (I.E., 
ENDS EVALUATION) will be administered after each flavor is tested (Kim et al., 
2016).  
v. OTHER ENDS EVALUATION MEASURES will also be administered weekly to 
understand positive and negative effects of study product use (including sensory 
effects) (e.g., adapted from Hatsukami et al., 2013), and other side effects 
(developed as part of P50DA036105-Project 3).  
1. These questionnaires will be supplemented by SEMI-STRUCTURED 
INTERVIEWS performed via phone at Weeks 2 and 5 weeks post-
randomization that are aimed at assessing potential perceived 
barriers/perceived benefits of study product use not captured in available 
assessments. We plan to interview all randomized participants at these 
two timepoints. If the participant consents to participate in this ~15 min 
discussion, it will be audio-recorded (using Zoom). Audio-recordings will 
be maintained in locked file cabinets and/or secure electronic location 
until they are transcribed and then the audio-recordings will be destroyed. 
All names/direct identifiers will be removed from the audio-recording 
transcriptions.  
vi. OTHER SELF-REPORT MEASURES administered at randomization and weekly visits 
include STAGE OF CHANGE (e.g., Prochaska & Goldstein, 1991), cigarette/ENDS 
dependence (e.g., Penn State Cigarette Dependence Measure; Foulds et al., 
2015), withdrawal/stress measures (e.g., Perceived Stress Scale; Cohen et al., 
1983; Minnesota Nicotine Withdrawal Questionnaire; adapted from Hughes & 
Hatsukami, 1986). A respiratory measure will be assessed during Weeks 0, 3, 6, 
and during the online follow-up survey (Clinical COPD Questionnaire; van der 
Molen et al., 2003). 
vii. CHANGES IN ABUSE LIABILITY related to study product assignment, three purchase 
tasks (Jacobs & Bickel, 1999; MacKillop et al., 2008) will be completed at Weeks 
0, 3, and 6: own brand cigarette, condition-specific ENDS, and cross-product 
purchase tasks. In each version, participants will be asked how many times they 
would consume a puff of a tobacco product (e.g., cigarette and/or ENDS) at each 
of 25 different prices offered (range $0.00-$20.48). In addition to measuring 
abuse liability for cigarettes and condition-specific ENDS, cross-product abuse 
liability will also be measured using a cigarette purchase task modified to assess 
how much participants are willing to substitute consumption of ENDS for their 
own brand cigarette.  
viii. ADVERSE EVENT/CONCOMITANT MEDICATION monitoring will be assessed after 
screening/enrollment at each weekly visit using comprehensive forms and 
procedures developed as part of P50DA036105-Project 3 to note the nature, 
relatedness, outcome, and action taken for all adverse events noted as part of 
this study (see DSMP for detail). For remote visits, participants will receive an 
additional study-related phone call to follow-up regarding any adverse events or 
changes in medications reported. 
ix. An END OF INTERVENTION questionnaire at week 6 will quantitatively assess 
participant reactions to their study product, reasons for non-compliance during 
the study, and potential reactions to future FDA regulatory policy.   
x. A FOLLOW-UP SURVEY FORM is included with the follow-up survey to allow 
participants to elaborate on their experiences since ending the intervention 
period. 

RVA-Flavors | Protocol | Page 11 
 
xi. BIOMARKERS (n=4) of tobacco/ENDS-related toxicant exposure will be assessed: 
(1) expired air CO, (2) urinary cotinine, (3) urinary total NNAL, and (4) propylene 
glycol. Expired air CO will be measured using a Micro+ ™ basic Smokerlyzer® 
(coVita, Santa Barbara, CA). Expired air CO and urine samples will be assessed 
at Weeks 0, 3 and 6. Urine samples will be stored for later analysis of 
quantitative levels of cotinine, total NNAL concentration (sum of NNAL and its 
glucuronides) as well as creatinine (for adjustment of the biomarker results), and 
propylene glycol by VCU’s Department of Pharmacy using liquid chromatography 
tandem mass spectrometry techniques (Naidongu et al., 2001; Shah et al., 2009; 
Shah et al., 2011). 
1. For participants who choose to complete in-person assessments at their 
home (Weeks 3 and 6), researchers will meet participants at their front 
door/building entrance. Staff will confirm participant identity verbally, and 
then provide a small cooler/bag containing the CO monitor/device, urine 
sampling materials, and if needed ENDS product supply. Participants will 
be asked to return to their home to provide a CO sample (result saved 
locally on the device), a urine sample, and to return any used/unused 
ENDS supplies (with the exception of the batteries/charging materials). 
Participants will return materials to the staff who will then dispense 
payment for study activities to date.  
xii. OTHER PHYSIOLOGICAL MEASURES (n=4) will also be assessed at 
screening/baseline and at in-person visits (Weeks 0, 3, and 6) to determine any 
condition-related effects over time: heart rate, blood pressure (systolic and 
diastolic), spirometry (e.g., FEV1, FVC) and weight. Height will be assessed once 
at screening/baseline. PFTs will only be performed for individuals who have not 
had eye/chest/stomach surgery in the past 6 weeks (assessed at 
screening/baseline) 
1. For participants who choose to complete in-person assessments at their 
home (Weeks 3 and 6), we will not collect these measures.  
 
c. 30-day follow-up. Outcomes measured at the 30-day follow-up online survey will repeat 
several of those measured during the screening/baseline and intervention phases 
including stage of change/quit attempt history, environmental smoke exposure, 
tobacco/drug/study product use via 7-day TLFB, adverse events, and cigarette/ENDS 
dependence. 
 
10. Compensation. Completion of daily text surveys is $1 a day with a $10 bonus for completing 7 
calls in a row for a total possible compensation of $119 (over 7 weeks). Please note, due to 
study visit windows at randomization (-1/+7 days) and the week 6 visit (-3/+3 days) it is possible 
participants may complete up to 10 additional daily surveys during the study period (up to $20 
additional compensation), but this is unlikely and thus not emphasized in the compensation 
description.  Participants will be compensated for compliance in bringing back their used/unused 
study product ($30 per visit – Week 3 and Week 6 - for a total of $60 over the course of the 
study). The in-person screening and baseline visit is estimated to take 60-120 min ($40), 
randomization visit=60-120 min ($60), week 3 and week 6 visit=60-120 min ($40 each). Remote 
visits during weeks 1, 2, 4, and 5 are expected to take <60 min ($20 each) and the online 30-
day follow-up survey is expected to take <60 min ($20). During week 2 and 5 participants will be 
paid an additional $20 per visit for completing the interview. In addition, participants receive a 
$75 bonus for completing all study visits as well as parking/traveling compensation ($10) at 

RVA-Flavors | Protocol | Page 12 
 
each in-person study visit (total $40). If participants attend all visits, comply with protocol, and 
complete the follow-up survey they could earn a total of $654 (text surveys=$119, product 
compliance=$60, study visits and follow-up survey=$360, attendance bonus=$75, 
parking/travel=$30). Participants who enroll but later become ineligible or withdraw for any 
reason can schedule a time to pick up their compensation earned to date at our study site or 
have us email an Amazon giftcard to them. 
 
If participants opt-in and are eligible to participate in the VYTP project, those who complete 
these measures will be compensated an additional $40 at the screening/baseline visit. 
 
If participants are eligible following the in-person screening they will be given 5 referral cards 
that have our lab information and a number/letter combination on them. The numbers/letters on 
the cards are linked (by us) to the participant’s name/e-mail address. They can give these cards 
to friends or family members who might want to participate in this study. If someone attends an 
in-person screening visit with the card, the participant can receive an additional $20 per 
returned card, paid in cash or Amazon gift card (email). They will not be told who brought us the 
card. The referral cards expire after one year\. 
 
11. Sharing Results with Participants. This study is not intended to diagnose any disease or 
condition. At any point in the study if results reach a critical value (defined by the medical 
monitor), such as repeated high blood pressure or low lung function, the research staff and/or 
medical monitor will discuss the result with the participant, provide them with a letter explaining 
their results, and advise the participant to seek care from their primary care physician. If the 
critical value is observed following screening/baseline and adverse event will be created 
automatically for documentation and medical monitor review. In the event that a person tests 
positive for pregnancy, the research staff will discuss the result with the participant and urge 
them to seek prenatal medical care. The research assistant will provide the participant with 
information about where to receive prenatal care (either with their regular physician or at free 
clinics).  
 
12. Statistical Analysis Methods and Sample Size/Power. Following data cleaning and 
verification of baseline characteristics equivalence across conditions, analysis of the primary 
outcomes (Aims 1-3) will follow. Linear mixed (random effects) models will be used to analyze 
the adjusted association between conditions, time (visit), and each outcome. These models 
have several benefits over traditional repeated measures ANOVA including more flexibility in 
handling correlation patterns among the error terms and the ability to examine and estimate 
within-subject (individual) effects (Krueger & Tian, 2004; Scott, Siminoff et al., 2013). We will 
use an intent-to-treat (ITT) approach for all analyses and test the sensitivity of our results to 
missing data using multiple imputation (Allison, 2002). Please note that analysis of our 
secondary/exploratory outcomes (e.g., liquid weight, spirometry, other self-report items) will 
largely follow similar methods.  
Aim 1. This aim tests the hypothesis that participants will report larger reductions in CPD (via 
daily text surveys) between baseline and week 6 in the M+T_Reg condition relative to the 
T_Reg condition. Using within-subjects and between-subjects analyses with 210 participants 
(70/condition), we will have 80% power given α<0.05 to detect differences in CPD between the 
M+T_Reg vs. T_Reg conditions of 50% or larger (e.g., 9 fewer CPD in M+T_Reg vs. 6 fewer 
CPD in T_Reg) assuming a moderate correlation within individuals across visits (r≥0.50; G 
Power Version 3.1.4). At week 6, we also predict participants will report taking more puffs per 

RVA-Flavors | Protocol | Page 13 
 
day from their ENDS in the M+T_Reg vs. T_Reg condition. These estimates are based upon 
P50DA036105-Project 3.  
Aim 2. This aim tests the hypothesis that participants will report larger reductions in biomarkers 
of cigarette exposure (CO, total NNAL), and larger increases in biomarkers of ENDS exposure 
(PG), between baseline and week 6 in the M+T_Reg than in the T_Reg condition. With 210 
participants (70/condition), we will be powered (>80%) to detect differences in CO reductions of 
50% or larger (e.g., 6 fewer ppm CO in M+T_Reg vs. 4 fewer ppm CO in T_Reg). These 
estimates are based upon P50DA036105-Project 3 and R21CA184634. We also predict that 
increases in PG will be correlated with reductions in biomarkers of cigarette exposure. 
Aim 3. This aim tests the hypothesis that behavioral economic abuse liability indices 
(Willingness to substitute from cigarettes to ENDS; Willingness to pay for ENDS) will be higher 
in the M+T_Reg than in the T_Reg condition. With 210 participants (70/condition), we will be 
powered (>80%) to detect differences of 50% or larger at week 6 in the breakpoint, or maximum 
participants are willing to pay for ENDS ($1.30 in M+T_Reg vs $0.86 in T_Reg). This study will 
also be powered to detect similarly sized differences in own-price elasticity, or how much 
demand for ENDS changes as ENDS prices increase (0.05 in M+T_Reg vs. 0.08 in T_Reg), 
and in cross-product price elasticity, or the willingness to substitute from cigarettes to ENDS as 
cigarette prices increase (0.07 in M+T_Reg vs. 0.04 in T_Reg). These estimates originated from 
Barnes et al. (2017). 
a. VTYP Project Analysis Plan:  
i. Prior to conducting analyses, the descriptive statistics and distributions of each 
variable will be examined. Every effort will be made to minimize participant 
attrition and missing data. However, in the event of missing data, analyses will be 
conducted to examine whether participants with missing data differ from 
participants without missing data in meaningful ways. Missing data may be 
addressed using multiple imputation or through use of Full Information Maximum 
Likelihood (FIML) parameter estimation techniques. 
ii. Aim 1 first evaluates whether racial discrimination and stress positively predict 
current tobacco use and total tobacco use. In order to evaluate this initial 
hypothesis, a longitudinal hierarchical linear model (HLM) will be specified in 
Mplus (or comparable data analysis software) to examine whether racial 
discrimination and stress predict cigarette and total tobacco use patterns at 
baseline. Date of tobacco use initiation and demographic characteristics (e.g., 
sex and income) found to be significantly correlated with our tobacco outcomes 
will be included in the analysis model as control covariates. This analysis will 
thus allow for a robust test of whether discrimination and stress experienced 
during the adolescent period predicts tobacco use at baseline. 
iii. Aim 2 evaluates whether protective factors, racial socialization, identity, and 
media perception, moderates the effects of predictor variables (discrimination 
and stress) on current and total tobacco use. Testing Aim 2 will involve an HLM 
analysis model and testing procedure similar to the analysis model used to test 
Aim 1 along with the interaction term. Again, any age of tobacco initiation and 
demographic variables found to be notably correlated with tobacco use will also 
be included in the analysis model as control covariates. It is expected that these 
moderation effects will be such that the magnitude of the association between 
discrimination and stress with tobacco use will be significantly greater (worse) for 
those who reported lower levels of racial socialization and identity (e.g., low 
centrality, low private regard) during adolescence. 
iv. Power analysis estimates were based on 5,000 hypothetical datasets simulated 

RVA-Flavors | Protocol | Page 14 
 
using the Monte Carlo procedures of Mplus Version 7.20. Results showed 
statistical power will be ≥ .80 to detect a significant discrimination × socialization 
x tobacco use interaction effect over time if the following expected and 
reasonable effects are present if the effect of discrimination on tobacco use is at 
least β = .2-.3, and the resulting discrimination × socialization interaction effect 
on tobacco use over time is β ~ .24-.25. Separate models will be run for 
discrimination and racial stress and with each protective factor. For continuous 
measures, a significant interaction will imply moderation, with the size of the 
estimated coefficient reflecting the moderated change in the effect. Significant 
interaction effects can be followed up by testing the significance of the 
intervention effect across various levels of the moderator (e.g., 16th, 50th, and 
84th percentile). We plan to examine the influence of age as a potential 
moderator in the proposed analyses. We do not expect power to detect effects 
will be impacted substantially by its inclusion.   
 
13. Withdrawing Participants 
Participation in this study may be stopped at any time by the investigator without participant 
consent. The reasons might include: 
● the investigator thinks it necessary for the participant’s health or safety 
● the participant is found to not be eligible for the study 
● the sponsor has stopped the study  
● the participant has not followed study instructions 
● administrative reasons require the participant’s withdrawal 
14. References 
Allison, P. D. (2002). Missing Data. Thousand Oaks, CA: Sage Publications. 
Barnes, A. J., Bono, R. S., Lester, R. C., Eissenberg, T. E., & Cobb, C. O. (2017). Effect of 
flavors and modified risk messages on e-cigarette abuse liability. Tob Regul Sci, 3(4), 347-
387. PubMed Central PMCID: PMC5711435 
Bono, R. S., Barnes, A. J., Lester, R. C., & Cobb, C. O. (2019). Effects of Electronic Cigarette 
Liquid Flavors and Modified Risk Messages on Perceptions and Subjective Effects of E-
Cigarettes. Health Educ Behav, 46(2), 197-203. doi:10.1177/1090198118806965 PubMed 
PMID: 30360645. 
Cobb, C. O., Lester R., Rudy, A., Hoetger, C., Scott, M.A., Austin, M., . . . Eissenberg, T. 
Behavior and toxicant exposure associated with dual use of cigarettes and electronic 
cigarettes. 2020. 
Cobb, C. O., Lopez, A. A., Soule, E. K., Yen, M. S., Rumsey, H., Lester Scholtes, R., . . . 
Eissenberg, T. (2019). Influence of electronic cigarette liquid flavors and nicotine 
concentration on subjective measures of abuse liability in young adult cigarette smokers. 
Drug Alcohol Depen, 203, 27-34. doi:10.1016/j.drugalcdep.2019.05.024 PubMed PMID: 
31401532. 
Cohen, S., Kamarck, T., & Mermelstein, R. (1983). A global measure of perceived stress. J 
Health Soc Behav, 24(4), 385-396. 
Dawkins, L., Turner, J., Roberts, A., & Soar, K. (2013). 'Vaping' profiles and preferences: an 
online survey of electronic cigarette users. Addiction, 108(6), 1115-1125. 
doi:10.1111/add.12150 
Donny, E. C., Denlinger, R. L., Tidey, J. W., Koopmeiners, J. S., Benowitz, N. L., Vandrey, R. 
G., . . Hatsukami, D. K. (2015). Randomized Trial of Reduced-Nicotine Standards for 
Cigarettes. N Engl JMed, 373(14), 1340-1349. doi:10.1056/NEJMsa1502403 PubMed 
Central PMCID: PMC4642683 

RVA-Flavors | Protocol | Page 15 
 
FDA. (2013). Preliminary scientific evaluation of the possible public health effects of menthol 
versus nonmenthol cigarettes. Retrieved from Rockville, MD: 
http://purl.fdlp.gov/GPO/gpo39032 
FDA. (2016). 21 CFR Parts 1100, 1140, and 1143. 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, 81(90), 28974-29106. 
FDA. (2017). Assessment of Abuse Potential of Drugs: Guidance for Industry. Retrieved from 
Silver Spring, MD: https://www.fda.gov/media/116739/download 
FDA. (2018). Regulation of Flavors in Tobacco Products. 21 CFR Parts 1100, 1140, and 1143, 
Docket No. FDA-2017-N-6565, RIN 0910-AH60. Federal Register, 83(55), 12294-12301. 
FDA. (2020). FDA finalizes enforcement policy on unauthorized flavored cartridge-based e-
cigarettes that appeal to children, including fruit and mint. Retrieved from: 
https://www.fda.gov/news-events/pressannouncements/fda-finalizes-enforcement-policy-
unauthorized-flavored-cartridge-based-e-cigarettesappeal-children 
Foulds, J., Veldheer, S., Yingst, J., Hrabovsky, S., Wilson, S. J., Nichols, T. T., & Eissenberg, T. 
(2015). Development of a questionnaire for assessing dependence on electronic cigarettes 
among a large sample of ex-smoking e-cigarette users. Nicotine Tob Res, 17(2), 186-192. 
doi:10.1093/ntr/ntu204 PubMed PMCID: PMC4838001 
Hajek, P., Pittaccio, K., Pesola, F., Myers Smith, K., Phillips-Waller, A., & Przulj, D. (2020). 
Nicotine delivery and users' reactions to Juul compared with cigarettes and other e-
cigarette products. Addiction. doi:10.1111/add.14936 
Hatsukami, D. K., Zhang, Y., O'Connor, R. J., & Severson, H. H. (2013). Subjective responses 
to oral tobacco products: scale validation. Nicotine Tob Res, 15(7), 1259-1264. 
doi:10.1093/ntr/nts265 
Hughes, J. R., & Hatsukami, D. (1986). Signs and symptoms of tobacco withdrawal. Arch Gen 
Psychiat, 43(3), 289-294. 
Krueger, C., & Tian, L. (2004). A comparison of the general linear mixed model and repeated 
measures ANOVA using a dataset with multiple missing data points. Biol Res Nurs, 6(2), 
151-157. doi:10.1177/1099800404267682 
Leavens, E. L. S., Stevens, E. M., Brett, E. I., Hebert, E. T., Villanti, A. C., Pearson, J. L., & 
Wagener, T. L. (2019). JUUL electronic cigarette use patterns, other tobacco product use, 
and reasons for use among ever users: Results from a convenience sample. Addict Behav, 
95, 178-183. doi:10.1016/j.addbeh.2019.02.011 
Lopez, A. A., Cobb, C. O., Yingst, J. M., Veldheer, S., Hrabovsky, S., Yen, M. S., . . . 
Eissenberg, T. (2016). A transdisciplinary model to inform randomized clinical trial methods 
for electronic cigarette evaluation. BMC Public Health, 16, 217-016-2792-2798. 
doi:10.1186/s12889-016-2792-8 PubMed Central PMCID: PMC4778292 
MacKillop, J., Murphy, J. G., Ray, L. A., Eisenberg, D. T., Lisman, S. A., Lum, J. K., & Wilson, 
D. S. (2008). Further validation of a cigarette purchase task for assessing the relative 
reinforcing efficacy of nicotine in college smokers. Exp Clin Psychopharm, 16(1), 57-65. 
doi:10.1037/1064-1297.16.1.57 
Maloney, S., A., E., Crabtree, M., Soule, E. K., Eissenberg, T., & Breland, A. (in press). Acute 
effects of JUUL and IQOS in cigarette smokers. Tob Control. 
Naidong, W., Shou, W., Chen, Y. L., & Jiang, X. (2001). Novel liquid chromatographic-tandem 
mass spectrometric methods using silica columns and aqueous-organic mobile phases for 
quantitative analysis of polar ionic analytes in biological fluids. J Chromatogr-Biomed, 
754(2), 387-399. 
NIDA. (2012). NIDA Drug Screening Tool. Retrieved from https://www.drugabuse.gov/nmassist 
Nondahl, D. M., Cruickshanks, K. J., & Schubert, C. R. (2005). A questionnaire for assessing 
environmental tobacco smoke exposure. Environ Res, 97(1), 76-82. 
doi:10.1016/j.envres.2004.02.005 

RVA-Flavors | Protocol | Page 16 
 
Prochaska, J. O., & Goldstein, M. G. (1991). Process of smoking cessation. Implications for 
clinicians. Clin Chest Med, 12(4), 727-735. 
Scott, M. A., Siminoff, J. S., & Marx, B. D. (2013). The SAGE Handbook of Multilevel Modeling 
(1 ed.). Los Angeles, CA: Sage Publications Ltd. 
Shah, K. A., Halquist, M. S., & Karnes, H. T. (2009). A modified method for the determination of 
tobaccospecific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in human urine 
by solid phaseextraction using a molecularly imprinted polymer and liquid chromatography 
tandem massspectrometry. J Chromatogr B, 877(14-15), 1575-1582. 
doi:10.1016/j.jchromb.2009.04.003 
Shah, K. A., Peoples, M. C., Halquist, M. S., Rutan, S. C., & Karnes, H. T. (2011). Microfluidic 
direct injection method for analysis of urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
(NNAL) using molecularly imprinted polymers coupled on-line with LC-MS/MS. J 
Pharmaceut Biomed, 54(2), 368-378. doi:10.1016/j.jpba.2010.09.001 
Sobell, L. C., & Sobell, M. B. (1992). Timeline follow-back: A technique for assessing self-
reported alcohol consumption. In R. Z. Litten & J. P. Allen (Eds.), Measuring Alcohol 
Consumption (pp. 41-72). Totowa, NJ: Humana Press. 
van der Molen, T., Willemse, B. W., Schokker, S., ten Hacken, N. H., Postma, D. S., & Juniper, 
E. F. (2003). Development, validity and responsiveness of the Clinical COPD 
Questionnaire. Health Qual Life Out, 1, 13.