Gender Differences in Standardized Research E-Cigarette (SREC) Product Use, Acceptability, Reinforcement, and Nicotine Dependence Symptoms
Phase: NA
Conditions: Cigarette Smoking-Related Carcinoma
Sponsor: M.D. Anderson Cancer Center

Protocol 2018-0794 
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Protocol 2018-0794 
Gender Differences in Standardized Research E-Cigarette 
(SREC) Product Use, Acceptability, Reinforcement, and Nicotine 
Dependence Symptoms 
PI: Jason D. Robinson, PhD 
Medical Monitor: Maher Karam-Hage, MD 
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Table of Contents 
A. 
Objectives .............................................................................................................................. 3 
B. 
Significance and Innovation ................................................................................................... 3 
Significance ............................................................................................................................... 3 
Innovation .................................................................................................................................. 4 
C. 
Approach ........................................................................................................................... 4 
Justification and Feasibility ........................................................................................................ 4 
Review of Relevant Literature ................................................................................................ 4 
Preliminary Studies ................................................................................................................ 7 
D. 
Research Design and Method ........................................................................................... 8 
Overall structure of the study team ........................................................................................... 8 
Recruitment and Retention Plan ............................................................................................... 9 
Participants .............................................................................................................................. 10 
Procedures .............................................................................................................................. 10 
Statistical Approach & Expected Outcomes ............................................................................ 18 
Potential Problems & Alternative Strategies ............................................................................ 20 
E. 
Protection of Human Subjects ............................................................................................. 22 
Risks to the Subjects ............................................................................................................... 22 
Human Subjects Involvement, Characteristics, and Design ................................................ 22 
Study Procedures, Materials, and Potential Risks ............................................................... 22 
Adverse Events and Serious Adverse Events ..................................................................... 22 
Specific Instructions for Adverse Events Recording ............................................................ 24 
Serious Adverse Event Reporting (SAE) Reporting ................................................................ 24 
Reporting to FDA: .................................................................................................................... 25 
Reporting to NIDA: .................................................................................................................. 25 
Adequacy of Protection against Risks ..................................................................................... 25 
Informed Consent and Assent ............................................................................................. 25 
Protection against Risks ...................................................................................................... 26 
Vulnerable Subjects ............................................................................................................. 26 
Potential Benefits of the Proposed Research to Research Participants and Others ............... 27 
Importance of the Knowledge to be Gained ............................................................................ 27 
F. 
Inclusion of Women ............................................................................................................. 27 
G. 
Inclusion of Minorities ...................................................................................................... 27 
H. 
Inclusion of Children ........................................................................................................ 27 
I. 
STUDY PRODUCT INVENTORY Control ........................................................................... 28 
J. 
Literature Cited .................................................................................................................... 29 
 
 
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A. OBJECTIVES 
The objective of this National Institutes of Health (NIH)-funded proposal is to 
characterize potential gender differences when switching from combustible cigarettes (CCs) to 
nicotine and placebo experimental electronic cigarettes, the National Institute on Drug Abuse's 
(NIDA) Standard Research E-Cigarettes (SRECs). We propose the following aims: 
Aim 1. To characterize the effects of switching to nicotine vs. placebo SRECs from 
CCs on product use, product acceptability, reinforcement, and nicotine dependence 
symptoms among adult daily CC smokers. We hypothesize that nicotine-containing SRECs 
(SREC-NIC; 5%; ~59 mg/ml nicotine) will lead to decreases in CC-specific measures, 
decreases in withdrawal symptoms, and increases in electronic cigarette (EC)-specific use, 
acceptability, and reinforcement compared to placebo SRECs (SREC-PLA; 0 mg/ml nicotine). 
The primary outcome measure for Aim 1 will be CPD. 
Aim 2. To characterize the differences between male and female CC smokers 
when switching to nicotine vs. placebo SRECs from CCs on product use, product 
acceptability, reinforcement, and nicotine dependence symptoms. We hypothesize that 
men, compared to women, will show more product use, acceptability, and reinforcement with 
SREC-NIC, relative to SREC-PLA, but that women will show overall less SREC use, and less 
CC reduction, than men. The primary outcome measure for Aim 2 will be CPD. 
Exploratory Aim: To characterize which factors moderate or mediate the effects of 
switching to nicotine and placebo SRECs from CCs among male and female CC smokers. 
In an exploratory fashion, we will examine whether baseline factors, including prior EC 
exposure/ flavor preference, menthol CC preference, nicotine dependence, exposure (nicotine, 
cotinine, anabasine), hormonal contraception use, age, and race/ethnicity, moderate the Aims 1 
& 2 hypotheses. We will also examine the mediating effects of product satisfaction, menstrual 
phase, and smartphone-collected withdrawal, craving, affect, product use on these hypotheses. 
B. SIGNIFICANCE AND INNOVATION 
Significance 
This project will provide NIDA with critical information on potential gender differences 
during the switching to nicotine and placebo Standard Research E-Cigarettes (SRECs) from 
combustible cigarettes (CCs) in terms of product use, product acceptability, reinforcement, and 
nicotine dependence symptoms among adult daily CC smokers. Additionally, this project is 
significant because it will examine the impact of SREC use separately for men and women, who 
are known to respond to CC products differently on measures of product use, product 
acceptability, reinforcement, and nicotine dependence symptoms. Ultimately, this proposal will 
help inform NIDA and the scientific field the extent to which the SRECs are useful models of 
electronic cigarette (EC) use for both men and women. 
While ECs are growing rapidly in popularity 1, the variety of devices and device 
components 2 make evaluating ECs a "moving target." By commissioning the creation of the 
SREC, NIDA has created a potential "reference" EC that can be used to generate more 
comparable data between studies. While the SREC has nicotine levels comparable to 
commercially popular JUUL products (5%; ~59 mg/ml), the SREC is only available in "tobacco" 
flavor, a flavor which relatively few EC users prefer, particularly among young adults 3. Our 
proposal will investigate factors that will the potentially moderate or mediate SREC use and 
acceptability.  
In terms of gender differences, there have been relatively few studies that have 
examined them in relation to EC use and acceptability, particularly with regards to specific EC 
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characteristics. However, there is evidence from CC users that suggests that there are gender 
differences in terms of what nicotine product factors influence use, acceptability, reinforcement, 
and dependence. For example, men have been found to be more sensitive to nicotine content 
than women e.g., 4-6, which suggests that male CC smokers may be more likely to use and 
accept EC products that produce nicotine content similar to CCs. Women, compared to men, 
have been found to be more influenced by sensory aspects of smoking 7 and to have 
expectancies about smoking's role in controlling negative affect 8 and weight maintenance 9. 
Thus, these findings suggest that there may be characteristics of the SREC that differentially 
impact their use and acceptability, by gender. 
Scientific Premise 
Justification for our research is based on the following observations and hypotheses 
from the EC and tobacco literatures: (1) EC variety makes it a moving target in need of a 
standard model, (2) EC prevalence is increasing and is subject to dual use, and (3) male and 
female CC smokers may have different responses to ECs. Additionally, our preliminary studies 
provide support for the feasibility of our approach. These contentions are developed in the 
Justification and Feasibility section, below.   
Innovation 
This project is innovative because it will be among the first to evaluate gender 
differences in the effect of switching from CCs to use of SRECs adult smokers using a 
prospective clinical trial. Additionally, we will take a multi-level approach to distinguishing 
between the effects of SREC (either nicotine [5%; ~59 mg/ml nicotine; SREC-NIC] or placebo [0 
mg/mL nicotine; SREC-PLA]) from usual brand (UB) CCs on the domains of product use 
(cigarettes/day [CPD], nicotine, cotinine, and a tobacco-specific minor alkaloid [MAs; anabasine, 
nicotelline]), product acceptability (explicit product liking, implicit product liking, perceived 
product harm, and product-specific expectancies [i.e., perceived outcomes of product use]), 
product reinforcement (relative reinforcing efﬁcacy [RRE]), and nicotine dependence symptoms 
(CC dependence, EC dependence, nicotine withdrawal, craving, and affect). The positive impact 
of this study will be to provide scientific information on whether the SREC is found to be used 
and accepted by CC smokers, whether it reduces reinforcement and nicotine dependence 
symptoms among CC smokers, and whether it could serve as a good model of future EC 
research for male and female users. 
C. APPROACH 
Justification and Feasibility 
Review of Relevant Literature 
 EC variety makes it a moving target in need of a standard model. ECs (also known 
as electronic nicotine delivery systems; ENDS) were introduced in the US in 2007. Public 
awareness among adults had grown to over 75% by 2012, and 88% of current smokers were 
aware of them 10. The technology is rapidly changing and many types of ENDS are available 2. 
NIDA's Standard Research E-Cigarette (SREC), a second generation-type device, is designed 
to provide a standardized platform for studying ECs 11. This proposal is in response to a 2-year 
FOA (PAR-18-220) to encourage evaluation of the SREC. 
EC prevalence is increasing and is subject to dual use. In a recent and 
comprehensive survey assessing use, prevalence, and demographics, Zhu and colleagues 10 
found that the prevalence of ever and current use of ECs was highest among adults who were 
current smokers (32.2% & 6.3%, respectively) and recent former smokers (26.8% & 6.1%, 
respectively), but negligible among long-term former smokers (2.4% & 0.2%, respectively) and 
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never smokers (1.0%, & 0%, respectively). In a study of nearly 6,000 people from the US, UK, 
Canada, and Australia, Adkison and colleagues 1 found that nearly half of the sample were 
aware of EC products, and the prevalence of trying ECs was higher among younger, nondaily 
smokers with a higher income who perceived such products as less harmful than traditional 
cigarettes. Current EC use was highest among nondaily and heavy smokers (>20 CPD) 1. Dual 
use appears to be most common among current smokers who were considering quitting in 6 
months 12, as well as among young adult smokers aged 18-24 13. A sizeable number of EC 
users continue to smoke combustible cigarettes 12,14, with nearly half reporting EC use in 
situations where they can’t smoke 10. Most smokers who report using ECs in the last 30 days do 
not report using them daily 10. In a recent internet survey, dual users reported nearly a 50% 
reduction in consumption of combustible cigarettes from baseline, although such changes were 
not maintained at 1 year 15. Thus, preliminary evidence suggests that most daily CC smokers 
who try ECs are not likely to completely switch to them and instead become dual users.  
Newer Generation IV e-cig products with higher nicotine content, such as the 
NIDA SREC, may be more reinforcing to adult smokers. Several studies that have surveyed 
the real-world effectiveness of using e-cigs to aid smoking cessation attempts have found e-cigs 
may reduce CC consumption or promote abstinence, although results are mixed, and can result 
in dual use of both products 16-20.The reason that smokers may not be able to switch to 
exclusive e-cig use may be due to many commercially available e-cigs not being able to deliver 
as much nicotine as CCs. While 2nd generation e-cigs have been found to increase blood 
plasma nicotine levels compared to 1st generation e-cigs 21,22, studies suggest that most e-cigs 
may not be capable of increasing blood plasma levels as rapidly as smoking CCs 23,24. Most e-
cig users reported using between 4 mg/ml and 24 mg/ml nicotine concentrations 25. Farsalinos 
and colleagues 21 found that, after 5 minutes of use, an 18 mg/ml nicotine e-cig delivered 25 to 
33% of the blood nicotine levels as smoking one CC, although blood plasma nicotine may 
become comparable to those attained by smoking CCs over a period of 30-75 minutes 21,26. 
Preliminary data suggest that the high-dose nicotine salts in generation IV e-cigs such as the 
NIDA SREC (i.e., 59 mg/ml) produce nicotine pharmacokinetics (i.e., Cmax and Tmax), 
satisfaction, and craving reduction comparable to CCs among adult CC smokers 27. Thus, we 
believe that offering smokers high nicotine-dose e-cigs, such as the NIDA SREC, may promote 
their use and acceptability, and reduce the use of CCs. 
The NIDA SREC may not be as appealing as commercial ECs due to a lack of 
flavor options. The SREC is currently available in one flavor, tobacco, which may not appeal to 
those with prior EC experience or a flavor preference. Most who have tried ECs or who use 
them routinely prefer flavors other than tobacco, with the most popular flavors being fruit flavors 
and candy/dessert flavors, with tobacco flavoring being among the least preferred flavor 3. 
Flavor preference is particularly strong among young adults 28, as 82.2% of current EC users 
reported using flavored (i.e., non-tobacco-flavored) ECs, compared to 69.3% of older adults 3. 
Additionally, NIDA SRECs are unavailable in menthol flavor, despite the significant number of 
menthol CC smokers, particularly among minority smokers 29. Thus, the availability of only 
tobacco-flavored NIDA SRECs may make them less appealing to CC smokers who have 
established flavor preferences. It is important to evaluate the SRECs among these users in 
order to provide a path for future research. 
Gender differences in nicotine reinforcement and nicotine withdrawal may 
influence EC use and acceptability. There is evidence that men are more influenced by 
nicotine reinforcement than women. Male daily CC users smoke more than women and report 
greater nicotine dependence 30,31. However, even among samples of CC smokers who do not 
differ in smoking amount, men have been found to have higher nicotine levels than women 32, 
possibly due to men puffing 33 and inhaling 34 more than women. Men have been found to self-
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administer nicotine nasal spray more frequently than women 35, use more nicotine gum than 
women 5, and have been found to be more sensitive to CC nicotine content than women during 
a progressive ratio reinforcement task 6. In men, nicotine administration has been found to be 
more effective in reducing withdrawal symptoms than for women 4,5. Perkins 36 has suggested 
that these results suggest that women may be particularly sensitive to the sensory aspects of 
CC smoking, whereas men may be more sensitive to nicotine dosing. He and his colleagues 7 
found that CC olfactory/taste stimuli influenced CC liking and reinforcement more for women 
than for men. Additionally, another study found that acute craving was reduced by denicotinized 
cigarettes in female but not male smokers 37. Taken together, these findings suggest that 
women may be receptive to SRECs to the extent that they mimic or substitute for the sensory 
aspects of nicotine, while men may be receptive to SRECs to the extent that they provide 
nicotine relative to CCs. SRECs, with their single flavor availability, may not be as appealing 
overall to women than to men, while the SREC-PLA may not be as appealing to men as to 
women. 
Men and women may differ in their response to SREC product characteristics. 
Population-based survey studies examining gender differences in EC use have yielded 
equivocal results 38, although one small recent survey study found that female CC smokers who 
took up ECs were less likely to report completely switching to them than male smokers were 39. 
In terms of clinical trials methodology, there have been few published studies that have 
examined gender differences in response to EC exposure among adult CC smokers. A study 
exposing CC smokers to a nicotine-containing first generation "cigalike" ECs in the lab found 
that women rated it as more satisfying than men did 40. In a brief laboratory exposure to ECs 
following 1-hr of CC abstinence, men reported significant reductions in craving following nicotine 
(18 mg) EC use but not to placebo EC use, while women showed no difference by EC dose 41. 
In terms of flavor, there is preliminary evidence that women who were switched to ECs for a 
week with a non-preferred flavor produce lower nicotine concentrations and rate the EC as less 
likeable than men 42, suggesting that EC flavor may be more important to women in terms of EC 
use and acceptability. While these clinical trials studies are few and mainly preliminary, they are 
consistent with the CC literature reviewed above in that they suggest that men are likely to be 
more responsive to EC nicotine content that women, and that women are likely to be more 
influenced by non-nicotine factors, such as EC flavor acceptability and similarity of the EC 
vaping experience to CC smoking. 
Gender differences in product-specific expectations may also influence SREC use 
and acceptability. Some evidence suggests that women have different expectancies (i.e., 
beliefs) about the impact of smoking than men that might reduce their likelihood of switching to 
ECs. For example, female smokers, compared to male smokers, have been found to hold 
expectancies about the weight-controlling benefits of smoking 9, to be more concerned about 
post-cessation weight gain 43, to identify weight gain as the cause for smoking relapse 44, and to 
report reduced motivation to quit smoking due to post-cessation weight gain concerns 45. 
Compared to men, women have been found to have greater expectancies that smoking reduces 
negative affect 8, to report smoking in response to negative affect 46, and to believe that smoking 
cessation will result in increased levels of stress and negative affect 47. Finally, there is some 
evidence that women, compared to men, hold less expectancies about the health benefits of 
quitting smoking 47 and are less motivated to quit because of health benefits 48. The question is 
whether these differences in expectancies exist for EC products. For example, if female 
smokers do not believe that ECs are effective at controlling weight or negative affect compared 
to CCs, they might be less likely to switch to ECs. Likewise, switching would be less likely to 
occur if ECs are not perceived as less harmful than CCs. We will assess for potential gender 
differences in CC and EC expectancies, and evaluate whether EC expectancies measured 
before and after exposure to SRECs mediate SREC use and acceptability. 
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Recent links between vaping and lung injury. Beginning in the summer of 2019, a 
nation-wide outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) was 
brought to the attention of the CDC. In terms of EVALI-related fatalities and lung injury, no 
specific electronic cigarette product has been linked to them, including the products proposed to 
be used here. In fact, recent (1/21/2020) CDC data suggests that this outbreak of lung injury, 
which began around June 2019 and which peaked in September 2019, has been experienced 
primarily by individuals vaping oils containing tetrahydrocannabinol (THC), the primary 
psychoactive ingredient in marijuana 49. The CDC data on 2051 patients with EVALI showed 
that 86% reported vaping THC oils, that 34% reported using THC oils exclusively (i.e., they did 
not vape nicotine), and that 11% reported only vaping nicotine products 49. Many of the samples 
tested by the FDA and other agencies found evidence of adulterants, including vitamin E 
acetate 50. A recent report (12/2019) found vitamin E acetate in the bronchoalveolar lavage fluid 
of all 48 of 51 individuals with EVALI who were tested using isotope dilution mass spectrometry 
methods 51. Additionally, as of 1/27/2020, 90% of those with suspected vape-related lung injury 
in Texas admitted to vaping THC products 52. While this does not exonerate nicotine-only 
vaping, these findings suggest that (a) lung injury due to vaping is due to a product or additive 
recently added to the market, (b) THC oils, or an additive to these oils, are likely the cause of 
this recent outbreak of lung injuries, and (c) closed-tank (i.e., resistant to adulteration) nicotine-
only electronic cigarette systems are unlikely to cause adverse events, including those related 
to lung injury. The CDC appears to be satisfied with this explanation, and discontinued data 
collection on 2/18/2020 52. However, it is possible that e-cigarettes may cause other lung injuries 
or other serious health problems, which study medical monitor Dr. Karam-Hage and his team 
will monitor, along with our collaborator from the Department of Pulmonary Medicine, Dr. Ostrin. 
Preliminary Studies 
We have expertise evaluating nicotine product switching. PI Dr. Robinson and Co-I 
Dr. Cinciripini were Co-I's of a TCORS (CENIC; U54DA031659; Donny & Hatsukami) designed 
to identify an optimal very low nicotine content (VLNC) cigarette nicotine dose that provides 
minimal levels of reinforcement and yet remains acceptable to smokers 53. Non-treatment-
seeking smokers participated in a 1-week baseline of UB CC smoking and were then 
randomized to smoke NIDA research cigarettes 54, ranging in nicotine dose from 15.8 mg/g to 
0.4 mg/g per cigarette, or UB CC, for 6 weeks. The data suggest that relative to the UB CC 
group, those in the VLNC cigarette 0.4 mg/g group smoked fewer cigarettes (7.58 CPD), and 
importantly, showed a precipitous drop (44%) in total nicotine equivalents (TNE). The 0.4 mg/g 
group also showed reduced dependency (FTND, minus the CPD item) over the 6 weeks of 
product use and no compensatory increase in CO, nicotine withdrawal, depression, or other 
adverse events. However, a significant portion of VLNC users were not compliant with their 
assigned product, with the majority of those in the 0.4 mg/g VLNC group using their UB CC at 
least once during the VLNC product use phase 53. The 2nd U54 project, which involved both Drs. 
Robinson and Cinciripini, examined whether a gradual or immediate reduction to the 0.4 mg/g 
VLNC cigarette results in better compliance over 20 weeks of use. Our initial findings suggest 
that CC smokers can switch to other products, even those with less nicotine, although 
compliance rates greatly decreased with lower nicotine products.  
We have expertise evaluating ECs. PI Dr. Robinson and Co-I Dr. Cinciripini have an 
active grant that is investigating dual use of ECs and VLNC cigarettes on abuse liability (2015-
0638). This R01 will provide the scientific community with critical information on the effects of 
dual use of VLNC cigarettes and ECs on multiple areas of concern, including abuse liability, 
nicotine compensation, product use, liking, and reinforcement (relative reinforcing efficacy), and 
the frequency of and circumstances surrounding dual product use. Many of the same behavioral 
and nicotine exposure measures that we are using in this funded trial are included in our current 
proposal, which will allow us to compare across smoking populations.  
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We have expertise examining gender differences in response to tobacco use. Co-I 
Dr. Blalock has examined behavioral and cognitive factors that might account for consistent 
findings of disparities among women in the prevalence of depressive and anxiety disorders 55-57. 
She has expertise treating pregnant smokers 58-65. Dr. Blalock has evaluated smoking behavior 
and smoking cessation interventions in female gender-disparate populations of smokers, 
including smokers with comorbid depressive 66,67 and anxiety disorders 68-70. PI Dr. Robinson 
examined gender differences to the hedonic properties of nicotine by exposing 12-h nicotine-
deprived and nondeprived smokers to nicotine and placebo nasal spray 71. While both nicotine-
deprived men and women produced reduced startle eye blink responding, a measure of 
aversiveness, following nicotine compared to placebo spray, nicotine nondeprived women 
showed larger startle eye blinks to nicotine than to placebo spray (there were no startle 
differences for nondeprived men). These findings suggest that women have a lower threshold 
for experiencing the aversive qualities of nicotine.  
We have expertise using smartphone ecological momentary assessments (EMA) 
of smoking behavior. Co-I Dr. Cinciripini has extensive experience designing and analyzing 
EMA data to assess smoking behavior and has previously published on this topic. Our EMA 
assessment approach permits examining both acute moments and patterns in momentary data 
(withdrawal, craving, affect) over time 72,73 collected in real-time. Examples of our previous EMA 
work include demonstrating that abstainers, early lapsers, and late lapsers exhibit significantly 
different withdrawal trajectories 72, that smokers report higher and more volatile craving to 
smoke on drinking days 74, and other studies examining smoking outcome expectancies and 
mood 75-77. All current EMA work has been assumed by Drs. Robinson, who also has an R01 
(R01CA184781) focusing on the use of smartphone technology to reduce attentional bias 
among smokers. 
D. RESEARCH DESIGN AND METHOD 
In the current COVID-19 pandemic environment, we will be expanding in-person 
procedures to a virtual setting, using an institutionally approved platform (e.g., Zoom), which will 
also allow us to recruit participants state-wide. The following sections have been modified to 
include the study team’s plan for adapting the identified in-person procedures to a virtual setting. 
However, in-person clinic visits will still be available for participants residing in the Houston area 
who prefer them. 
Overall structure of the study team 
The objective of this project is to characterize potential gender differences when 
switching to nicotine and placebo SRECs on product use, product acceptability, reinforcement, 
and nicotine dependence symptoms among adult daily CC smokers. This project is an MD 
Anderson sponsored Investigational Tobacco Product (ITP) study that will be led by PI Dr. 
Jason Robinson (MD Anderson). The investigative team will include Co-Is Drs. Paul Cinciripini 
(product switching and tobacco clinical trials expertise; MD Anderson), Janice Blalock (expertise 
in tobacco-related gender differences; MD Anderson), Maher Karam-Hage (study physician; MD 
Anderson), Edwin Ostrin (respiratory symptom assessment; MD Anderson), and Sanjay Shete 
(biostatistics; MD Anderson). Together, we provide the necessary background and intellectual 
complementarity needed to fulfill all aims of this project. MD Anderson is the sole site and will 
perform all administrative, data coordinating, and participant enrollment functions. Nicotine, 
cotinine, and anabasine will be analyzed by collaborator Dr. Peiying Yang, Associate Professor 
of Integrative Medicine Research at MD Anderson. The collaborators will meet weekly with the 
research staff throughout the duration of this project. 
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Recruitment and Retention Plan 
Study participants will be individuals residing in the State of Texas. Recruitment efforts 
may include direct mail from registries, mailing flyers, public service announcements, media 
interviews, and advertisements on online 
social media, radio , television, and 
newspaper outlets (see Appendix R), and 
digital advertising companies. Institutional 
channels may be used to aid study 
recruitment, including, but not limited to, 
patient database data mining (e.g., EPIC, 
TRTP database) for potentially eligible 
patients and other internal recruitment 
methods (e.g., MyChart to send messages, 
newsletters, inside MD Anderson television 
channels). The Tobacco Research and 
Treatment Program’s web screener database 
for tobacco users, outlined in IRB-approved 
PA18-0423, also may be used as a 
recruitment source for this study. This 
database houses data collected from an 
internet-based screening questionnaire to 
recruit tobacco users from the Houston area, 
as well as across Texas more broadly, who 
may be interested in participating in tobacco 
use and cessation studies at MD Anderson 
Cancer Center. PA18-0423 allows the sharing 
of data with IRB-approved MD Anderson 
protocols. We will rotate through various 
venues throughout the recruitment period. We 
have many years of experience using these 
venues for quitting and nonquitting tobacco 
clinical trials recruitment. The MD Anderson 
Marketing and Communications departments 
may also assist in arranging interviews, public 
service announcements, and social media 
communications to assist in study recruitment. 
Additionally, we may engage the services of 
external clinical trials recruitment services to 
obtain contact information of prospective 
study participants. We anticipate no difficulty 
in recruiting the required number of 
participants.  
To facilitate participant retention and 
compliance with study procedures, we will 
offer financial compensation. Enrolled 
participants will have the opportunity to 
receive a potential maximum compensation of 
$522 each (see Appendix V). Participants will 
be compensated up to $25 for each in-person 
or virtual visit (up to $100) (excluding the telephone AE follow-up), up to $40 for completing 
Table 1. Inclusion Exclusion Criteria. 
 
Inclusion Criteria: 
- Aged 21 years or older 
-Reports being a daily or non-daily smoker (any self-
reported smoking in the past 30 days) 
- Have an address where he/she can receive mail  
- Able to follow verbal and written instructions in English 
and complete all aspects of the study as determined by 
PI 
- Willing to have urine biospecimen samples taken, 
either in-home and returning them by mail, or in-person 
at an approved collection site. 
- Willing to use tobacco-flavored study electronic 
cigarettes  
-Agrees to comply with all MD Anderson institutional 
policies related to COVID-19 screening prior to any in-
person research visit. 
-The individual agrees to not engage in study 
procedures or interactions with study personnel while 
operating a vehicle. 
 
Exclusion Criteria: 
-   
- Individuals who report depressive symptoms in the 
moderately severe or severe range on the PHQ-9 
(scores of 15 or above) or who report current suicidal 
ideation on the PHQ-9 
- Uncontrolled or unstable medical condition (e.g., 
uncontrolled hypertension, angina, diabetes).  
- Evidence of cognitive deficits or instability that would 
preclude reliable study participation. 
-Being pregnant, engaging in breast-feeding, or being of 
childbearing potential and engaging in sexual activity 
that could lead to pregnancy and is not protected by a 
medically acceptable, effective method of birth control 
while enrolled in the study, as determined by self-report. 
Medically acceptable contraceptives include: (1) 
approved hormonal contraceptives (such as birth control 
pills, patches, implants or injections), (2) barrier 
methods (such as a condom or diaphragm) used with a 
spermicide, or (3) an intrauterine device (IUD). 
Contraceptive measures sold for emergency use after 
unprotected sex are not acceptable methods for routine 
use. 
- Considered by the investigator to be an unsuitable or 
unstable candidate (including but not limited to the 
following situation: unwilling or unable to comply with 
study procedures) 
-Individuals who reside in an area that is outside of our 
shipping company's area of operation or in a jurisdiction 
outside of our medical staff's licensure (if unable to 
attend in-person clinic visits) AND who decline or are 
unable to come in to clinic to provide necessary samples 
and/or collect study products. 
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study questionnaires prior to visit ($10/instance), $2/instance for completing short message 
service (SMS)-prompted once daily smartphone Qualtrics assessments of product use for 42 
days (up to $84), and $2/day for completing random smartphone EMA assessments (completed 
2 times/day) for 42 days (up to $168). Additionally, we will provide $50 to participants at the end 
of both phases 2 & 3 contingent upon the return of all used and unused SREC cartridges (up to 
$100 total). We have used this EMA compensation scheme successfully in other studies, 
obtaining over 75% response rate to individual EMA assessments. We also use automated text 
messaging to remind participants of appointments and provide feedback on missed EMA 
assessments. Also, because participants will be asked to use their personal smartphone 
devices and personal data plans for study related assessments, they will receive an additional 
$30 at the end of study participation. Participants without a smartphone, or who would prefer not 
to use their own device, may be provided with a smartphone and service plan for the duration of 
the study. For this group, they will receive the additional $30 for returning the smartphone at the 
end of study participation. Participants wil not be compensated for the final safety telephone call 
since no research assessments will be administered. Payment for the visits will be issued either 
upon receipt of the samples at MD Anderson or upon shipping package tracking showing 
sample movement back to our clinic. 
COVID-19 adaptation: No adaptations needed. 
Participants 
We will recruit up to 196 participants (98 male and 98 female adult CC smokers) from 
the state of Texas and/or Houston metropolitan areas. Inclusion/exclusion criteria are described 
in Table 1. Note:  For the purpose of eligibility requirements and ongoing smoking status, 
“cigarettes” will also include the tobacco product that is commonly known as “little cigars”.  Little 
cigars are machine-manufactured and sold in packs similar to cigarettes. They are often 
smoked by individuals of limited means because they are cheaper than conventional cigarettes.   
COVID-19 adaptation: While this study is being conducted virtually, we will expand 
participant recruitment to the state of Texas. 
Procedures 
 Phone screen: Initial eligibility. All participants will be screened by phone (see 
Appendix S) by a trained study staff member to determine initial eligibility (e.g., age, interest in 
trying ECs). Women of child-bearing potential will be asked about pregnancy and lactation 
status and contraception use at phone screen. In the event a female subject becomes, or is 
found to be, pregnant while active in the study, the subject will be withdrawn from the protocol, 
referred to their primary care physician (PCP), and will be offered smoking cessation counseling 
at that time. 
Eligible participants will be scheduled for the initial screening visit (V0), which may be 
done in-person or virtually through an institutionally approved platform (e.g., Zoom). All 
participants who are initially eligible will be informed that they may be sent an email with a 
questionnaire consent statement, and, should they consent, they will be automatically 
connected to questionnaires hosted on MD Anderson’s Qualtrics platform, prior to their 
scheduled screening visit. Participants may receive a phone call, email, and/or text message 
before their laboratory or virtual sessions to remind them of the appointment. Eligibility criteria 
including age, CPD, stable address, interest in trying ECs, and pregnancy-related criteria will be 
collected through self-report during the telephone screening. 
COVID-19 adaptation: As applicable during the SARS-CoV-2 pandemic and recovery 
phase, MD Anderson institutional screening requirements will be reviewed with the participant 
and their verbal acknowledgement obtained before scheduling the in-person screening visit. 
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In-person or virtual screening session (V0). The consenting staff member will review 
the Informed Consent Document and all relevant study information. They will then review any 
questions the patient may have, and confirm that they understand the nature of the research 
being performed. Fluency in spoken and written English will be assessed by a TRTP study staff 
member during the consenting process by asking the participant to read aloud a section of the 
Informed Consent Document. This will be noted in the Documentation of Informed Consent. 
Additionally, information provided at the time of the phone screen may be verified prior to 
consent. 
Participants will be instructed to smoke ad libitum prior to this session. Prior to the 
session, the participant will be asked to complete basic demographics, smoking, tobacco 
product use, and health history questionnaires used in our previous studies 78 that will be 
reviewed and approved for eligibility by a licensed medical provider following the visit. CC, 
SREC, and other tobacco product use eligibility criteria will be evaluated using a timeline follow 
back procedure 79 and smoking history measures used in previous studies 80. These 
questionniares may be pushed by our institutional Qualtrics server to be completed 
electronically (via text or email) prior to the session. Current major depressive disorder (MDD) 
and suicidality will be identified using the Patient Health Questionnaire (PHQ-9; see Appendix L) 
81.The screening session and the three return visits are each expected to last approximately 3 
hours. The final safety telephone call will assess any ongoing adverse effects and should last 
approximately 10 minutes.   
COVID-19 adaptation: Eligible participants will be scheduled for a virtual screening 
session using an institutionally approved platform, such as Zoom. If we are unable to collect any 
required biological specimens through mail, the participant may be asked to go in-person to 
conduct the tests through an approved collection site. Approved sites may include University of 
Texas MD Anderson, University of Texas sister institutions including the Center for 
Neurobehavioral Research on Addiction (CNRA) at University of Texas Medical School, other 
universities or hospitals located in Texas, and/or contracted commercial vendors.   
Baseline Medical Clearance. Following the completion of the baseline visit, a member 
of the medical team (Physician assistant and/or the Physician) will review all relevant data 
collected at screening and will provide their clearance for the participant to proceed to Visit 1. 
The study Physician will have the final review of the data and will complete the final eligibility 
sign off prior to randomization. In the event the Physician is not able to sign-off prior to the visit 
(due to being out of office), the Principal Investigator may provide the initial sign-off so that the 
visit may proceed, and the physician will sign-off upon their return.  
Following the medical team clearance to proceed to Visit 1, a study supply kit will be 
sent containing the urine specimen collection supplies and other study materials.  
Study Supply Kit: Baseline Screening Visit.The following items are incuded in the initial 
study supply kit: 
• 
Written instructions  
• 
Urine collection kit 
• 
Reloadable gift card (e.g., Bank of America or another approved institutional option) 
• 
Return address label, postage-paid, and box for shipment 
• 
Biospecimen bag, absorbant test tube sleeves 
The study specific supplies wil be shipped to eligibile participants and tracked through 
eShipGlobal or a comparable system within two business days of completion of the Baseline 
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Screening Visit. Mailing time may be adjusted due to carrier delays, holidays, or any other factor 
impacting delivery time. Written instructions will be provided and the research team will be 
available to guide participants through the sample collection process as needed. The participant 
must complete and return the required samples to the MD Anderson research team prior to Visit 
1, or Visit 1 may be rescheduled.  
Phase 1: UB Baseline (weeks 1-2). During this phase, participants will be instructed to 
smoke their usual brand ad libitum. Measures specific to this phase will be captured at a virtual 
or in-person visit at the end of week 2. Daily smartphone EMA assessments, as described 
below, will occur throughout Phase 1. Refer to Figure 1 for a timeline of study procedures. 
COVID-19 adaptation: No adaptations needed. 
Phases 2 & 3: SREC-NIC and SREC-PLA use (weeks 3-4, 5-6). During Phases 2 & 3, 
participants will be provided with SREC-NIC or SREC-PLA, in a counter-balanced fashion (i.e., 
half will receive SREC-NIC during phase 2 and SREC-PLA during phase 3). The subjects will be 
randomized on a 1:1 ratio and will be assigned to their randomization group through the protocol 
specific TRTP database. 50% (70 subjects) will receive the Active study product first and the 
placebo second and 50% will receive the Placebo study product first and the active study 
product second. During the randomization process, participants will be stratified by gender for 
order of exposure to SREC-PLA and SREC-NIC. At the beginning of each phase, each 
participant will receive 2 SREC devices with non-removable rechargeable batteries (3.3 v, 1000 
mAh battery), 1 USB recharger, a 2-week supply of sealed SREC tanks (14 pods; containing 
either nicotine or placebo e-liquid), a user manual, and a carrying pouch. The SRECS are 
produced by NJOY LLC (Glenns Ferry, ID) under NIDA contract, and are available in two 
nicotine doses, 5% (~59 mg/ml nicotine) and 0% (0 mg/mL nicotine; placebo), a single flavor 
(nicotine), and in sealed disposable pods that deliver <350 puffs/pod 11. Participants will be 
instructed to use the SREC during Phases 2 and 3 whenever they get the urge to smoke, but 
will not be penalized for using their UB CCs or other nicotine products (including other ECs), as 
product use is a dependent measure in this study. The use of UB CCs and the study products 
will be documented daily by the participant in Qualtrics as part of the EMA. 
At the beginning Phase 2, participants will receive training in how to use the SREC 
product. They may be shown a brief video demonstrating its use followed by a hands-on training 
which will include assembly (battery and tank), turning the SREC on and off, puffing, and 
recharging the battery. The training session will last 30 minutes and will include a minimum of 
three bouts of 10 puffs each in which the user will be encouraged to vary puff topography to 
maximize desired sensory qualities of product use. This procedure is currently being used by us 
in our active EC grant (R01DA042526), and has been found to result in users achieving 
cigarette or near-cigarette levels 
of blood nicotine among EC-
naive CC smokers in other 
studies 82. The study staff will 
receive instruction on the use of 
the SREC device by the 
Program Director. The training 
will be documented on Protocol 
Training Logs and will be stored 
in the regulatory binders for 
monitor review. 
Participants and study 
staff will be blind to SREC 
Figure 1. Timeline of study procedures. 
 
 
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condition. The Program Director, who will not have participant contact, will manage the 
inventory and labeling of blinded products. Blinded study staff will distribute the product to 
patients at each visit. The study medical monitor (Dr. Karam-Hage) and collaborator on 
respiratory symptom assessment (Dr. Ostrin) will be provided unblinded information on SREC 
condition by the Program Director, per their request. In the case an unblinding needs to occur, 
the study team will notify the IND sponsor Clinical Trials Safety Team, the DSMB, and the IRB. 
The SRECs will be obtained through NIDA's procurement process.  
Measures specific to these phases will be captured at in-person or virtual visits at the 
end of each phase (weeks 4 & 6). Daily smartphone EMA assessments will occur throughout all 
phases. 
COVID-19 adaptation: Participants will be mailed their 2-week allotment of study ECIGs 
prior to the start of phases 2 and 3 by a study staff member blinded to the nicotine dose. 
Additionally, participants will be asked to provide the urine samples during each phase and mail 
those back to the primary MD Anderson site. All supplies to collect the samples, as well as 
shipping materials and postage will be provided. Visit payment will be issued once MD 
Anderson staff are able to track movement on the return package. Alternatively, participants 
may be asked to collect the study ECIGs and/or provide their urine samples in-person from an 
approved site. Approved sites may include University of Texas MD Anderson, University of 
Texas sister institutions including the Center for Neurobehavioral Research on Addiction 
(CNRA) at University of Texas Medical School, other universities or hospitals located in Texas, 
and/or contracted commercial vendors. 
Study Supply Kit: Treatment visits. The following items are included in each treatment 
visit study kit. 
• 
Urine collection kit 
• 
Return address label, postage-paid, and box for shipment 
• 
Biospecimen bag, absorbant test tube sleeves 
• 
e-cigarette kit 
• 
Written instructions 
Treatment study kits will be mailed approximately 5-7 days prior to each treatment visit. 
Mailing time may be adjusted due to carrier delays, holidays, or any other factor impacting 
delivery time. Participants will be instructed to complete the required visit samples and place in 
the mail to be returned to MD Anderson.   
 
Adverse Event Safety Assessment. 30 days (+/- 7 days) following the end of Phase 3, 
study participants will complete a telephone visit with study staff to assess ongoing adverse 
events. 
Post-study smoking cessation treatment. We will offer all participants 8 weeks of free 
smoking cessation treatment, which may include nicotine replacement therapy (NRT; nicotine 
patch and lozenge) and smoking cessation counseling, at the end of their study participation. 
Alternatively they may be referred to another smoking cessation study. It is not the intention of 
this phase of study to evaluate the efficacy of EC for smoking cessation, but rather to facilitate 
smoking cessation by offering free treatment at the conclusion of EC exposure. This fulfills what 
we see as a strong ethical obligation to treat smokers that enter our research programs. NRT 
and counseling will be administered by MD Anderson's Tobacco Treatment Program (TTP), 
headed by Drs. Cinciripini (Co-I) and Karam-Hage (Co-I), which provides free treatment to all 
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MD Anderson patients, family members, 
and employees, or by the Tobacco 
Treatment Program Quitline, also headed 
by Dr. Cinciripini. The TTP has a 9-month 
cessation rate of 36%-47% 83. An 
alternative options would be a referral to a 
cessation trial, based on availability.  
Measures 
The behavioral measures 
described below will be obtained at 
baseline (week 0) and the end of each 
phase (weeks 2, 4, and 6), except for 
smartphone EMA, which will be collected 
daily in each participant's home 
environment throughout the 6 weeks of 
study participation. All questionnaires will 
be administered using MD Anderson's 
Qualtrics platform. Missed visits and 
associated assessments will be recorded 
in the study database, but will not be 
logged as protocol deviations because 
they are expected in smoking cessation 
trials. In our previous tobacco-related 
trials over the past 20 years, we have 
found that participants only attend about 
75% of scheduled sessions. Refer to 
Table 2 for a list of the project 
measurement domains and assessments. 
COVID-19 adaptation: We will ask 
participants to collect and ship their urine 
samples to us, using postage-paid 
supplies that we will mail to them (see 
Appendix BB). Alternatively, community 
participants may be asked to provide a 
urine sample at an approved collection 
site within a week of their scheduled 
virtual "in-person" visits. Approved sites 
may include MD Anderson, University of 
Texas sister institutions including the Center for Neurobehavioral Research on Addiction 
(CNRA) at University of Texas Medical School, other universities or hospitals located in Texas, 
and/or contracted commercial vendors. TLFB will be collected virtually by study staff. We will 
also provide postage-paid shipping supplies for participants to return all used and unused e-cig 
pods. Questionnaires will continue to be administered electronically via the institutionally-
approved web-based Qualtrics platform administered over the study smartphones.  
Demographics, smoking, tobacco product use, and health history. As part of the 
screening session, and to capture information for the exploratory aim, participants will complete 
basic demographics, smoking, tobacco product use, and health history questionnaires used in 
our previous studies (see Appendices C and I) 78. Menthol CC preference will also be captured. 
Recent (past 30 days) and prior EC use and EC flavor preference (if ECs have been used in the 
Table 2. Project measurement, by time point. 
 
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past) will be collected using the EC items of the Tobacco Products and Risk Perceptions Survey 
(TPRPS; see Appendix P) 3, a survey developed by the Georgia State University Tobacco 
Center of Regulatory Science (TCORS) 84. We will also collect participants’ exposure to 
cigarette smoke at home and at social setting using the Environmental Tobacco Smoke 
Exposure Questionnaire (ETSEQ) at the screening session. 
At visits 0, 1, 2, and 3, we will collect self-reported information on hormonal 
contraception use and menstrual phase (estimated from the start date of the last menstrual 
period) in premenopausal women. Because withdrawal symptoms may influence product 
switching, we will examine these factors as potential mediators in our analyses (Exploratory 
Aim). Both being in the luteal phase, compared to follicular phase 85, and use of hormonal 
contraception have been found to increase nicotine withdrawal symptoms 86. Because these are 
exploratory factors, we elected to not collect blood at every session for hormonal confirmation 
using progesterone, or to exclude women with factors that would influence these factors (e.g., 
being post-hysterectomy or post-menopausal). 
Assessment of product use. As part of Aims 1 & 2, we will collect measures of CC and 
EC product use and exposure. At each visit, study staff will complete a Time Line Follow Back 
(TLFB; see Appendix O) 87 interview to record nicotine product use since their last visit, 
including daily CC use (all phases; CPD), SREC use (Phases 2 & 3; SREC sessions/day), and 
other nicotine product use (all phases; including other tobacco and non-study EC products). 
Participants will be required to return used and unused SREC sealed pods at weeks 4 and 6 for 
product accounting.  
During each phase, participants will provide a urine sample to measure total nicotine 
equivalents (TNE) and the tobacco minor alkaloids (MA) anabasine and nicotelline, which will be 
analyzed by Dr. Peiying Yang, associate professor of Integrative Medicine Research at MD 
Anderson, using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-
ESI-MS/MS) 91,92. TNE is the sum of total nicotine, cotinine, 3'-hydroxycotinine, and nicotine N-
oxide excreted in urine ("total" refers to the analyte and its glucuronide conjugate), comprising 
85 to 95% of the nicotine dose received by a tobacco user 93. Use of TNE will enable us to 
quantify changes in nicotine exposure throughout the study. The MAs anabasine and nicotelline 
will allow us to estimate differential use in combustible vs. EC use, because MAs are almost 
exclusively derived from tobacco, and not nicotine 94. 
During all phases, participants will complete SMS-prompted once daily smartphone 
Qualtrics assessments of product use (CPD, number of EC episodes [Phases 2 & 3], other 
tobacco use) and 2 daily random assessments of nicotine dependence symptoms (withdrawal, 
craving, and affect; see Assessment of Product Reinforcement, below). For the daily 
assessments of product use, the SMS will arrive on the participant's smartphone approximately 
2 hours before his or her self-determined bed time, and will contain a link to a questionnaire 
provided through MD Anderson's Qualtrics survey platform. The random EMA assessments of 
nicotine dependence symptoms will be restricted to 2 instances per day to limit participant 
burden. To do so, each day will be divided into 2 blocks, based on each participant’s reported 
wake and bed time that is collected at the screening visit (see Appendix X). Our SMS/Qualtrics 
backend software, running on a Microsoft SQL Server, will prevent random assessments from 
occurring within 2 hours of other assessments. The primary outcome measure of Aims 1 & 2, 
CPD, will come from the smartphone daily diary data of CC use over the past 24 hours. TLFB 
collected at each phase will be used as a secondary source of CC use to supplement missing 
smartphone daily diary data.  
The total time to complete the once daily product use and 2 random EMA assessments 
of nicotine dependence symptoms will be approximately 15-20 minutes/day. Our previous 
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research has obtained EMA compliance rates of >75% 72,74 and found EMA reactivity to be 
nonexistent or small 95. We have extensive experience implementing and developing EMA 
programs and analyzing EMA data related to smoking behavior and anticipate no issues in 
carrying out this aspect of our proposal 72,74,96. Because prompts may occur at inconvenient 
times (e.g., driving), participants will be instructed that they can delay responding for up to 90 
minutes, and they will receive a "missing assessment" SMS reminder if they fail to complete a 
daily or random assessment within 90 minutes of it being sent. The SMS/Qualtrics app will 
provide feedback on percentage of completed assessments, as well as compensation earned 
(see Recruitment and Retention Plan, above). We have successfully used this SMS/Qualtrics 
platform to collect similar EMA data in our current EC/VLNC product switching grant (2015-
0638). Participants without a smartphone, or who would prefer not to use their own device, will 
be provided with a smartphone and service plan for the duration of the study. Given that 77% of 
adults own smartphones, as of 2016 97, we anticipate that relatively few participants will need a 
study smartphone. 
Assessment of product acceptability. As part of Aims 1 & 2, product acceptability will 
be evaluated in terms of explicit product liking, perceived product harm, and implicit product 
liking (i.e., attitudes) at the end of each phase. Explicit product liking will be measured using 
Product Evaluation Scales (PES), which are modified versions of the Cigarette Evaluation Scale 
(CES) 98. The CES is an 11-item questionnaire that evaluates the cigarette smoking experience 
in terms of satisfaction, tastiness, dizziness, ability to calm, concentration, wakefulness, 
reduction of hunger, nausea, irritability, enjoyment of sensations of smoke, and craving 
reduction. We will use 2 product-specific versions of the PES to evaluate CC and SREC product 
liking (with SRECs evaluated at weeks 4 & 6 only; see Appendix M). 
To assess perceived product harm, we will administer modified Perceived Health Risk 
Questionnaires (PHRQs; see Appendix K) 99 that will assess participants' beliefs about their 
risks of developing lung cancer, emphysema, bronchitis, other cancers, heart disease, risk of 
addiction, and stroke on a scale of 1 (very low risk of disease) to 10 (very high risk of disease). 
These scales will be modified so that participants will assess the perceived risks associated with 
their UB CCs and ECs (i.e., electronic cigarettes "in general") at each time point, and a SREC-
specific version at weeks 4 & 6 only. 
To assess implicit product liking, participants will complete 2 Implicit Association Tests 
(IAT) designed to evaluate attitudes towards CCs and ECs during each phase (see Appendix 
Q). The IAT has been used to evaluate attitudes toward consumer products 100,101 and is 
comprised of two tasks. In the first task, participants are instructed to rapidly distinguish 
between two paired products and attributes (e.g., cigarettes + good vs. ECs + bad) using two 
assigned response buttons. In the second task, the pairings are switched. By calculating a 
standardized difference score between the reaction time differences, one can determine which 
products and attributes are more strongly associated in memory, thus determining whether an 
individual has a relatively more positive or negative attitude toward one product vs. the other 102. 
We have substantial previous experience with this task using established methods in our 
studies 103. We are currently using this task in our active EC study (2015-0638). For both 
products of interest, we created 24 pictures that minimize product branding, and the good and 
bad attribute words came from a previously published set from our lab 104. To score the IAT, we 
will use the standardized difference score (D) method 105. Each IAT product comparison will take 
approximately 8 minutes to complete. 
COVID-19 adaptation: We will adapt the IAT to Qualtrics, an institutionally approved 
web-based platform, and will ask participants to complete the task electronically by accessing a 
hyperlink using a smartphone.  
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To assess product-specific expectancies (i.e., perceived outcomes of product use), we 
will administer the Brief Smoking Consequences Questionnaire-Adult (BSCQ-A) 106 to assess 
CC-specific expectancies (see Appendix F) and the EC-specific Brief Smoking Consequences 
Questionnaire-Adult (EC-BSCQ-A) 107 to assess EC-specific expectancies (see Appendix G). 
Both are 25-items questionnaires that assess beliefs (i.e., expectancies) about what happens 
when they smoke CCs (BSCQ-A) or use ECs (EC-BSCQ-A) on 10 scales, including Negative 
Affect Reduction, Stimulation/State Enhancement, Health Risks, Taste/Sensorimotor 
Manipulation, Social Facilitation, Weight Control, Craving/Addiction, Negative Physical Feelings, 
Boredom Reduction, and Negative Social Impression, using a 10-point Likert scale 
(0="completely unlikely" to 9="completely likely"). We will administer these questionnaires at all 
4 phases and expect the EC-BSCQ-A to be sensitive to SREC dose (Aim 1) and both to be 
sensitive to gender differences in expectancies (Aim 2). 
Assessment of product reinforcement. As part of Aims 1 & 2, we will assess CC and 
SREQ product relative reinforcing efﬁcacy (RRE) using two separate product-specific purchase 
tasks (PT) at each in-person or virtual visit (with SRECs evaluated at weeks 4 & 6 only; see 
Appendices D and E). PTs are behavioral economic reward valuation tasks that have been used 
to assess the RRE of food 108, alcohol 109, illicit drugs 110, and nicotine products 111. PTs provide 
an estimate of how much a participant is willing to pay (i.e., its valuation) for a given product 
(UB, SREC) over a range of unit price intervals ($0.01 to $1,000). Responses will be used to 
compute five demand indices, including breakpoint (first price at which consumption goes to 
zero, i.e., unwilling to pay), demand intensity (consumption at the lowest price), Omax (maximum 
financial expenditure on the product), Pmax (price at which expenditure is maximized), and 
elasticity of demand (sensitivity of product consumption to increases in cost). These relative 
values will be compared between CCs and SRECs to determine their RREs. 
Assessment of nicotine dependence symptoms. As part of Aims 1 & 2, participants 
will complete questionnaires assessing nicotine dependence symptoms, including CC 
dependence (Fagerström Test for Cigarette Dependence [FTCD; formerly the FTND; see 
Appendix C]) 112,113, EC dependence (Penn State Electronic Cigarette Dependence Index 
[PSECDI; see Appendix J]) 114, nicotine withdrawal (Minnesota Nicotine Withdrawal Scale-
Revised [MNWS; see Appendix H]) 115, affect (Positive and Negative Affect Scales [PANAS; see 
Appendix I]) 116, and craving to smoke (Questionnaire of Smoking Urges-Brief [QSU-Brief; see 
Appendix N]) 117 at each study visit.  
During all phases, SMS/Qualtrics will be used to collect 2 daily random smartphone EMA 
measures of nicotine dependence symptoms, including nicotine withdrawal, craving, and affect, 
based on 8 items from the QSU, PANAS, and MNWS. Further details about the 2 daily 
smartphone EMA measures, as well as the once daily assessments of product use, are 
described above in the "Assessment of product use" section. 
Assessment of respiratory and other symptoms. We will also assess respiratory 
symptoms at each visit using the American Thoracic Society questionnaire (ATSQ) 118. The 
ATSQ is an 8-item questionnaire that assesses symptoms including coughing, wheezing, 
phlegm production, shortness of breath. An email will be sent to project staff when a participant 
completes the ATSQ and has a total score of >3 on questions #4-8. Staff will assess symptoms 
with the participant at the next visit. If symptoms present prior to the start of study product (V0 or 
V1), staff will add the conditions to the medical history. If the elevated score presents while on 
study product, staff will assess changes in symptoms and severity and log an adverse event, if 
indicated.   
Study Medical Monitor Dr. Karam-Hage will oversee the collection, review, and 
attribution of adverse events (AEs) in this study and will consult with Dr. Ostrin on respiratory-
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related AEs, as needed. The physician may delegate to other members of the medical team the 
task of a preliminary review of the adverse event, attribution, and recommended action plan. 
The physician will then complete the final review of the adverse event, confirm attribution and 
sign off on the adverse events. 
Statistical Approach & Expected Outcomes 
General Data Analytic Strategy. To analyze our aims, we will use a crossover design 
model 119 with n = 140 subjects (assuming 15% attrition of n=164) and k = 3 periods. In this 
design, t0 and t1 will be the two SREC types, with t0 for SREC-PLA and t1 for SREC-NIC. We will 
use the following model for y (e.g., CPD): yij = b1 + b2t(i,j),t(I,j -1) + eij, where b1 is the effect of 
subject i, and b2 is the effect of treatment t01 when preceded by treatment t10. T(i,j) is the 
treatment assigned to subject i in period j, for 1 ≤ i ≤ n and 1 ≤ j ≤ k. The residual errors eij are 
assumed to be independent and identically distributed with expectation 0 and variance σ2. In 
this design, each subject will act as its own control reducing the influence of confounding, 
reducing variance and improving accuracy and sensitivity for the estimated effect of interest. In 
the interaction models (Aim 2), gender will be entered in the equation and interacted with b2t(i,j),t(I,j 
-1) to estimate gender by treatment interaction effects on all outcomes. Period and carryover 
effects will be evaluated by testing equivalence of effects across time (e.g., CPD collected using 
TLFB). We will utilize a mixed model approach for estimation using the "glmer" function of the 
"lme4" R package 120. Missingness will be treated as missing-at-random within maximum 
likelihood estimation and we will utilize not-missing-at-random approaches (e.g., pattern mixture 
model) if non-ignorable missingness is suspected 121,122. Given the large number of outcomes, 
the analyses will address issues of multiplicity by applying the False Discovery Rate 123. 
Hypothesis Testing: Aim 1. To characterize the effects of switching to nicotine vs. 
placebo SRECs from CCs on product use, product acceptability, reinforcement, and 
nicotine dependence symptoms among adult daily CC smokers. Assessments will include: 
product use (CPD, number of EC vaping sessions, nicotine, cotinine, minor tobacco alkaloids); 
product acceptability (explicit product liking, implicit product liking, and perceived product harm); 
reinforcement (RRE) and nicotine dependence symptoms (withdrawal, craving, and affect). We 
hypothesize that SREC-NIC will lead to decreases in CC-specific measures (CPD, minor 
tobacco alkaloids, and CC dependence), decreases in withdrawal symptoms, and increases in 
EC-specific use, acceptability, and reinforcement compared to SREC-PLA. The primary 
outcome measure for Aim 1 will be CPD. 
Hypothesis Testing: Aim 2. To characterize the differences between male and 
female CC smokers when switching to nicotine vs. placebo SRECs from CCs on product 
use, product acceptability, reinforcement, and nicotine dependence symptoms. This aim 
will examine the moderating role of gender on the impact of SREC type on the assessments 
described in Aim 1. We hypothesize that men, compared to women, will show more product 
use, acceptability, and reinforcement with SREC-NIC, relative to SREC-PLA, but that women 
will show overall less SREC use, and less CC reduction, than men. The primary outcome 
measure for Aim 2 will be CPD. 
Exploratory Aim: To characterize which factors moderate or mediate the effects of 
switching to nicotine and placebo SRECs from CCs among male and female CC smokers. 
In an exploratory fashion, we will examine whether baseline factors, including prior EC exposure 
and prior flavor preference, menthol CC preference, nicotine dependence, baseline TNE, and 
race/ethnicity, moderate the Aims 1 & 2 hypotheses. We will also examine the potentially 
mediating effects of product satisfaction, hormonal contraception use, menstrual phase, and 
smartphone-collected withdrawal, craving, affect, product use on these hypotheses.  
Power and Sample Size 
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Our power analyses were conducted using a sample size of n=140 total participants. 
However, we will recruit and randomize n=164 because we expect a 15% drop-out rate by 
Week 6, based on the attrition rate of our existing EC product switching protocol (2015-0638).To 
demonstrate that we have adequate statistical power to detect likely effect sizes with n=140, we 
conducted power analyses for Aim 1 (i.e., the main effect of SREC type) and Aim 2 (i.e., the 
interaction between gender and SREC type) on our primary outcome measure, CPD collected 
from TLFB. However, in our attempt to estimate likely CPD effect size differences by gender as 
a function of SREC exposure (Aim 2), we were limited because there were no published studies 
that reported gender differences in CC and EC product use among CC smokers who were 
switched to nicotine and/or placebo ECs. Instead, to estimate the effect size of switching from 
CCs to ECs on CPD, we used a study 124 that examined the impact of switching to 18 mg ECs 
over 2 weeks that found that participants reduced their CPD by 96.3% (16.2 to 0.6 CPD). This 
allowed us to estimate the impact of switching to an EC with nicotine amounts similar to that of 
the SREC. To estimate the impact of product nicotine dose and gender on CPD, we used a 
study 125 that examined the impact of switching CC smokers to either VLNC (0.05 to 0.09 mg 
nicotine yield) CCs alone or combined VLNC cigarettes and NRT (21 mg patch). While this 
study did not include ECs, it allowed for the examination of the impact of nicotine on CPD, by 
gender, and found that men in the nicotine group (VLNC+NRT) smoked less VLNC CCs at 
week 2 than women 125.  
Because of the absence of reliable effect sizes of the interaction effect under study in the 
literature, we estimated power for a series of effect sizes for both the direct and indirect effect. 
To perform the power analysis we first generated the matrix for our crossover design using the 
"samplingDataCRT" R package to sample data that reflects our prospective analysis. After 
generating the sample data, we calculated power for both the main effect of SREC type on CPD 
(Aim 1) and the SREC type by gender interaction (Aim 2) using three steps: 1) generate new 
CPD values from the crossover model defined above, 2) refit the model to the simulated data, 
and 3) evaluate the true positive success rate using the "simr" package 126. We ran 1000 
simulations for each estimation for a series of effect sizes and for both the main effects and 
interaction models. Figure 2 presents the power curves of these analyses. For the gender by 
SREC type interaction (Aim 2), Figure 2 indicates that we have 80% power to detect a 
difference of 3.5 CPD or larger between the genders during SREC-NIC. For the SREC type 
main effect (Aim 1), Figure 2 (inset) indicates that we have 80% power to detect a difference of 
1.75 CPD or larger between SREC-NIC and SREC-PLA. The minimal detectable effect size is 
larger for the interaction effect compared to the main affect due to the increased power required 
to detect subgroup effects in randomized trials 127,128. Since the main modeling framework is 
linear, the interaction effect under study has an additive interpretation, such that the combined 
effects of SREC-NIC and being male contributes more to CPD reduction than the individual 
effects of the two factors. Additive interaction effects are more relevant for public health decision 
making and require a lower sample size than multiplicative interaction effects 129. In conclusion, 
our proposed sample size of 140 provide enough power to detect a CPD change of 1.75 for the 
main effect of SREC type and a CPD reduction of 3.5 for the proposed interaction effect, which 
we believe will be adequate to detect the likely differences we would observe.  
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Potential Problems & Alternative Strategies 
It is possible that the NIDA SREC use rates and product acceptability may be low in this 
study. Potential reasons for this have been described above, including (1) a lack of SREC 
flavors other than nicotine despite evidence that most EC users prefer flavors other than 
tobacco 3, (2) a lack of menthol SREC flavoring despite the ubiquity of menthol CC use among 
ethnically diverse populations 29, and (3) a level of nicotine in the SREC-NIC that, while 
comparable to other commercial ECs 11, may produce nicotine pharmacokinetics that are less 
reinforcing for DCS than those of CCs 21,26. One way to increase higher NIDA SREC use rates 
would be to incentivize their use, such as by paying participants a bonus if specific biomarkers 
indicated no CC product use (e.g., using anabasine, which is derived from tobacco and is not 
affected by EC use) 94. However, we elected to evaluate NIDA SREC use without incentivizing it 
because we are seeking to provide NIDA with "naturalistic" information about SREC use and 
acceptability, as dependent variables, among a diverse sample of male and female adult CC 
smokers. We believe that even if SREC use and acceptability are low, this information would be 
of importance to NIDA. 
The lengths of the SREC dose phases (2 weeks each) could be insufficient to determine 
stable responding. However, one study that switched CC users to ECs, using a within-subjects 
design, found that 2 weeks product exposure resulted in significant associations between EC 
nicotine dose and CPD, EC product use, and craving 130. Additionally, in our prior TCORS study 
we observed that most changes occurred within the initial 2 weeks of product use among CC 
smokers who were administered experimental CCs, including VLNC cigarettes 53. These 
findings suggest that 2 weeks of SREC exposure should be adequate to capture changes in 
response to switching to these novel nicotine products. 
Despite the lack of a menthol-flavored SREC, we decided to include menthol smokers in 
this study. A significant number of minority CC smokers prefer menthol 29, and preliminary 
evidence suggests that adult menthol CC smokers prefer menthol over tobacco-flavored ECs 
131. Additionally, menthol smokers typically represent ~55% of the community participants 
recruited for our non-treatment-seeking nicotine studies 132. Thus, to exclude menthol smokers 
would reduce the generalizability of the SREC findings in terms of use and acceptability. 
This proposal will not include biochemical confirmation of menstrual phase or hormonal 
contraception use, and instead will rely upon self-report (e.g., menstrual phase estimated from 
start of last menstrual period), unlike other similar studies 85. In studies that use biochemical 
verification, most use serum measures of progesterone and estradiol levels to more precisely 
differentiate the luteal from the follicular phase 133. We also will not exclude women using 
hormonal contraception, 
despite the impact of such 
contraception on the 
menstrual cycle. We elected 
not to collect serum 
hormone levels at each 
phase because we do not 
want to burden or expose 
participants to the risks 
associated with 4 blood 
draws for what we consider 
to be exploratory factors in 
this project. Similar 
reasoning led us to not 
exclude women taking 
Figure 2. Power Curves (and 95% confidence intervals) for the Gender by 
SREC type Interaction Effect (Aim 2; main plot) and for the main effect of 
SREC type (Aim 1; inset plot). 
 
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hormonal contraception. However, 
we will capture self-report of both 
factors and use them as 
moderators (hormonal 
contraceptive use) and mediators 
(menstrual phase) as part of the 
exploratory aim. 
Safety of EC products. 
Our current ECIG study suggests 
that use of a closed-tank ECIG device among adult smokers results in relatively few adverse 
events. In this protocol (2015-0638; R01DA042526), which is ongoing, we are testing the 
strategy of simultaneously providing a smoker uninterested in quitting with both VLNCs as well 
as an ENDS product to determine if they will compensate for the reduction in nicotine from the 
VLNC’s with the ENDS product. This is critical to the regulatory strategy aimed at determining 
nicotine levels in future ENDS product, because we may wish to maximize compensation in 
order to move people away from combustibles and increase the likelihood of cessation. Thus 
far, we have exposed 176 adult smokers to NIDA's VLNC combustible cigarette for up to 9 
weeks and to commercially available closed-tank electronic cigarettes for up to 6 weeks (the 
same product being used in many other studies across the country). In terms of adverse events, 
similar proportions of participants have reported adverse events during the exclusive cigarette 
phases (18.0%) than during the phase where they are encourage to use electronic cigarettes 
instead of smoking (15.3%). The most frequently reported adverse events during the electronic 
cigarette phases included depressive symptoms (n=4), sore throat (n=3), diarrhea (n=2), 
toothache (n=2), and vomiting (n=2). For the exclusive cigarettes phases, the most common 
adverse events included cough (n=6), irritability (n=5), headache (n=4), back pain (n=2), 
diarrhea (n=2), limb edema (n=2), insect bite (n=2), nausea (n=2), panic attack (n=2), and 
urinary tract infection (n=2). No severe adverse event was reported during the electronic 
cigarette phases, but one was reported during the exclusive cigarette phases, brachycardia 
(n=1). None of these were determined to be of probable or definitive relation to the study 
product. No serious respiratory symptoms have been reported. Our retention rate through the 
end of study has been 77%. The preliminary findings suggest that closed-tank electronic 
cigarettes are not associated with more adverse events than smoking combustible cigarettes.  
Consideration of Relevant Biological Variables. We will recruit an equal number of 
male and female adult daily smokers for this study because gender differences form the main 
focus of this proposal. While biological sex is the primary independent variable, we will also 
account for other relevant biological variables, such as age, by including them as covariates of 
interest in our statistical models. We are using multilevel models to partially pool the estimate 
from each covariate toward the overall mean of all estimates.  This is a natural away to account 
for multiple comparisons without sacrificing power (which we do in the case of Bonferroni 
correction).  Each effect is shrunk toward the overall estimate. The higher the uncertainty of a 
specific effect the more it shrinks toward the overall estimate. 
Timetable. After a 3-month study setup, we expect to enroll between months 6 and 20, 
at a rate of 10 subjects per month (see Table 3). The final participant session will be during 
month 22, and data analysis and initial manuscript drafting will occur by month 24.  
Future directions. At the project’s conclusion, we will be able to provide scientific 
information on gender differences in terms of the extent to which the NIDA SREC is used and 
accepted by adult CC smokers, which would indicate whether it could serve as a good model of 
future EC research. We will also identify factors that moderate or mediate the effects of 
switching to nicotine and placebo SRECs from CCs. Our next steps will be to submit proposals 
Table 3. Study Timeline. 
 
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that will (1) directly compare 
longer-term use of the NIDA 
SRECs to commercial EC 
devices among EC-naive and 
experienced male and female 
dual users, and (2) compare 
the SREC to EC devices with 
higher nicotine yields, such 
36 mg/ml, a dose that we are 
using in a current funded 
study (2015-0638), among 
male and female adult CC 
smokers.  
E. 
PROTECTION OF 
HUMAN SUBJECTS 
Risks to the Subjects 
Human Subjects Involvement, Characteristics, and Design 
The Houston population is estimated at over 4 million with an ethnic distribution of 59% 
Caucasian, 19% African-American, 5% Asian, and 0.4% Native American, with 33% Hispanic or 
Latino of any race 134. We expect to recruit English-speaking minority smokers in proportion to 
the population demographics, and smoking prevalence. Inclusion and exclusion criteria are 
listed in Table 1. All smokers meeting these qualifications will be accepted into the study. All 
data collection will occur at MD Anderson Cancer Center.  
Study Procedures, Materials, and Potential Risks  
Participants will be providing biological samples in the form of urine (nicotine, cotinine, 
anabasine, nicotelline), and vitals. Questionnaire data will be obtained that assess previous 
smoking, smoking cessation history, current and past health and psychiatric conditions, mood, 
CC dependence, EC dependence, nicotine withdrawal, craving, and cigarettes smoked. All data 
will be collected specifically for research purposes and will be assigned a subject identification 
number in the Tobacco Research and Treatment Program (TRTP) database and an accession 
number in CORe to maintain confidentiality. The official database for this study is the TRTP 
database (APPID-264846) maintained by in-house data programmers. Relevant medical 
screening data will be shared with the participant as appropriate for referral and follow-up 
medical care. It is highly unlikely that any legal, social, or psychological problems will result from 
this research. Any participant who spontaneously reports mood, hopelessness, anxiety and/or 
other symptoms suggesting a persistent change in mood, or who expresses suicidality, will 
activate the mental health procedures described in  Appendix T. Any individual who is deemed 
ineligible for study participation for medical/psychiatric reasons will be referred to local medical 
and/or psychiatric resources. 
Adverse Events and Serious Adverse Events 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the investigational component even if the event is not 
considered to be related to study component. Medical conditions/diseases present before 
starting study component are only considered adverse events if they worsen after starting study 
drug. Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, are considered clinically significant, or require therapy.  
Table 4. Recommended Adverse Event Recording Guidelines. 
 
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The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. The physician may delegate to other members of the medical team the task of 
a preliminary review of the adverse event, attribution, and recommended action plan. The 
physician will then complete the final review of the adverse event, confirm attribution and sign 
off on the adverse events.Since this is an ITP study, safety will be monitored by the MD 
Anderson IND Office. Adverse event terminology and grades will be determined using the 
Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, published by the U.S. 
Department of Health and Human Services. Adverse events will be reviewed by our medical 
personnel and the PI. Adverse event monitoring will continue up to 30 days after medication is 
completed. If an AE is spontaneously reported after the AE reporting period is over, the AE will 
be recorded in the patient’s progress notes. Those AEs that are probably, possibly or definitely 
related to treatment will be followed until resolution or end of study, whichever comes first. In the 
case of reports of suicidal ideation, depression or anxiety which we believe may be related to 
treatment, if possible, we will engage in our normal psychological assessments. The Addiction 
Psychiatrist will determine the course of clinical management according to methods of good 
clinical practice. The PI or physician is responsible for determining the final attribution of 
adverse events to study medication. 
Based on the new safety information related to vaping and e-cigarette use, this protocol 
will be reviewed every 6 months for safety monitoring by IRB Continuing Review and MD 
Anderson's Data Safety Monitoring Board (DSMB).  
Adverse experiences associated with specimen collection. The collection of urine by 
the participants using specimen cups are not expected to result in adverse events.  
Adverse experiences associated with electronic cigarettes. Use of ECs has been 
found to increase the risk of acute upper respiratory irritation, cough, phlegm production, 
headache, dry mouth/throat, vertigo, and nausea 16,20. Participants using SRECs, particularly the 
placebo version, may experience nicotine withdrawal effects, including increased irritability, 
difficulty concentrating, insomnia, anxiety, dysphoria, and hunger. None of these effects should 
result in serious adverse health consequences. However, it is possible that e-cigarettes may 
cause lung injuries or other serious health problems, which study medical monitor Dr. Karam-
Hage and his team will monitor, along with our collaborator from the Department of Pulmonary 
Medicine, Dr. Ostrin. 
In the event of a new health risk associated with the electronic cigarettes used in this 
protocol that is identified, we will take the following steps: (1) the newly identified risk will be 
discussed within 5 days by study chair Dr. Paul Cinciripini, collaborator and Study Physician Dr. 
Maher Karam-Hage, pulmonology collaborator Dr. Ostrin, and collaborator Dr. Robinson to 
determine its relevance to the study products used in this protocol; (2) if the risk is deemed by 
the collaborators to be related to the study products used in this protocol, we will contact all 
active subjects by phone within 5 days and submit a PI memo to MD Anderson's IRB and IND 
offices that describes this new health risk (also within 5 days); (3) Upon determination by the 
IRB, the protocol and ICD will be revised to incorporate information about the newly identified 
risk, the DSMB will be informed at the next semi-annual review of this protocol, and active 
participants will be reconsented with the details of these new risks. We will keep a log of any 
new risks communicated by the CDC and/or the Texas HHS that are deemed relevant to the 
study products used in this protocol, including participants who are contacted and/or 
reconsented and the date of this contact. 
Adverse experiences associated with questionnaires. It is unlikely that completing 
questionnaires would lead to any potential risks for participants, although some participants may 
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be uncomfortable answering certain questions and may refuse to do so. To the extent that 
answers to these questions are required for study participation (e.g., psychiatric and medical 
history), participants who do not wish to answer will not be eligible for participation. It is highly 
unlikely that any legal, social, or psychological problems will result from this research.  
Specific Instructions for Adverse Events Recording 
 
For this project, adverse events will be recorded according to the Recommended 
Adverse Event Recording Guidelines for Phase III protocols (see Table 4). Relevant medical 
history and baseline symptoms will be collected at the initial screening visit (V0) and V1, and will 
be graded according to the CTCAE 5.0 criteria and sent to the medical team for review. Any 
member of the medical team may review the medical history as part of the pre-randomization 
review process to clear the participant to V1. The study physician will complete a final eligibility 
review and sign-off prior to randomization. Adverse events will be recorded starting at every 
contact once the participant has started study product, which will be V2 and V3. In addition, the 
participant will complete a 30-day Adverse Event telephone assessment (30 days after V3, with 
a window of +/- 7 days) to follow up on any ongoing adverse events only.  
Serious Adverse Event Reporting (SAE) Reporting  
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience - any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe 
form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 
CFR 312.32). 
• 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must 
be reported to the IND Office, regardless of attribution (within 24 hours of knowledge of the 
event). 
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• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office.   
• 
Unless otherwise noted, the Oncore SAE report form will be utilized for safety reporting to 
the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after completing the study participation, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study participation must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
Reporting to NIDA: 
Serious adverse events will be reported to NIDA by the study team. The email address 
to report SAEs to NIDA is to the grant’s Project Scientist, Jana Drgonova, PhD 
(jana.drgonova@nih.gov) with a CC: to the Program Officer (Evan Herrmann; 
evan.herrmann@nih.gov).   
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
Adequacy of Protection against Risks 
Informed Consent and Assent 
All smokers will be prescreened by telephone for basic eligibility requirements. The data 
will be collected in electronic source document forms through the Qualtrics platform. Qualtrics is 
an institutionally approved platform for data collection. The data will then be automatically 
transferred from the Qualtrics platform in to the study specific TRTP database located behind 
the MD Anderson firewall. Hard copies of the electronic CRFs will be available in the event of 
any technological difficulties. An initial description of the study design will be provided and data 
will be obtained on age, smoking history, other tobacco use, medical and psychiatric history, 
medication use, and pregnancy/lactation status. All participants who remain eligible after pre-
screening will be scheduled for subsequent combination Informational Session and baseline 
visit (V0) where the study requirements will be explained in more detail and the informed 
consent reviewed. 
Ideally, the Informational Session will occur within 14 days of the telephone screen but it 
may occur anytime between the pre-screening phone assessment and the  Screening visit (V0). 
The Informational Session can also be combined with the Screening visit. During this session, 
the study purpose, other study requirements, side effects and contraindications of the use of 
ECs will be reviewed. The information presented may be in the form of a slideshow (either 
paper or electronic), which will be developed by the PIs of the study, and will be based on 
current studies using ECs from the informed consent document itself. Participants will be given 
the opportunity to ask questions about the informed consent document or any aspect of the 
study. Any medical questions that arise during the process, if not addressed in the 
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documentation or discussion provided, will be referred to the medical staff and the information 
will be provided to the potential participant prior to consenting. 
The informed consent document may be sent to the participant by email for their pre-
review prior to the scheduled screening visit. During the visit, the consent will be sent to the 
participant by text and/or email through an institutionally approved platform (e.g., Docusign) and 
will be signed at the screening visit prior to initiation of any study related procedures and covers 
a detailed description of the study including all procedures that take place for the duration of 
study. Paper consent forms may be used as an alternative back-up method during down-time 
procedures. The informed consent review includes discussion of assessments that are required 
in order to determine eligibility and are not optional. Participants will be informed that actual 
study participation requires approval from the study medical team based upon review of 
screening visit information and medical records (if applicable). Participants will be encouraged 
to ask questions for understanding and, if in agreement, will sign the informed consent 
document with the trained staff member. Participants who sign the consent document will be 
registered into OnCore. 
After completing forms required for joining the study, the participant will complete the 
visit assessments with a trained staff member. If seen in the laboratory, participants will have 
biospecimens collected in the form of urine (nicotine, cotinine, anabasine, nicotelline), and 
vitals, using procedures approved by the MD Anderson IRBs. Urine specimens will be collected, 
stored, and shipped to our collaborators, as detailed in the protocol. If the participant is seen 
virtually they will complete all questionnaires at the time of the screening visit. If they are 
seemingly eligibile at the end of the visit, a staff member will mail a study kit to the address on 
file, containing a reloadable gift card and urine collection supplies. The participant will be 
instructed on how to complete the required screening urine sample and will be instructed to mail 
back the urine specimen using the provided pre-paid materials.  
Protection against Risks 
If an AE is reported, the physician, nurse practitioner, and/or clinical nurse on staff in the 
MD Anderson Tobacco Treatment Program (TTP) will manage it. The TTP, directed by Co-I's 
Dr. Paul Cinciripini, and Maher Karam-Hage, provides clinical smoking cessation services to all 
MD Anderson patients and employees. The TTP medical staff, which includes an addiction 
psychiatrist, a physician's assistant, a nurse, and several clinical psychologists, participate in 
clinical trials and laboratory studies as part of their support for tobacco research conducted in 
the department. 
Confidentiality will be protected by identifying participants only by numbers in all data 
files. Identification numbers will only be connected to individual participant names in a separate 
file that will be accessible only by the PI and his staff. All study data files will be server-
maintained with limited access by using passwords and logins restricted to study staff. All 
information will be reported in aggregate form, and individual participants will not be identified in 
any public reports or documents.Data collected from study-provided smartphones will be de-
identified and the smartphones will be factory reset when returned to study staff. No data will be 
destroyed at the conclusion of this study. All data will be housed in the approved TRTP 
database(s), and data will be locked and de-identified prior to final analysis. We expect these 
procedures to be highly effective for protecting participant confidentiality. See the "Data and 
Safety Monitoring Plan" section for further details concerning protection against risks.  
Vulnerable Subjects 
Vulnerable subjects will not be enrolled in this study. 
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Potential Benefits of the Proposed Research to Research Participants and Others 
While there is no assurance that individuals will benefit from participation, their study 
experience could lead to a greater awareness of their smoking patterns, a reduction in cigarette 
consumption and/or a cessation attempt. For those who are interested in quitting smoking, we 
will provide 8 weeks of free smoking cessation treatment at MD Anderson's Tobacco Treatment 
Program after study participation is complete. 
Importance of the Knowledge to be Gained 
The potential benefit to society as a result of this study will be determine whether e-
cigarettes serve as a potentially reduced risk nicotine product compared to combustible tobacco 
smoking in male and female adult smokers. This proposal will investigate gender differences in 
the impact of switching to e-cigarettes on adult combustible tobacco smokers, who are currently 
uninterested in quitting smoking, on a variety of domains, including product use, product 
acceptability, reinforcement, and nicotine dependence symptoms. These potential benefits 
outweigh the risks associated with the proposed research. 
F. INCLUSION OF WOMEN 
Women will comprise approximately 50% of the targeted sample. In our previous 
nicotine research, we encountered no difficulty in recruiting women participants. 
G. INCLUSION OF MINORITIES 
According to the U.S. Census Bureau (2010), the population of the Houston community 
from which the sample will be drawn (including Harris County) is estimated at 4,070,989 people. 
The ethnic distribution has been reported as 73% white (35% of whom are not of Hispanic 
origin), 19% African American, 6% Asian, and 40% Hispanic or Latino (of any race). We expect 
to recruit minority smokers in proportion to the population demographics and CDC 2009 
smoking prevalence. We have had good success in recruiting from ethnic minority populations, 
especially African Americans, across all of our studies. Our success with Hispanic smokers has 
been more modest, although it must be noted that smoking rates are lower in the Hispanic and 
Latino community compared with rates in the non-Hispanic community. 
If needed, we may also attract minority smokers to the proposed study by using direct 
public service advertisements targeted to minority smokers on Houston radio stations and 
newspapers supporting a large minority audience. Houston has two television stations and 
several radio stations and newspapers that serve the Hispanic community. The Office of Public 
Affairs at MD Anderson has also agreed to assist us by arranging for our participation in 
institution-wide cancer prevention outreach programs directed at the Hispanic community. Such 
events are sponsored several times a year in areas of the community with high concentrations 
of minority Houstonians. We will focus additional recruitment effort on these venues to increase 
our recruitment of Hispanic smokers. Such efforts will be in addition to the normal interviews, 
advertisements, and news releases conducted on our behalf by the Office of Public Affairs at 
MD Anderson. 
H. INCLUSION OF CHILDREN 
We are not recruiting children because we are targeting adult combustible cigarette 
smokers who are currently uninterested in quitting but who are interested in trying electronic 
cigarettes to change smoking behavior, and limiting recruitment to smokers 21 years or older 
because recent changes to Texas law (as of 9/1/2019) make the use of tobacco products by 
those younger illegal. Also, children are likely to differ qualitatively and quantitatively from adults 
in the behaviors and biomarkers of interest. Therefore, a study investigating the transition from 
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combustible cigarette smoking to electronic cigarette use in children would require a separate 
focus that accounts for differences in this population.  
I. 
STUDY PRODUCT INVENTORY CONTROL 
Inventory control will be managed by the study team and overseen by the Program Director. 
Custody and distribution of the SREC device and the SREC tanks will be tracked from date of 
receipt into inventory at the study site through unique identifiers (serial numbers and batch 
codes) assigned by the manufacturer. The devices and tanks will be tracked on a log with a staff 
signature and date of distribution to the study participant as well as the date of return to the 
study site by the participant. See Appendix YY for the tracking template. Study product will be 
stored in locked cabinets with keys assigned to designated study staff. 
 
 
 
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J. LITERATURE CITED 
 
1. Adkison SE, O'Connor RJ, Bansal-Travers M, et al. Electronic nicotine delivery systems: 
international tobacco control four-country survey. Am J Prev Med. 2013;44(3):207-215. 
2. Brown CJ, Cheng JM. Electronic cigarettes: product characterisation and design 
considerations. Tob Control. 2014;23(3 (suppl 2)):ii4-ii10. 
http://tobaccocontrol.bmj.com/content/23/suppl_2/ii1.full.pdf+html. 
3. Harrell MB, Weaver SR, Loukas A, et al. Flavored e-cigarette use: Characterizing youth, 
young adult, and adult users. Prev Med Rep. 2017;5:33-40. 
doi:10.1016/j.pmedr.2016.11.001. 
4. Hatsukami D, Skoog K, Allen S, Bliss R. Gender and the effects of different doses of nicotine 
gum on tobacco withdrawal symptoms. Exp Clin Psychopharmacol. 1995;3:163-173. 
5. Killen JD, Fortmann SP, Newman B, Varady A. Evaluation of a treatment approach 
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