Effects of Nicotine Salt Aerosol on Cigarette Smokers
Phase: NA
Conditions: Electronic Cigarette Use
Sponsor: Eastern Virginia Medical School

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“Effects of Nicotine Salt Aerosol on Cigarette Smokers” 
Institutional Review Board Study Protocol 
 
Investigators and Co-Investigators 
Paul T. Harrell, Ph.D., Division of Community Health & Research, Department of Pediatrics, 
Eastern Virginia Medical School 
Laurie Wellman, Ph.D., Biorepository Director, Department of Pathology and Anatomy, Eastern 
Virginia Medical School 
Julius O. Nyalwidhe, Ph.D., Associate Director, Leroy T. Canoles, Jr. Cancer Research Center, 
Eastern Virginia Medical School 
Andrew D. Plunk, Ph.D., Division of Community Health & Research, Department of Pediatrics, 
Eastern Virginia Medical School 
Thomas Eissenberg, Ph.D., Co-Director, Center for the Study of Tobacco Products, Department 
of Psychology, Virginia Commonwealth University 
Alison B. Breland, Ph.D., Co-Director, Center for the Study of Tobacco Products, Department of 
Psychology, Virginia Commonwealth University 
 
Background: Cigarette smoking continues to be the greatest preventable cause of death in the 
US, responsible for more deaths per year than illegal drugs (including opioids), alcohol, guns, 
car accidents, and HIV combined (Mokdad et al., 2004; Seth et al., 2018; US Department of 
Health and Human Services, 2014). Despite considerable declines in smoking, projections 
suggest that over 5 million youth, or 2 out of every 27 children alive in the US today, will die 
prematurely from cigarette smoking (US Department of Health and Human Services, 2014). 
Cigarette smoking is a health disparity issue, with higher rates among Native Americans, 
multiracial individuals, and those with less education and lower income (Wang et al., 2018). The 
combustible cigarette is an unreasonably dangerous, defective product, killing half of all long-
term users (Gray and Boyle, 2000; Peto et al., 1992; Proctor, 2013; Yang, 2018). Most smokers 
report wanting to quit, but are unable to maintain abstinence (CDC, 2011). Quit rates can be 
enhanced by Nicotine Replacement Therapies (NRT) and other pharmacotherapies. In clinical 
trials, NRT performs superior to placebo with quit rates of 18-31% (Fiore et al., 2008). However, 
among the general population, many do not use NRT. Among those who do, only 5 to 15% are 
able to quit (Curry et al., 2003), partially because the majority of NRT users discontinue use 
early, largely due to dissatisfaction with NRT (Fiore et al., 2004; Shiffman et al., 2002; Wiggers 
et al., 2006). The development of a safe method of nicotine delivery that is appealing to 
cigarette smokers has potential to be a major public health advancement. 
Electronic nicotine delivery systems (ENDS) aerosolize liquid nicotine that the user 
inhales in a process similar to cigarette smoking. ENDS are considered tobacco products under 
US law as long as they include plant-derived nicotine and are not marketed with therapeutic 
intent (Sottera, Inc v. FDA, 627 F.3d 891, DC Cir. 2010). Although many ENDS deliver nicotine, 
flavor additives, and other potentially addictive or harmful chemicals, they do not burn tobacco, 
a process that yields an estimated 7000 chemicals, including at least 70 carcinogens (Douglas 
et al., 2018; US Department of Health and Human Services, 2014). Former smokers who use 
ENDS rate ENDS as less risky, better tasting, more satisfying, and better at reducing craving, 
negative affect, and stress than FDA-approved NRT (Harrell et al., 2015). Smokers who switch 
completely to ENDS substantially reduce their exposure to numerous toxicants and carcinogens 
present in combustible cigarettes, thus improving their health in the short term (Goniewicz et al., 
2014; Harrell et al., 2014). In a 2018 report reviewing the scientific evidence, the National 
Academies of Sciences Engineering and Medicine (NASEM) determined there is “conclusive 
evidence that completely substituting e-cigarettes [ENDS] for combustible tobacco cigarettes 

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reduces users’ exposure to numerous toxicants and carcinogens present in combustible 
tobacco cigarettes (NASEM, 2018).” 
From 2015-2017, an ENDS marketed as “Juul” went from being a little-known brand with 
low sales into being the largest retail ENDS brand in the US, lifting sales of the entire ENDS 
category (Huang et al., 2018). Juul differs from many other ENDS in the use of nicotine salts 
(protonated nicotine). Nicotine salts may play an important role in the effects of Juul, but this 
has not been systematically assessed. Preliminary research on Juul devices suggest they may 
be safer than other ENDS devices (Reilly et al., 2018), which, as noted previously, appear 
substantially safer than cigarette smoking (National Academies of Sciences Engineering and 
Medicine, 2018). 
 
Research questions: Does the use of nicotine salts (protonated nicotine) differ from regular 
(unprotonated) nicotine or own-brand cigarette in: 1) cigarette craving reduction; 2) withdrawal 
symptoms reduction; and 3) appeal as measured on a variety of dimensions regularly assessed 
for tobacco products? 
Study design: 
 
Laboratory space: Laboratory space in Williams Hall contains filtration devices to remove 
any secondhand smoke or aerosol (from cigarettes or ENDS). In consultation with Thomas 
Eissenberg at Virginia Commonwealth University and S. Doug Martin, Executive Director of 
Facilities at EVMS, approximately $50,000 was spent designing and equipping these rooms. 
This laboratory was designed for smoking research and includes a ventilation system so that 
others are not exposed to second-hand smoke unduly.  
Sample size: A total of 30 participants are planned to allow for statistical power to 
examine differences (Within-Subjects) in the physiological and subjective effects of the 
products. Using a Repeated Measures Within-Subjects design, this will allow for detection of a 
large effect size (Cohen, 1992; Faul et al., 2009). We may consent up to 75 participants in order 
to obtain 30 participants who complete the entire study.  
Recruitment: We will recruit current cigarette smokers using a recruitment database 
submitted separately (PR-2871-EVMS). Potential participants will find this recruitment database 
via advertising on Craigslist, newspapers, internet forums, flyers in the local area, and local 
clinics. There is a flyer specifically for this study that will direct individuals to participate in the 
registry online questionnaire Screening data will be obtained from this online questionnaire. See 
separate protocol submitted. Screening data will be compared against the inclusion and 
exclusion criteria listed below to determine if participant is eligible for this study. Eligible 
participants will be contacted to provide more information about the study. Participants will be 
told they can smoke as normal for their first visit, but must abstain for 12 hours (typically 
overnight) before the 3 other visits. Those who meet screening criteria and are still interested in 
the study will be scheduled to come in for laboratory visits. 
Inclusion Criteria: All participants must be healthy (determined by self-report), between 
the ages of 18-55, willing to provide informed consent, and willing to attend the EVMS lab 4 
times and abstain from smoking for 12 hours (typically overnight) for 3 of these visits. 
Participants must smoke at least 10 cigarettes per day (i.e., be regular cigarette smokers). Self-
report of smoking will be bioverified on the initial screening visit. 
Exclusion criteria: Individuals will be excluded based on a self-reported history of (1) 
unstable or significant current medical condition (recent heart attack or other heart conditions 
including high blood pressure); (2) severe immune system disorders (uncontrolled HIV/AIDS, 

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unstable multiple sclerosis symptoms), (3) respiratory diseases (exacerbations of asthma or 
COPD, require oxygen, require oral prednisone), kidney (dialysis) or liver diseases (cirrhosis) or 
any medical disorder/medication that may affect participant safety, study outcomes, or 
biomarker data will be excluded. Individuals who report more than 25 days of alcohol use in the 
past 30 days or more than 15 days of marijuana use in the past 30 days will be excluded. 
Individuals with past month use of cocaine, opioids, benzodiazepines, and methamphetamine 
will be excluded. Participants with current, diagnosed psychiatric conditions will also be 
excluded. Participants will be excluded for any use of an ENDS product in the past 30 days, or 
any report of daily use of ENDS for a week or more. Regular use of ENDS is excluded as we 
are interested in understanding the effect of these liquids on smokers who are relatively naïve to 
ENDS use so that prior experience does not obscure laboratory experience of use.  
 Initial laboratory screening visit: Potential participants will be informed prior to this 
session to provide a list of current prescription medications or bring in their medication bottles in 
with them to confirm any medications listed on the screening survey.  When participants arrive, 
air filters will be on in the laboratory space in order to encourage familiarity with the noise during 
laboratory sessions. Potential participants will be provided with a copy of the informed consent 
document. (See attached.) Research Assistants will review the informed consent document with 
the potential participant and answer any questions. If still interested, the form will be signed and 
a copy provided. Next, participants will breathe into a Carbon Monoxide (CO) monitor. 
(Cigarette smoking involves the inhalation of Carbon Monoxide.) In addition, participants will 
provide a saliva sample to test for cotinine, a metabolite of nicotine. If participants do not have a 
CO level of at least 15 ppm and a cotinine test strip level of at least 3 (indicating 100-200 ng/ml 
cotinine), then they will not be allowed to continue with the study. These results would indicate 
that they are not regular cigarette smokers. Female participants will also provide a urine sample 
using the nearby restroom. A pregnancy test strip will be used. If the test does indicate 
pregnancy, the result will be discussed with the participant and she will be urged to seek 
prenatal medical care. Information will be provided about where to receive such care (either with 
their regular physician or at a free clinic). Otherwise, staff will next assess heartrate and blood 
pressure using an arm blood pressure cuff and a pulse oximotor. Participants will deemed 
ineligible at screening if their resting heart rate (HR) exceeds 110 beats per minute (bpm), 
systolic blood pressure (BP) exceeds 140 mm Hg, or diastolic BP exceeds 100 mm Hg. If they 
do demonstrate eligibility (regular cigarette smoker, not pregnant, acceptable vital signs), they 
will complete a W9 to facilitate payment processing and complete baseline questionnaires 
(DemographicPersonalHealthInfor, PennState, Fagerstrom, BaselineExpectancies) on the 
REDCap system. (See attached document.) Finally, following completion of the baseline 
questionnaires, the Research Assistant will review with the participant the next 3 scheduled 
visits and emphasize the need to abstain from smoking and nicotine products for 12 hours 
(typically overnight) and pass testing before their next visit.  
Smoking/”Vaping” Lab Sessions: The sessions will occur no more than 2 days per week and 
will be separated by at least 48 hours. The approximate total time that participants will be in the 
laboratory is 12.5 hours (30 minutes for screening and 12 hours for 3 4-hour long sessions). 
This does not include the 12 hours before each session that we ask participants to abstain from 
smoking. 
Note: Most questionnaires are completed via computer in the laboratory. The only exception 
for subjects is the glms, administered via pen & paper. EnrollmentInformation, 
SessionInformationSheet, BiochemicalTestResults, and the SaltStudySessionSheet are 
completed by Research Staff. 

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The session will begin with the participants’ self-report of their last cigarette, CO expired air 
testing, and cotinine saliva testing. If the last cigarette smoked was within 12 hours or CO is 
above 10 ppm, the participant will be told they need to reschedule for another time and must 
abstain for 12 hours before the next visit. If there are 2 consecutive sessions indicating non-
compliance, the participant will be disqualified from the study and paid as outlined in the 
compensation section. If participant’s tobacco abstinence is bioverified, they will begin a 1-hour 
waiting period to ensure nicotine abstinence. Nicotine abstinence (e.g., ENDS, NRT) 
unfortunately cannot be bioverified quickly. Blood analyses at VCU CSTP have indicated high 
rates of lack of compliance, but much better data in protocols that involve a 1-hour waiting 
period in the lab. After this waiting period, the participant will continue on with physiological 
equipment attachment and catheter insertion. Physiological equipment (Criticare 506DNP3R, 
includes blood pressure cuff and SpOv2 sensor) will continuously measure BP/HR by trained 
Research Assistants or the study PI.   
Self-report measures for tobacco product evaluation: Self-report measures were based on 
established batteries used by VCU CSTP and others (e.g., (Spindle et al., 2018). Four of the 
five measures use a computerized visual analog scale (VAS) containing a word/phrase in the 
middle of a horizontal line with “not at all” on the far left and “extremely” on the far right. 
Participants will record responses by clicking on any point on the line, with scores expressed as 
a percentage of total line length (i.e., 0-100). Nicotine abstinence symptoms will be assessed 
via the Hughes-Hatsukami withdrawal scale (Hughes and Hatsukami, 1986). Craving will be 
assessed by the Tiffany Drobes-QSU Brief consisting of 10 items involving 2 factors: (1) 
intention to smoke a cigarette and (2) anticipation of relief from abstinence symptoms by 
smoking (Tiffany and Drobes, 1991). Additional VAS questionnaires will include the Direct 
Effects of Nicotine (Cappelleri et al., 2007; Evans et al., 2006) and the Direct Effects of ECIG-
use scales (10 items; adapted from (Foulds et al., 1992; Pickworth et al., 1994). The fifth 
questionnaire (the general labeled magnitude scale, gLMS; adapted from (Green et al., 1993) 
will assess the flavor sensation, harshness/irritancy, and throat hit provided by the tobacco 
product using a category-ratio scale with 7 semantic labels ranging from (0) “no sensation” to 
(100) “strongest imaginable sensation of any kind.” The questionnaire will be administered via 
pen and paper after the two tobacco product use bouts in each session.  
An additional questionnaire will assess changes in expectancies after product use. The 
questionnaire uses items from the Smoking and Vaping Consequences Questionnaires – Brief 
(Hendricks et al., 2015) as well as the Comparing E-Cigarettes and Cigarettes questionnaire 
(Hersberger et al., 2017). Responses range from “completely unlikely” to “completely likely”. 
Depending on which product was assigned for the session, either the vaping (VCQ-B) or 
smoking (SCQ-B) items will be used.  
Product consumption: The participant will use one of the following three products: 
o Own brand cigarette 
o ENDS: Subox Mini C with 18 mg nicotine salt (protonated) 
o ENDS: Subox Mini C with 18 mg nicotine regular (unprotonated) 
The product that is used will be based on pre-established Latin-square order procedure 
(similar to random assignment) to avoid any order effects. For example, a participant may use 
the Subox Mini C with 18 mg regular (unprotonated) nicotine the first session, own brand 
cigarette the second session, and Subox Mini C with protonated nicotine on the last session. 
Participants will use a different product each session and use all 3 products by the completion of 
the study. 

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The cigarette will be purchased at a local retailer based on the participant’s self-report in the 
baseline questionnaire of cigarette brand typically smoked. Smokers are often very loyal to a 
brand, so this will allow for a control condition of understanding standard reactions to cigarette 
smoking. The ENDS device will be a Subox Mini C, as recommended by VCU collaborators, 
who have had prior and current success using this device. The Subox will include a solution with 
either 18 milligrams/milliliter (mg/mL) of nicotine salt (protonated nicotine) or 18 mg/mL of 
regular (unprotonated) nicotine. The flavor will match their usual brand of cigarettes (tobacco-
flavored or menthol-flavored). 
Using a stopwatch, research assistants will instruct participants to take one puff of the 
tobacco product (cigarette or ENDS) every 30 seconds for 5 minutes. Participants will also 
complete another set of questions involving evaluation of the product consumed and nicotine 
withdrawal symptoms. Next, participants will be given 90 minutes to use ad lib, i.e., as much as 
desired. Smoking/vaping sessions will be videorecorded to allow for measurement of puff 
topography (puff duration, inter-puff interval, etc.). Final questionnaires will be completed. The 
participant will then be reminded of their schedule for the next session, if another session 
remains. 
 
Experimental session timeline (approximate times): 
 
● Participant arrives, CO test to confirm tobacco abstinence 
 
● 1-hour waiting period (to help ensure nicotine abstinence), then the rest of the session 
will begin, as described below 
 
● 0 Hr 0 min - Attach physio equipment, insert catheter, begin questionnaire administration 
 
● 0 Hr 30 min - record Carbon Monoxide 
 
● 0 Hr 35 min - 10 puffs from product (30s inter-puff interval) 
 
● 0 Hr 45 min Record Carbon Monoxide, 2nd set of questionnaire administration 
 
● 1 Hr 05 min record Carbon Monoxide, 3rd set of questionnaire administration, ad lib use 
period begins (undirected use, participant can use as little or as much as they like) 
 
● 2 Hr 35 min (ad lib period ends) 
 
● 2 Hr 40 min Record Carbon Monoxide, 4th set of questionnaires 
 
● 2 Hr 45 min Remove Catheter, Stop Physio Monitoring 
 
● Payment 
 
● Reminder of next appointment or thank participant for completion of study 
 
Compensation: Participants will complete a W9 at their initial screening visit. Participants will 
receive $75 after completing the first session, $100 after completing the second session, and 

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$125 after completing the third session (not counting the first lab visit for screening), resulting in 
a total payment of $300. If a participant chooses to leave the study early, he or she will keep the 
amount earned up to that point. In addition, if a session must be discontinued for reasons 
beyond the control of the participant (e.g., difficulties with catheter insertion), the participant will 
be paid for the time spent complying with study conditions before the session began ($15) and 
also the time spent in the laboratory ($15/hour). The compensation amount of $300 was chosen 
because of the number of hours that participants are asked to be in the laboratory (12.5 hours), 
which does not include the 12 hours that we ask them to abstain from tobacco products prior to 
each lab session (which can be very unpleasant for regular cigarette smokers). Thus, the 
compensation is felt to be appropriate. 
 
Risks to subjects: The protocol uses established methods and procedures and involves only 
minimal risks to participants. Twelve hours of tobacco abstinence may cause mild discomfort 
and nicotine abstinence symptoms, but is not medically dangerous. Symptoms may include: 
irritability, anxiety and restlessness, excessive hunger, difficulty concentrating, and sleep 
disturbance. The risks of using ENDS/tobacco products/nicotine are routine for the target 
population. As participation involves consumption of widely available, legal, over-the-counter 
products that can reduce the harm associated with their current nicotine use, they do not involve 
significant risks to participants. Risks of nicotine use by nicotine-naïve individuals include 
sweating, lightheadedness, dizziness, nausea, vomiting, and nervousness. These effects are 
unlikely in individuals who use nicotine-containing products regularly. In addition, some people 
who use e-cigarettes have reported experiencing seizures. Some of these individuals reported a 
prior history of seizures or using other substances at the same time as their e-cigarette. In many 
cases e-cigarette use has led to respiratory illnesses such as difficulties breathing, shortness of 
breath and/or chest pain before hospitalization.  In some cases, e-cigarette use has led to 
death, and the Centers for Disease Control and Prevention has advised people to stop vaping. 
In some cases symptoms of mild to moderate gastrointestinal illness such as vomiting, diarrhea, 
or fevers or fatigue have been reported. 
 
It is unlikely that the questionnaires will pose any potential risk or discomfort (no 
sensitive questions are asked). Sessions are relatively short and can be completed at the 
participants' own pace. With any research, there is always risk of loss of confidentiality. 
However, the risk is very low for the reasons listed below. 
 
Steps taken to minimize risks / harms: Participant safety and rights will be protected by highly 
trained staff. Participants will be informed of the potential symptoms of nicotine 
abstinence/withdrawal and will be told they are free to leave the study at any time.  
 
 
An additional set of respiratory health questions will be administered by the nurse and/or 
RA to the participant at screening and then again prior to beginning each session. This will 
essentially minimize risk as these questions will serve as a supplementary screening tool which 
will help to determine whether the participant is in good health or ineligible for the study.  These 
questions are included as an attachment (Additional Respiratory Questions). If 1 or more 
symptoms have increased since the participant’s last visit, symptoms will be flagged for review 
by the medical monitor and will need to be reviewed prior to the participant’s next session. If 3 
or more symptoms have increased since the last visit, the medical monitor will need to be called 
in before the session can proceed. 

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In addition, non-invasive computerized monitoring equipment allows for minute-by-
minute, real time monitoring of participants’ heart rate (HR) and blood pressure (BP). Research 
personnel will be instructed to alert biorepository staff if HR exceeds 120 beats per minute, if 
systolic BP exceeds 150 mm Hg, or if diastolic BP exceeds 100 mm Hg. If HR and BP become 
elevated, research personnel will be instructed to alert the PI and the session will be stopped. 
The medical monitor will be available for consult during study sessions if needed. If systolic BP 
exceeds 180 or diastolic BP exceeds 120, 911 will be alerted. Emergency medical coverage is 
available across the street. Emergency medical care is available of the expense of the subject 
and/or their insurance. If systolic BP is between 150-179, diastolic is between 100-119, or HR is 
over 120, the subject will be monitored until these vital signs are reduced. If this does not occur 
within 1 hour, 911 will be called. These are anticipated to be very unlikely occurrences, as we 
exclude participants with resting HR above 110 BPM, systolic above 140, and diastolic above 
100, and they are regular smokers in withdrawal consuming levels of nicotine that should be 
within or below their standard range.  
 
In regards to nicotine abstinence symptoms, the products administered will likely 
alleviate these risks. Participants will be provided with water at all times. 
 
Participants will be able to view all questionnaires used in sessions before attending 
sessions, and will be informed of the length of each session. If participants do not want to 
answer the questionnaires, or feel the length of the sessions are too long, they can choose to 
not participate. 
 
Data Storage: Risk of loss confidentiality will be minimized by only connecting participant data to 
participants by alpha numeric identifiers. These data can only be linked with identifiable 
information by using a key that is stored in locked cabinets. REDCap is a secure web 
application that is approved for compliance with 21 CFR Part 11, FISMA, and HIPAA. (See 
https://www.project-redcap.org ) Documents completed on paper will be secured in a file cabinet 
in a locked lab room. Research staff will not release any participant study information to others 
without signed written approval from a participant. Video recordings will only be stored locally 
and will be deleted 5 years after completion of the study.  
 
Data are identified by alphanumeric code only. Participants’ names are not directly 
linked to data. An alphanumeric code is assigned to each participant when they provide 
informed consent, and the numeric part of the code relates to the order in which the individual 
consented. The alphanumeric code is used in place of identifying information on all subsequent 
documents/data forms. A key is maintained so that we can demonstrate that a particular data 
set is associated with a particular consent document. The key and consent documents are kept 
separately from one another and separate from all data. Access to the key and the consent 
documents is restricted to study investigators and staff who conduct the study with the 
participants, so are already familiar with the participants and observe the participants as data 
are collected. Data keys will be destroyed 5 years after completion of the study. 
 
Data Analysis: Analysis will begin with cleaning, outlier assessment, and normality assessment. 
Descriptive statistics will be examined for all variables. Similar to prior research (e.g., (Harrell et 
al., 2016; Spindle et al., 2018), Repeated Measures Analyses of Variance (ANOVAs) will be 

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used for each dependent variable. There are three within-subject tobacco products (own-brand 
cigarette, ENDS with unprotonated nicotine, ENDS with protonated nicotine) and four within-
subject time points (pre-use, post-directed 10 puff session, pre-ad lib use session, post-ad lib). 
Three (condition) x four (time) repeated measures ANOVAs will assess plasma nicotine and 
heart rate (HR). Questionnaire items (or craving factors) will be examined individually using 
separate ANOVAs. Analyses conducted on the Hughes-Hatsukami Withdrawal scale, the 
Tiffany Drobes Questionnaire of Smoking Urges, and the Direct Effects of Nicotine (DEN) have 
4 levels of time. The Direct Effects of E-cigarettes scale, unlike the DEN, only assesses 
reactions to the tobacco product and thus will have only 2 levels of time. Videorecordings will be 
evaluated via established methodology (Blank et al., 2009). 
Any violations of sphericity will be adjusted using Huynh-Feldt corrections. In order to 
maintain statistical power and limit type 1 error for plasma nicotine, HR, and subjective effects, 
planned contrasts (paired samples t-tests) will be conducted across conditions at the two time 
points immediately after each use bout (e.g., each post-use session). At these two post-use 
timepoints, the mean value for each outcome measure in the protonated nicotine condition will 
be compared to the corresponding mean values in the unprotonated nicotine and cigarette 
conditions. Because these comparisons are non-orthogonal, a Bonferroni correction will be 
applied (Keppel, 1991).   
 
 

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