Comparison of Leading E-cigarette Product Types on Relative Reinforcement Value and Tobacco Use Patterns Among Current Smokers
Phase: NA
Conditions: Smoking, Tobacco Use
Sponsor: Medical University of South Carolina

 
 
 
 
Comparison of Leading E-cigarette 
Product Types on Relative 
Reinforcement Value and Tobacco 
Use Patterns Among Current 
Smokers 
NCT04237272  
5-6-2020 

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May 6, 2020 
Title: Comparison of leading e-cigarette product types on relative reinforcement value and tobacco use 
patterns among current smokers 
 
ABSTRACT 
Some smokers who try e-cigarettes transition completely from cigarettes to e-cigarettes, but others continue to 
use both products, or abandon e-cigarettes and return completely to cigarettes. One factor that likely impacts 
these tobacco use patterns is the e-cigarette device used. The majority of e-cigarettes purchased today are one 
of two “types:” customizable tanks or pods. These e-cigarette types differ from each other in critical ways, like 
nicotine delivery and sensory characteristics, that are likely to impact use by influencing the relative 
reinforcement value of the product. The present study will be a randomized trial investigating the impact of e-
cigarette device type on reinforcement value and use among current smokers. Current smokers (n=100) will be 
randomly assigned to either a control group that does not receive an e-cigarette or one of two e-cigarette types: 
a customizable tank, or a pod. The impact of device type on relative reinforcement value will be assessed using 
a choice task. Participants will also take home their assigned e-cigarette for a three-week sampling period. 
Primary outcomes include relative reinforcement value (choices to smoke in the lab-based choice task), cigarette 
smoking behavior (cigarettes smoked per day during sampling), and uptake (e-cigarette puffing episodes per 
day during sampling).  
 
 

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Comparison of leading e-cigarette product types on relative reinforcement value and tobacco use 
patterns among current smokers 
 
Specific Aims 
The prevalence of e-cigarettes has risen dramatically in the United States, and the impact of these products 
on public health remains controversial. Proponents of e-cigarettes argue that because e-cigarettes deliver lower 
levels of toxicants than conventional cigarettes1-4, they may offer reduced health risks for current smokers who 
switch completely1,4,5. However, while e-cigarettes appear to offer a path away from smoking for a subset of 
smokers, a large proportion of those who try e-cigarettes abandon them after a short trial period, or continue to 
use both products (i.e., dual use)6-8. Complete switching from cigarettes to e-cigarettes among those who try 
them is modest at best. Since the ultimate impact of e-cigarettes is likely dependent on their ability to curb 
cigarette smoking9, it is important to understand the device characteristics (in addition to user characteristics: 
not studied here) that contribute to their uptake. One major and perhaps most visible device factor that 
determines uptake is the type of e-cigarette itself. The sheer volume of e-cigarette brands makes it impossible 
to test the impact of each brand (over 400 estimated brands)10. However, most e-cigarettes can be categorized 
into one of four broad types with distinct characteristics: cig-a-likes, tanks, customizable tanks, and pods11.  
There is strong evidence that cig-a-likes deliver less nicotine, are less satisfying, and are less likely to 
promote switching than other device types12,13. Thus, these devices are not included in the proposed project. 
Tank devices have a nicotine delivery profile differs markedly from traditional cigarettes14, and thus have also 
not been included here. The other two types, customizable tanks and pods, corner significant portions of the e-
cigarette market and differ from each other in critical ways that would be expected to impact uptake, and thus 
constitute our primary focus. Customizable tanks deliver nicotine in a profile that more closely models the nicotine 
delivery of traditional cigarettes14. These devices offer a high level of customization that allows users to adjust 
the device until they reach their desired sensory and nicotine delivery settings. However, the customization 
renders them relatively complicated to learn to use. Pods (e.g., JUUL) are the newest type of e-cigarette on the 
market. Pods utilize nicotine salts, rather than free-base nicotine, which the company claims allows them to 
deliver high levels of nicotine in a profile that is comparable to traditional cigarettes 15. They offer no 
customization, making them easy to use. The combination of high nicotine delivery with increased usability may 
increase the relative reinforcement value of these products, resulting in greater uptake than other device types. 
There is almost no existing research that directly compares these device types against each other14. The 
goal of this application is to provide a preliminary assessment comparing e-cigarette device types 
(customizable tanks, pods) in a head-to-head design. 
In a between-subjects design, adult daily smokers (n=100) who are interested in trying e-cigarettes will be 
randomly assigned in 1:2:2 fashion to either a control group that receives no product (n=20), or to receive one 
of two types of e-cigarettes to sample over a three-week period: a) customizable tank, or b) pod, (n=40/group). 
The design is naturalistic in that participants receiving an e-cigarette will be told to use the e-cigarette as much 
or as little as they would like, allowing for assessment of self-determined uptake and reinforcement. Methods 
include both ecological assessments (electronic daily diaries) and experimental sessions (choice and purchase 
tasks). Biomarkers (expired carbon monoxide) will corroborate self-reported indices of use.  
Primary Specific Aim: to assess the impact of e-cigarette product type (customizable tanks vs. pods) on product 
satisfaction ratings and relative reinforcement value (choices to smoke vs. use product in choice task, 
hypothetical purchase task).  We hypothesize that pods will produce greater satisfaction ratings and relative 
reinforcement value than the customizable tanks.   
Secondary Aim: to assess the impact of e-cigarette product type on tobacco use patterns including cigarette 
smoking (cigarettes per day, expired breath carbon monoxide) and e-cigarette uptake (e-cigarette puffing 
episodes). We hypothesize that pod style e-cigarettes will produce greater reductions in cigarette smoking 
compared to customizable tanks and greater uptake of e-cigarettes. Secondary analyses will compare the impact 
of e-cigarette sampling (control vs. all e-cigarette groups) on smoking during the sampling period. 
Relevance to Tobacco Regulation: We recognize that e-cigarette device types differ from each other in multiple 
ways, and it will not be possible to isolate the mechanism by which one type performed better than others (e.g., 
nicotine delivery, appearance, customization). We view device heterogeneity as a strength since this design 
mimics the real-world options that smokers face when adopting e-cigarettes but with randomized design to 
enhance rigor. The goal here is to provide useful information to regulatory agencies and consumers about which 
types provide the highest reinforcement value and lead to the greatest uptake, inclusive of the differences 
between types. Understanding the impact of device type would provide guidance about which e-cigarette 
smokers might choose, while at the same time providing key information to the FDA about how to better regulate 

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e-cigarettes for the improvement of public health. This proposal is in line with funding opportunities from FDA 
and NIDA.  

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Significance 
A1. Patterns of E-cigarette Use: E-cigarettes have dramatically risen in popularity in recent years16-18. 
Proponents of e-cigarettes argue that because e-cigarettes deliver lower levels of toxicants than conventional 
cigarettes1-4, they could offer reduced health risks for current smokers who switch completely1,4,5. However, the 
impact of e-cigarettes on cigarette smoking remains largely unknown9.  
A2. The Impact of Product Type on Reinforcement Value and Use: Smokers have 400+ different e-cigarette 
brands from which to choose,10 which vary across many characteristics including appearance, nicotine 
concentration, device power, flavoring, e-liquid constituents, potential for customization, throat hit, and volume 
of aerosol production. Full scientific evaluation of these characteristics would be difficult. Instead, we believe it 
is better and more ecologically valid to test different types of products.  Here, we focus on two popular device 
types that collectively comprise about 90% of the e-cigarette market32 and can deliver nicotine at levels that are 
comparable to combustible cigarettes14,33,34. Customizable tanks use refillable tanks and are activated by pushing 
a button, but are larger in appearance and offer a high degree of customization to the user (e.g., wattage, 
resistance, air flow)11. Pods, the newest category of devices, often resemble a flash drive in appearance, are 
activated by drawing on the device rather than pushing a button, are low in wattage, and use a high nicotine 
concentration e-liquid11. JUUL, the most popular pod, has recently surged in popularity35. These types of devices 
have different characteristics that are likely to collectively impact the relative reinforcement value of the product 
in comparison to a current smoker’s usual brand. Relative reinforcement value refers to the degree to which 
users like/enjoy/want/prefer these alternative e-cigarettes, in comparison to combustible cigarettes. Estimates of 
relative reinforcement (e.g., purchase tasks, preference tasks) are well-established measures of drug abuse 
liability and have been utilized for making drug-related policy and regulatory decisions36-39. Because the e-
cigarette market is changing rapidly, we know relatively little about the impact of device type on 
reinforcement value, nor do we have sufficient studies of cross-device comparisons.  
A2a. Nicotine Formulation, Sensory Characteristics, and Customization Potential: Pods deliver nicotine 
using nicotine salts, rather than free-base nicotine used by customizable tanks. There is no published research 
directly examining the impact of salts on reinforcement or use, but the makers of JUUL, the most popular pod, 
claim that using nicotine salts allows for high nicotine delivery with a smooth nicotine hit15,46.  
Several sensory characteristics may be important. First, because pods devices are low powered devices, 
they produce less visible aerosol than customizable tanks50,51. Second, the two device types generate different 
user topographies. Pod devices are often vaped into the mouth before being inhaled into the lung (i.e., mouth-
to-lung), while customizable tanks are inhaled directly to the lungs without first lingering in the mouth (i.e., direct-
lung)52. Third, “throat hit” is often described as an important sensory characteristic of tobacco use, and the two 
device types may offer throat hits with different strengths52,53.   
One of the characteristics that distinguishes customizable tanks from pods is that they are, indeed, highly 
customizable. No published research has directly examined the impact of e-cigarette customization on 
reinforcement value or use. We know that in general, people are more motivated to engage in an activity when 
there is choice involved54, but added customization also introduces more complexity, which could lead to 
decreased uptake. User satisfaction can also be decreased when there are too many options available55.  
A3. Scientific Premise: The ultimate impact of device type on consumer uptake and downstream changes in 
cigarette use is likely dependent on the combined impact of all of these characteristics (nicotine delivery, sensory 
characteristics, customization potential), which together function to change the relative reinforcement value of 
using e-cigarettes compared to smoking. Despite the importance of device type, there are no published studies 
which directly compare the type of e-cigarette device on reinforcement value or use. Thus, the goal of the 
proposed IDEA award project is to provide a preliminary assessment, through a randomized design, of the impact 
of e-cigarette device type on reinforcement value, uptake, and cigarette smoking behavior.  We hypothesize that 
pod e-cigarette devices, which are sleek in appearance, easy to use, have sufficient nicotine delivery, are used 
in a mouth-to-lung topography that is similar to cigarette smoking, and have a strong throat hit, are likely to 
generate the highest level of reinforcement value and uptake. 
Reviewers will be quick to note that any comparison of devices will inherently introduce a number of potential 
confounds. We view this as a strength, not a weakness. We considered an alternative approach that would hold 
all aspects of a single device constant and isolate specific e-cigarette characteristics. However, research 
isolating individual characteristics is also quite limited in its implications because devices differ from each other 
in multiple ways. The ultimate impact of any given e-cigarette on reinforcement value and use will depend on the 
combined effect of all device and e-liquid characteristics. The proposed research takes a complementary 
approach which is more ecologically representative of the current market: testing differences in e-cigarette 
characteristics in the same way consumers experience them, as different device types. Thus, this is the most 
“real world” cross-product test of different e-cigarettes on behavior. 

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A. Innovation 
The proposed study is highly innovative, timely, and important given the current landscape. First, this will be 
the first trial to compare customizable tanks and pods using an experimental design. Large, longitudinal trials, 
like the Population Assessment of Tobacco and Health62, provide information about the relative popularity of 
these device types. However, these datasets are limited because smokers are not randomized to a specific 
device, and thus, cannot provide critical information about the causal impact of device type on reinforcement 
value and use. The randomized design utilized in this study is one of its primary strengths. Second, this project 
is innovative for its use of the JUUL product specifically. In 2016, JUUL (a popular pod brand) comprised 2% of 
sales in retail outlets35, but that number climbed to 29% in December of 201735 and 76% in November of 2018 
63. Because of how rapid the rise in popularity has been, there is almost no existing research which investigates 
its impact. To the best of our knowledge, there are no published experimental studies investigating JUUL and 
no published reports focusing on JUUL use among current smokers.  
C. Approach 
C1. Design and Procedures: Consented participants will 
complete screening measures to determine eligibility. 
Eligible adult smokers will be randomly assigned in a 1:2:2 
between-subjects design to either not receive an e-cigarette 
(control group, n=20) or receive one of two e-cigarette types: 
a customizable tank, or pods (n=40/each). Participants will 
sample their assigned e-cigarette, complete questionnaires, 
and then complete the choice task (described below). Participants will be provided with an e-cigarette device 
and e-liquid to sample over a three-week period (Figure 1). Across the study, participants will complete daily 
electronic diaries that assess their daily use of cigarettes and e-cigarettes. Participants will also complete weekly 
phone calls where they will complete assessments regarding tobacco use, craving, dependence, and product 
perceptions. At the end of the sampling period, participants will return to the lab to complete a series of 
questionnaires. complete the sampling and choice tasks again, and return the device.  
C2. Participants: Daily cigarette smokers (n=100) will be recruited from the community. In/exclusion criteria are 
designed to enroll smokers who have limited experience with e-cigarettes. Inclusion criteria include adults who 
a) have been smoking at least five cigarettes daily for the past year (baseline CO > 8ppm), b) rate their interest 
in using e-cigarettes as >5 on a 0-10 scale, c) willing to use an e-cigarette as part of the trial, d) have a 
smartphone that can receive text messages and has access to the internet or have an e-mail account they check 
daily (necessary for daily diary completion) and e) be at least 21 years of age. Exclusion criteria include a) 
purchasing an e-cigarette within the last six months, b) weekly use of e-cigarettes over the last six months, c) 
any e-cigarette use in the past 30 days, d) use of tobacco products other than cigarettes on ten or more days in 
the past 30 days, e) current use of cessation medications, f) pregnant, trying to become pregnant, or 
breastfeeding, g) recent history of cardiovascular distress in the last three months, h) history of a seizure 
disorder, or i)household member currently enrolled. We will stratify group assignment based on age (21-30 vs. 
31+) and motivation to quit (0-6 vs 7-10) to prevent these variables from being confounded with group. 
C3. E-cigarettes and e-liquids:  The best exemplars will be chosen from each of two device type categories 
based on market share data. Currently these include the Mirage DNA 75C e-cigarette (customizable tank style), 
and a JUUL e-cigarette and pre-filled pods (pod).   
Participants will be provided with one device, one charger, and a choice of e-liquid flavors. Participants will 
be able to choose up to two flavors (to allow for switching of flavors during sampling) from a menu of four flavors. 
For the customizable tank/Mirage device, e-liquid is sold separately which is the case with all customizable tanks. 
E-liquid will be available in a wide array of flavors, and will be provided in 12 mg/ml nicotine concentration. For 
the pod/JUUL devices, we will provide each participant with one pre-filled e-liquid pod for each day of sampling. 
These pods provide enough nicotine to compare to one pack of cigarettes, and thus one pod per day should be 
sufficient. E-liquid will be 5% nicotine, which JUUL states is the most popular nicotine concentration they sell. All 
participants will receive instructions on how to operate their device, fill it with e-liquid or replace the pods, and 
be given a lab phone number to call with questions. Participants assigned to the customizable tank device will 
be shown how to adjust their customization settings.  
C4. Compensation Participants will receive $50 for the screening/randomization if they are eligible and $15 if 
they are not. Participants will receive $50 for the Week 3 visit, $20 each for the Week 1 and Week 2 phone calls, 
and a $50 completion bonus if they complete all assessments. Participants will also receive up to $25/week for 
completing daily diaries (up to $75). Thus, participants who attend all visits and complete all diary entries could 
earn $265. 

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C5. Measures 
C5a. Screening Assessments: Preliminary eligibility will be determined on the phone before participants are 
either consented electronically or invited for an in-person visit to provide consent. Alternatively, participants may 
complete a Redcap survey to determine initial eligibility. Participants will see a script that briefly explains the 
study. Consented participants will attend an in-person visit where they complete screening questionnaires related 
to demographics, tobacco use history, and expired carbon monoxide. 
C5a. Measures of Subjective Effects: Subjective effects will be assessed using a modified version of the 
Cigarette Evaluation Questionnaire (mCEQ)66, which assesses product satisfaction, psychological reward, 
craving reduction, enjoyment of sensations in the respiratory tract, and aversion. First, participants will sample 
their usual brand cigarette to standardize time since last cigarette. Participants will then sample their assigned 
e-cigarette and e-liquid. Immediately after sampling, participants will complete the mCEQ. 
C5b. Measures of Relative Reinforcement: Relative reinforcement will be assessed using a lab-based choice 
task, a well-validated measure of reinforcement value67. After participants sample their assigned product, they 
will complete choice task in which over a period of 30-minutes and 10 trials, participants choose between taking 
two puffs of the e-cigarette, two puffs of their usual (own) brand cigarette, or abstaining from both. Participants 
in the control group will choose between their usual brand cigarette and abstaining. In this case, the task will 
measure the impact of device type on changes in the relative reinforcement value of smoking compared to using 
the e-cigarette. The primary outcome is the number of choices to smoke. A secondary measure of reinforcement 
value will be purchase tasks—hypothetical tasks in which participants estimate the intensity with which they 
would use cigarettes and e-cigarettes at a variety of prices68,69. The purchase tasks can be used to calculate 
several demand parameters, which are estimates of reinforcement value36. Additional dependence measures 
will be included 707172.  Dr. Smith is utilizing these measures in recently completed and upcoming projects.  
C5c. Measures of Tobacco Use and Biomarkers: Daily cigarette use will be captured using an electronic daily 
diary (<2 min/day) in which participants report the number of e-cigarette puffing episodes per day and the number 
of cigarettes they smoked. This electronic daily diary was used in Dr. Smith’s recently completed trial with 
compliance > 90%. We will collect expired breath carbon monoxide at Randomization and the Week 3 visit, 
which provides an objective measure of recent smoke exposure but is unaffected by e-cigarette aerosol.  
C5d. Other Self-Report Questionnaires: We will also use questionnaires to assess demographics, tobacco 
use history, expectancies, perceived health risks, and adverse events over time.  
C6. Statistical Analysis, Power, and Predicted Outcomes  
C6a. Statistical Analysis: We focus on changes in 
reinforcement value of cigarettes because the public health 
impact of e-cigarettes will be driven by changes in the use of 
cigarettes, rather than any direct effects of e-cigarettes. Our 
primary outcome is the percentage of choices for each 
participant to smoke the conventional cigarette during the 
choice task at Week 3 (ranging from 0 to 100%). A one-way 
ANOVA model will be used to compare the e-cigarette groups, 
while excluding the control group, to examine the effect of e-cigarette type. If there is no significant difference 
between e-cigarette types, e-cigarette participants will be combined and compared to the control group via a t-
test to examine the effect of e-cigarette sampling. Other outcomes will be analyzed using general linear mixed 
models (GLMMs) controlling for baseline values and repeated measurements per participant will be used to 
examine group, time, and group by time interactions. Our secondary aim focuses on the average number of 
cigarettes smoked per day during Week 3 while also examining average e-cigarette puffing episodes, expired 
carbon monoxide. These outcomes will be examined in a similar manner via GLMMs. We will also conduct 
exploratory analyses to determine whether the effect of e-cigarette type or e-cigarette sampling depended on 
individual characteristics such as age, gender, race, and motivation to quit. Given the innovative and exploratory 
nature of this trial, there are no existing datasets that directly apply for the purposes of conducting a power 
calculation. However, a sample size of 30 per e-cigarette group will provide 80% power to detect moderate 
between-group differences in a one-way ANOVA comparing the primary outcome with a two-sided alpha=0.05.  
C7c. Predicted Outcomes:  We hypothesize that the pod e-cigarette will result in further reductions in choices 
to smoke during the choice task and in cigarette smoking (Figure 2).  
C8. Future Directions: The goal of the proposed application is to gain preliminary data on the impact of e-
cigarette type. An R01 grant application will follow the proposed project and will include a longer sampling period, 
longer follow up period, a more thorough investigation of the health effects of e-cigarette types, and a full 
investigation of any critical moderators (e.g., age). 

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C9. Timeline: The proposed study will take one year. The first three months will be devoted to study start up, 
measurement finalization, IRB approval, obtaining product, etc. Our prior studies will steer this process efficiently. 
We will recruit approximately eight participants/month for 9 months, until 100 participants have been randomized. 
An R01 grant application will be submitted in the Fall of 2020. 
 
 

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Protection of Human Subjects 
 
1. 
Risks to Human Subjects 
 
1.1 Human Subjects Involvement, Characteristics, and Design: 
Current smokers will be randomly assigned in a 1:2:2 between-subjects design to either not receive an e-
cigarette (control group, n=20) or to receive one of two e-cigarette types: a customizable tank, or pods 
(n=40/each). All participants will receive an e-cigarette and e-liquid to sample over a three-week period.  
 
1.2 Study Procedures, Materials, and Potential Risks: 
 
Study Procedures: 
Participants will be screened over the phone to determine initial eligibility. Alternatively, participants may 
complete a redcap survey to determine initial eligibility. Participants will see a script that briefly explains the 
study. Once participants have been determined to be initially eligible, they will be invited to participate in the 
consent process. The consent process will take place via one of the following modalities: 1) Remote electronic 
consent (e-consent) via REDCap facilitated with a discussion over the phone, 2) Remote consent via doxy.me, 
or 3) in-person consent (in-person visit at start of Visit 1). We have built in the option for electronic consent to 
reduce the length of the first in-person visit and while still providing ample time for the consent process. 
Consented participants will be asked to attend an in-person screening session. We will provide transportation 
via a taxi cab company (Yellow Cab) for participants who are eligible, but do not have reliable transportation to 
in-person visits. We will pay the cab company directly, the participant will not need to contribute. Participants will 
be asked to provide a carbon monoxide sample to confirm smoking status, and women will provide a urine 
sample for pregnancy testing. Participants will then complete a series of interview-administered and participant-
administered questionnaires that assess brief medical history, tobacco use history including prior and current e-
cigarette and cigarette use, current use of smoking cessation products, and demographics. After all 
questionnaires have been completed, study staff will determine participant eligibility.  
Participants who are eligible will then complete additional baseline questionnaires including measures of nicotine 
dependence. Participants will be randomized as described above and will have the opportunity to sample their 
usual brand cigarette and their assigned e-cigarette and e-liquid for the first time. After sampling each product, 
participants will complete additional questionnaires and complete the preference assessment where they choose 
between their cigarette and assigned e-cigarette. At the end of Visit 1, participants will receive a three-week 
supply of e-liquid to take home with their assigned e-cigarette, will be enrolled in the daily electronic diary system, 
and will be provided with instructions for completing diaries.  
Participants will complete weekly phone calls after one and two weeks of sampling and will return to the lab for 
an in-person visit after three weeks of sampling. At each visit or phone call, we will assess tobacco use during 
the prior week, adverse events will be assessed, and participants will complete questionnaires about their 
assigned e-cigarette and e-liquid. At each in-person visit, participants will provide an expired breath carbon 
monoxide sample. At the fourth and final weekly visit, participants will complete the sampling and preference 
assessment again, and return any unused study product.  
 
Modified Procedures to be Implemented During COVID-19 Restrictions: After passing initial screening, all 
participants will be consented into the study through our established remote procedures, instead of having the 
option to complete the consent process in person. All in-person screening questionnaires that can be 
administered over the phone prior to the visit will be completed over the phone (demographics questionnaire, 
physiological & medical history, & tobacco use history). Participants who are ineligible based on these 
questionnaires will be paid for the visit, but not required to come in to the lab to complete the remaining screening 
assessments. If the participant is still eligible after completing these questionnaires, we will then schedule them 
to come into the laboratory to complete the remainder of the visit. For visit 2, we will complete any questionnaires 
remotely that we can be completed remotely. For interview-administered questionnaires, we will call participants 
in advance of the visit and complete the questionnaire over the phone via interview with study staff. For 
questionnaires that are completed independently by the participant, we will send them a RedCAP link prior to 
the visit and request that they complete the questionnaires on their own. If participants fail to complete these 
questionnaires on their own or we are unable to reach them to complete the questionnaires, we will ask the 
participant to complete them at the visit in the lab.  
Participants will be called 24 hours prior to all visits to confirm they are not experiencing any symptoms of COVID-
19. All participants for each visit will be required to wear a mask and remain six feet away from the research staff 

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and others when possible. When staff and participants must interact (for CO collection and e-cigarette disbursal), 
at least six feet of distance will be maintained by placing materials on a desk/table six feet away from the 
participant and then staff stepping away while the participant approaches to retrieve materials. All surfaces will 
be sanitized prior to the visit and after the visit. 
 
Materials: 
Research material obtained from the participants include responses to questionnaires collected directly by our 
research team and entered directly within secure databases. Data will be stored in a password protected redcap 
database and on password protected network storage. Consent forms will be stored in a separate locked filing 
cabinet or electronically on Redcap or a secure Box account. Physiological measures include: urine collected for 
pregnancy testing, as well as expired breath carbon monoxide. Research data will be obtained specifically for 
research purposes. Every effort will be made to maintain subject confidentiality, in accordance with HIPAA. 
 
Potential Risks: 
The research protocol calls for smokers to use e-cigarettes in the lab and (if they desire) at home. E-cigarettes 
are no more harmful than conventional cigarettes, and various studies suggest that they may offer reduced harm. 
Questionnaires and interviews are all non-invasive and involve minimal risk to study participants.  
 
Potential risks are as follows:  
 
E-Cigarettes   
E-Cigarettes are not combusted, and therefore levels of carcinogens are markedly reduced, if not eliminated, 
comparable to trace levels seen in nicotine replacement products (97).  E-liquid will contain propylene glycol, 
which some suggest may be harmful.  Propylene glycol is an FDA approved food additive, but with uncertain 
effects upon inhalation.  
 
As for adverse events, the majority of e-cigarette studies are based within on-line surveys.  We report here on 
three moderate to large such surveys.  In the first (98), three side effects were reported by >20% of respondents: 
headaches (21%), cough (27%), and increased phlegm (25%).  In the second (99), the most common negative 
effect of e-cigarette use was throat and mouth irritation, and fewer than 3% “reported a high level of side effects.”  
Finally, the largest online survey to date (100) did not fully assess adverse events, but reported that 26% of e-
cigarette users reported burning in throat. In a cross-over study of 40 smokers given e-cigarette for four days 
(101), the four most common adverse events (within highest dosage group) were mouth/throat irritation (38%), 
nausea (29%), vertigo (21%) and headache (22%).  All other adverse events were rare (<5%).   
In the recent RCT from New Zealand (102), there was a higher number and proportion of adverse events among 
active e-cigarette group, but the event rate did not significantly differ as compared to nicotine patches.  In the 
RCT from Italy (103) there was no differential rate of adverse events among high, medium, or placebo e-cigarette 
groups.  The five most common adverse events were dry cough, mouth irritation, shortness of breath, throat 
irritation, and headache, with no serious adverse events.  The study also reported no significant changes in body 
weight, resting heart rate, or blood pressure. 
 
There have been a small number of reports to the FDA of people using e-cigarettes and experiencing seizures, 
with most reports involving youth or young adult users. This is rare and will be monitored.  We have added an 
exclusionary criteria for history of seizure disorder. 
 
There have been a number of reports of respiratory illness, and even some deaths from that respiratory illness, 
among individuals using e-devices.  No specific substance or product has been linked to these cases. Many of 
but not all of the cases involved users vaping THC, the active ingredient in marijuana.  Some of the instances 
are specific to nicotine alone.  We advise all participants not to add any substances to the devices we give them.  
We advise against using any e-device or e-liquid that is obtained by questionable or unknown sources (such as 
off the street or on the black market). While we believe that e-cigarettes are less harmful for adult smokers than 
regular cigarettes on a long-term basis, there may still be short term risks of using e-cigarettes.  We will continue 
to monitor your health in our study by asking you at every study contact a set of specific questions about any 
changes you have experienced since the last study contact.   
 
Concurrent use of e-cigarettes and smoking 

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If smokers engage in dual use, the major concern will be too much nicotine intake.  Symptoms of nicotine 
intoxication include nausea, dizziness, headache, and stomachache (104). In Dr. Carpenter’s two prior studies, 
wherein participants who used nicotine gum/lozenge and smoked concurrently, there was no evidence of nicotine 
intoxication (105, 106), nor have we seen serious adverse events in our current e-cigarette studies.  We recently 
completed a literature review (107) that showed combined NRT, as well as concurrent use of NRT and smoking, 
were both safe.   
A recently completed short-term observational study included 20 smokers who were provided e-cigarettes for ad 
libitum use over a 2-week period. Data below demonstrate that changes (increases) in e-cigarette use increased 
in direct proportion with changes (decreases) in cigarette smoked (1st and 2nd panel), resulting in no net change 
in nicotine (3rd panel).  Thus, smokers who engage in dual use are likely to NOT increase total nicotine intake, 
a finding replicated elsewhere (108).  These findings are very much consistent with Dr. Carpenter’s prior work 
on smokeless tobacco, wherein smokers were provided with snus to use ad libitum over two weeks, finding no 
net increase in nicotine intake.    
 
 
Undermining Cessation 
Another potential risk is that the sampling intervention will decrease rather than increase future cessation.  We 
are aware of one recent longitudinal study (109) that showed numerically lower but still statistically similar rates 
of non-smoking among e-cigarette users vs. non-users, but this study did not assess for timing of e-cigarette 
use.  This is the only study to show this that we are aware of.  However, most of the available data available 
suggest that e-cigarettes either do not affect cessation or increase it (98, 100, 102, 103, 110-112).  
 
Use of E-cigarettes among non-participants and non-smokers, including children 
Whenever a product is given to a smoker to take home and use, there is potential that the product will be used 
by someone else, inclusive of non-smokers and even children.  In Dr. Carpenter’s recently completed snus trial 
in which he mailed tins of smokeless tobacco to smokers all over the country, such “diversion” was not a problem. 
We will advise participants who receive e-cigarettes to keep them out of reach of children and pets.  
 
Confidentiality 
A final risk is breach of confidentiality. 
 
2. 
Adequacy of Protection Against Risks 
 
2.1 Informed Consent: 
All research personnel have up to date CITI Certification for Protection of Human Subjects, and will keep this 
training current throughout the course of the study.  Study participants will be recruited through local media 
outlets (e.g., craigslist, flyers, print ads, facebook).  Those who call expressing interest in study participation will 
be screened for an initial eligibility determination. Once initial eligibility has been determined, the consent process 
will be initiated. The consent process will take place via one of the following modalities: 1) Remote electronic 
consent (e-consent) via REDCap facilitated with a discussion over the phone, 2) Remote consent via doxy.me, 
or 3) in-person consent (in-person visit at start of Visit 1). During COVID-19 restrictions, all consenting will be 
done remotely. We have built in the option for electronic consent to reduce the length of the first in-person visit 
and while still providing ample time for the consent process.  All participants will be provided with a hard copy 
and/or electronic copy of the consent form. Participants will be given time to review the consent documents, as 
well as a detailed overview of the consent documents by study staff. After participants have read the documents 

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and the documents have been described by the study staff, participants will demonstrate that they understand 
key aspects of the study by verbally answering questions from study staff about participation (e.g., “Can you tell 
me what the risks of participation are?”). Participants will sign the consent form only after both the participant 
and the study staff member are confident that the participant understands their participation and the risks 
associated with participating. Consent/HIPAA signatures may be collected on paper or electronically. When 
consent is collected electronically, our study team has a combination laptop/tablet that will be used for the 
eProcess. No information will be stored locally on the laptop/tablet; all information will be stored securely in 
REDCap/Box folder if captured electronically. Instead of signing on paper, a participant will enter his/her name, 
date, and sign electronically (with mouse or finger) in REDCap. Each signed consent/HIPAA can be downloaded 
from REDCap as a PDF. Only those participants who provide consent will complete the additional screening 
questionnaires. Additional screening measures include additional questionnaires, an expired carbon monoxide 
sample to confirm smoking status, and (if female) a urine pregnancy test. Participants who are deemed eligible 
at that point will then complete additional baseline questionnaires. On all correspondence with potential 
participants, we provide our toll-free number if any questions or problems arise. We will abide by all HIPAA 
regulations as set forth by our institution.  Dr. Smith will supervise all aspects of the recruiting process.      
 
2.2 Protection Against Risk: 
Use of E-cigarettes 
Participants will be screened for general medical precautions (pregnancy, cardiovascular disease), and all 
participants will be monitored for adverse events during the study period. We will clearly advise against use of 
e-cigarettes during pregnancy and breast-feeding and will verify non-pregnancy at study onset. Participants will 
be educated about potential risks of e-cigarette use, including concurrent use with cigarettes. Any adverse events 
will be reported to the IRB. The most likely adverse event (potential for nicotine overdose) is anticipated to be 
rare (~5%) and mild (mouth/throat irritation, headache, nausea, headache), and will be handled quickly (i.e., 
advice to participant to reduce or stop e-cigarettes). Lab studies of toxin exposure (above) suggest that e-
cigarettes confer no greater risk to health than do conventional cigarettes. It is unlikely that e-cigarette users will 
become addicted to the product in the 3-week sampling period.  All participants will be provided with cessation 
information (referrals to Quitline) as part of this study.  
 
Concurrent Use of E-cigarettes & Smoking 
Per above, the most common effects from too much nicotine are nausea, headache, and disturbed sleep. The 
sampling period is three weeks in duration, and thus we do not expect sustained patterns of dual use.  We will 
track adverse events at every study contact, and will have a toll-free number available for participants to call if 
they experience an adverse event (AE).  All study contacts will remind participants of this number. Participants 
will be encouraged to contact study staff as soon as possible for serious events. If they wish, they may contact 
their local MD or give the study medical advisor permission to do so. We will withdraw participants who have a 
serious AE, become pregnant or begin breast-feeding. For other AEs, if the participant’s physician or the 
participant wishes it, the participant will be withdrawn from the study.  
 
Undermining Cessation  
We emphasize that this is not a cessation trial, though we will collect various cessation outcomes.  Nonetheless, 
it is possible that use of e-cigarettes will undermine quitting (though this would be contrary to existing literature).  
At the end of the study, participants will be advised to stop using all tobacco products, including e-cigarettes. 
 
Diversion of e-cigarettes  
We will strongly advise participants that they are not to share the study product with others, and that they should 
store the product in a secure area that is out of reach of children and pets. We cannot directly assess any 
diversion/uptake from the perspective of adolescents, since that would require separate consent, and is a 
separate research question.   
 
Confidentiality 
We will use the participant’s name only on the screening and informed consent documents and these will be 
kept in a locked file, to be kept centrally at our study office, or electronically in Redcap.  Copies of informed 
consent will be kept by research personnel under lock and key, or on recap when collected electronically. When 
consent is collected electronically, our study team has a combination laptop/tablet that will be used for the 
eProcess. No information will be stored locally on the laptop/tablet; all information will be stored securely in 
REDCap if captured electronically. The HIPAA form can be signed on paper or electronically. For the electronic 

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process, all pages of the approved HIPAA document will be uploaded into REDCap, using a SCTR-developed 
template and procedures, for review by the participant. Instead of signing on paper, a participant will enter his/her 
name, date, and sign electronically (with mouse or finger) in REDCap. Each participant will still receive a paper 
copy of the "Notice of Privacy Practices" and each signed HIPAA can be downloaded from REDCap as a PDF. 
These procedures will be done on our research team's combination laptop/tablet, but no data will be stored on 
the laptop/tablet; all data will be stored securely in REDCap. 
The research materials will become part of the modern record keeping facility of the Institute of Psychiatry, which 
will minimize risks to the privacy of participants. All interviews, records, charts, rating scales, and other patient 
information will be kept in locked files at the Cancer Control Program, with limited access to the study personnel. 
All database files will include password protection to further ensure confidentiality. 
 
3. 
Potential Benefits of the Proposed Research to the Participants and Others  
This study is not likely to offer any direct benefit to the participants in the study. 
 
4.   Importance of the Knowledge to be Gained 
In an ever-changing marketplace of tobacco-produces and nicotine-delivery devices, e-cigarettes are arguably 
the most popular new products available to smokers.  The most important question about e-cigarettes is whether 
it will have a positive or negative impact on public health. The impact on public health is largely dependent on 
whether e-cigarettes reduce combustible cigarette use. This study will provide information about whether one e-
liquid characteristic will impact reinforcement value of e-cigarettes among current combustible cigarette users.  
 
 

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Data and Safety Monitoring Plan 
All participants entering into the study will be closely supervised by the research staff during the study 3-
week study period. Providing e-cigarettes to smokers over a short sampling period incurs minimal risk, with no 
invasive procedures. Cessation resources will be provided to all participants upon end of study procedures. The 
PI will directly monitor all aspects of study procedures, including recruitment, assessment, and test sessions.