Assisting Smokers to Switch to a JUUL E-Cigarette by Devaluing Combustible Cigarettes
Phase: NA
Conditions: Smoking Cessation, Harm Reduction, E-Cig Use, Cigarette Smoking, Tobacco Dependence, Tobacco Use Cessation
Sponsor: Rose Research Center, LLC

Assisting Smokers to Switch to a JUUL E-
Cigarette by Devaluing Combustible Cigarettes 
 
 
NCT04188197 
 
Protocol V9.0 – 29 Sep 2020 

……………………………………………………………………………………………………………
…………………………….. 
Main Office • 7240 ACC Blvd. • Raleigh, NC 27617 
 
 
Clinical Study Protocol 
 
 
Study Title: 
Assisting Smokers to Switch to a JUUL E-Cigarette by 
Devaluing Combustible Cigarettes 
Version Number:   
Version 9.0 
Version/Revision Date:  September 29, 2020 
Principal Investigator: 
Jed E. Rose, Ph.D. 
Medical Supervision & 
Sub Investigator:   
Dr. Perry Willette, M.D., FAAFP 
Authors: 
Jed E. Rose, Ph.D.,  
President and CEO, 
Rose Research Center 
 
Dr. Perry Willette, M.D., FAAFP 
Medical Director, 
Rose Research Center 
Tanaia Loeback 
Executive Vice President,  
Rose Research Center 
 
David Botts 
Executive Vice President, 
Rose Research Center 
 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of United States law. No part of this document may be publicly 
disclosed without the written consent of the Rose Research Center, LLC. 
 

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TABLE OF CONTENTS 
List of Abbreviations ..................................................................................................................................... 5 
 
Introduction .......................................................................................................................................... 7 
1.1 
Background ................................................................................................................................... 7 
1.2 
Purpose of the Study ..................................................................................................................... 9 
1.3 
Study Design.................................................................................................................................. 9 
 
Study Objectives and Endpoints ........................................................................................................... 9 
2.1 
Switching from CC to the JUUL ..................................................................................................... 9 
2.2 
Measurement of Smoking Reward ............................................................................................. 10 
 
Investigational Plan ............................................................................................................................. 10 
3.1 
Overall Study Design and Plan .................................................................................................... 10 
3.2 
Reconditioning Instructions ........................................................................................................ 10 
3.3 
General Study Procedures .......................................................................................................... 10 
3.4 
Study and Session Durations ....................................................................................................... 11 
 
Study Population ................................................................................................................................. 11 
4.1 
Selection of Study Population ..................................................................................................... 11 
4.2 
Recruitment Strategies ............................................................................................................... 13 
4.3 
Subject Retention in the Study ................................................................................................... 13 
4.4 
Discontinuation of Subjects from Study ..................................................................................... 13 
4.5 
Lost to Follow-up ........................................................................................................................ 14 
4.6 
Violation of Inclusion/Exclusion Criteria ..................................................................................... 14 
4.7 
Subject Compensation ................................................................................................................ 14 
4.8 
Session and Response Windows ................................................................................................. 14 
 
JUUL e-Cigarette Device and Pods ...................................................................................................... 15 
5.1 
Description of JUUL ..................................................................................................................... 15 
5.2 
Description of JUUL Pods ............................................................................................................ 15 
5.3 
Product Use Timeframe .............................................................................................................. 15 
5.4 
Accountability and Compliance .................................................................................................. 15 
 
Study Procedures and Activities ......................................................................................................... 16 
6.1 
Informed Consent and Guidance ................................................................................................ 16 
6.2 
Safety Laboratory and Other Assessments ................................................................................. 16 
6.3 
JUUL Product Use Period ............................................................................................................ 20 

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6.4 
Schedule of Events ...................................................................................................................... 21 
 
Risk / Benefit Information ................................................................................................................... 21 
7.1 
Potential Risks ............................................................................................................................. 21 
7.2 
Protection Against Risks .............................................................................................................. 22 
 
Quality Control and Quality Assurance ............................................................................................... 23 
8.1 
Training of Staff ........................................................................................................................... 23 
8.2 
Audits and Inspections ................................................................................................................ 23 
 
Reporting of Adverse Events ............................................................................................................... 23 
9.1 
Definitions ................................................................................................................................... 23 
9.2 
Collection of Safety Events from Subjects .................................................................................. 24 
9.3 
Assessment of Adverse Events ................................................................................................... 25 
9.4 
Follow-up of Non-serious and Serious Adverse Events .............................................................. 25 
9.5 
Reporting of Safety Events .......................................................................................................... 25 
9.6 
Reporting and Follow-Up of Pregnancies ................................................................................... 25 
9.7 
Adverse Event Leading to Discontinuation ................................................................................. 26 
 Data Management .............................................................................................................................. 26 
10.1 
Data Collection Procedures ......................................................................................................... 26 
10.2 
Protocol Deviations / Noncompliance ........................................................................................ 26 
10.3 
Data Capture ............................................................................................................................... 26 
10.4 
Data Handling .............................................................................................................................. 27 
 Data Analytic Approach ...................................................................................................................... 27 
11.1 
Primary Outcome Measure ......................................................................................................... 28 
11.2 
Secondary Outcome Measure .................................................................................................... 28 
 Ethics and Regulations ........................................................................................................................ 28 
12.1 
IRB Approval ................................................................................................................................ 28 
12.2 
Ethical Conduct of the Study ....................................................................................................... 28 
12.3 
GCP and Regulatory Requirements ............................................................................................. 29 
12.4 
Subject Information and Consent ............................................................................................... 29 
12.5 
Amendment to Informed Consent Form .................................................................................... 29 
 Administrative Considerations ............................................................................................................ 29 
13.1 
Subject Confidentiality ................................................................................................................ 29 
13.2 
Record Retention ........................................................................................................................ 30 
 References .......................................................................................................................................... 31 

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FIGURES 
Figure 1 – Craving for cigarettes ................................................................................................................... 8 
Figure 2 - Satisfaction Ratings ....................................................................................................................... 8 
Figure 3 – Satisfaction Ratings ...................................................................................................................... 9 
Figure 4 - Timeline ........................................................................................................................................ 9 
Figure 5 - Schedule of Events ...................................................................................................................... 21 
 
APPENDIX 
Appendix 1 – Medical History Form ............................................................................................................ 32 
Appendix 2 – Patient Health Questionnaire (PHQ-9) ................................................................................. 37 
Appendix 3 – Registration Form ................................................................................................................. 38 
Appendix 4 – Research Payment Verification Form ................................................................................... 39 
Appendix 5 – Review of Systems ................................................................................................................ 40 
Appendix 6 – Session Payment Form .......................................................................................................... 42 
Appendix 7 – Smoking History .................................................................................................................... 43 
Appendix 8 – modified Cigarette Evaluation Questionnaire (mCEQ) ......................................................... 45 
Appendix 9 – Assessment of Behavioral OUTcomes (ABOUT).................................................................... 46 
Appendix 10 – Employment History ........................................................................................................... 48 
Appendix 11 – Fagerström Test for Nicotine Dependence (FTND) ............................................................. 50 
Appendix 12 – Reasons to Smoke ............................................................................................................... 51 
Appendix 13– SMS Daily Survey .................................................................................................................. 52 
Appendix 14 – JUUL Flavor Assessment Questionnaire.............................................................................. 53 
Appendix 15 - 6 Month Follow Up Survey………………………………………………………………………………………………54 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
ALT 
Adverse event 
 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CC 
Combustible cigarette 
CFR 
Code of Federal Regulations 
CO 
Carbon monoxide 
CRF 
Case report form 
CRM 
Customer relationship management 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration  
FTND 
Fagerström Test for Nicotine Dependence 
GCP 
Good Clinical Practice 
HCG 
Human chorionic gonadotropin 
HTTPS 
Hyper Text Transfer Protocol Secure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
mCEQ 
modified Cigarette Evaluation Questionnaire 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mg 
Milligram 
mL 
Milliliter 
NRT 
Nicotine Replacement Therapy 

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PHQ-9 
The Patient Health Questionnaire 
ppm 
Parts per million 
RBC 
Red blood cell (count) 
RRC 
Rose Research Center, LLC. 
SAE 
Serious adverse event 
SMS 
Short Message Service 
SREC 
Standardized Research E-Cigarette 
SOP 
Standard operating procedure 
SQ 
Sensory Questionnaire 
SSL 
Secure Sockets Layer 
TLS 
Transport Layer Security 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
 
 
 

 INTRODUCTION 
1.1 BACKGROUND 
The burden of disease and death attributable to combustible cigarette (CC) smoking is enormous, with 
an estimated 540,000 premature deaths annually in the United States [1]. Considerable progress has 
been made toward reducing the prevalence of smoking, through education about the harms of smoking, 
increased taxation/regulation and the greater availability of cessation treatments. However, despite a 
gradual reduction in smoking prevalence over the years, in 2015, 15% of the adult U.S. population, or 35 
million individuals, continued to smoke [2]. 
The 2010 U.S. Surgeon General’s Report [3] implicated combustion products, rather than nicotine, in 
contributing to the major smoking-related diseases. Therefore, e-cigarettes may reduce health risks to 
the user by avoiding combustion. Instead, they heat a solution (usually a mixture of propylene glycol and 
glycerol) that also contains nicotine and flavorings, in order to generate an aerosol at much lower 
temperatures than burning cigarettes [4]. Measures of constituents in e-cigarette aerosol show 
substantial reductions in most toxicants, including carbon monoxide, carcinogens (including tobacco-
specific nitrosamines and polycyclic aromatic hydrocarbons), and volatile organic compounds such as 
acrolein, acrylamide, acrylonitrile, 1,3-butadiene and ethylene oxide [5, 6]. This reduction in toxicant 
yield could potentially translate into a marked reduction in risk to the smoker. 
Previous studies have shown that smokers who are offered e-cigarettes as an alternative to combustible 
cigarettes (CCs) show substantial reductions in CC use. Nides et al. [7], for example, showed that there 
was a 39% average reduction in the number of cigarettes smoked daily when smokers were offered a 
nicotine-containing e-cigarette. A Cochrane Collaboration Review [8] summarized evidence that 
nicotine-containing e-cigarettes were significantly more effective than placebo in producing substantial 
reductions (at least 50%) in smoking; in two studies that were reviewed, 36% of smokers reduced their 
CC use by at least half compared to 27% with placebo (Relative risk of 1.31, 95% CI 1.02 to 1.68). 
Moreover, in an additional study, nicotine-containing e-cigarettes were also more effective than 
nicotine skin patches in reducing CC use: 61% of smokers reduced their CC use by at least half with e-
cigarettes versus 44% with nicotine patch (relative risk of 1.41, 95% CI 1.20 to 1.67). Although these 
findings are encouraging in showing promise of e-cigarettes, they also indicate that a high percentage of 
smokers in these studies continued to use CC after the introduction of e-cigarettes. Population-based 
surveys also suggest that there is a high rate of failure to completely convert from CC to e-cigarettes. For 
example, the U.S. National Health Interview Survey of 2014 [9] found that, while 12.6% of adults (>90% 
of whom were current or former smokers) had ever tried an e-cigarette, only about 3.7% currently used 
e-cigarettes every day or some days. Similarly, a cross-sectional survey of 28-member states of the 
European Union also found that only about 9% of ever e-cigarettes users were current daily users. 
Although cross-sectional data cannot provide definitive conclusions about longitudinal trajectories of 
product use, these data suggest that the majority of smokers who try e-cigarettes do not adopt them 
exclusively to replace combustible cigarettes. Additionally, a recent population study found no 
significant reductions in toxicant exposure among dual users of combustible cigarettes and e-cigarettes, 
but extensive reductions of most toxicant levels were observed in exclusive e-cigarette users [9]. 

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Therefore, much progress needs to be made in helping CC smokers make a complete transition to e-
cigarettes, in order to realize the full potential of e-cigarettes as a harm reduction strategy. 
To evaluate the cigarette devaluation strategy, we conducted a pilot study with six smokers, who 
participated in a laboratory session as well as a one-week home evaluation. Subjects (two Caucasians, 
three African Americans, and one “other”) included one male and five females, all of them menthol 
smokers, with a mean age of 42 (SD=11.1), and an average baseline cigarette consumption of 9.3 
(SD=2.3) cigarettes/day. Subjects had a mean FTND 
score of 4.7 (SD=2.3), indicating a moderate level of 
dependence. The e-cigarette studied was the 
MarkTen® brand, with 32 mg of nicotine per 800 mg 
of e-liquid in each cartridge.  
In the laboratory session, craving for cigarettes was 
substantially alleviated by the use of the e-cigarette 
(Figure 1). These data are particularly impressive 
given that the subject sample consisted of menthol 
smokers and the e-cigarette used was non-menthol.  
Participants also rated the rewarding effects of smoking their usual brand of cigarette, either preceded 
by use of an e-cigarette or after 60 minute deprivation. The results, depicted below in Figure 2, show 
that the reported satisfaction ratings were significantly attenuated when the usual brand cigarette was 
smoked immediately after the e-cigarette.  
Moreover, the results in Figure 2 show that the 
satisfaction from smoking the usual brand was 
reduced to a point comparable to that of the e-
cigarette. This result, after a single experience, 
supports the hypothesis that over the course of 
days, the cigarette devaluation procedure will 
level the playing field to allow subjects to more 
completely switch from CC to an e-cigarette. 
Indeed, data collected during the subsequent 
seven days were quite promising and are 
summarized below in Figure 3. In this home 
evaluation, self-reported compliance with the 
pairing instruction (in the absence of coercion or 
financial incentives) was excellent. Participants reported using the e-cigarette immediately prior to CC 
over 95% of the time. 
Satisfaction ratings showed a trend over time in the predicted direction. It is particularly striking that, 
although subjects rated their usual brands of cigarettes more satisfying initially, by the end of the seven 
1
2
3
4
5
Craving rating  (1-7 scale)
Pre E-cig use
Post E-cig use
Craving for cigarettes before and after ten puffs from an E-cigarette. 
Figure 1 – Craving for cigarettes 
1
2
3
4
5
6
7
Satisfaction rating (1-7)
e-Cigarette 
Usual brand right 
after e-Cigarette 
Usual brand after 60 
min. deprivation 
Satisfaction ratings of the e-cigarette and usual brand of cigarette, either 
preceded by e-cigarette use or after 60 min deprivation.
Figure 2 - Satisfaction Ratings 

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days there was a trend for the e-cigarette to be rated 
more satisfying. These results provide support for the 
feasibility of the cigarette devaluation procedure and 
suggest that this procedure will have marked effects on 
the rewarding value of CC and the JUUL. 
1.2 PURPOSE OF THE STUDY 
This study will evaluate the effects of a reward 
devaluation strategy on switching from CC to JUUL. There 
is no therapeutic intent in that smokers’ nicotine/tobacco 
dependence will not be treated; the goal is to switch from 
one form of nicotine/tobacco dependence (CC) to dependence on a different tobacco product (JUUL e-
cigarettes). Subjects will not be encouraged to terminate their use of e-cigarettes If they switch 
completely to use of JUUL.  The switching strategy being evaluated is one in which smokers use the JUUL 
e-cigarette immediately before any combustible cigarettes (CCs) are smoked. This procedure is 
predicted to accomplish three goals: 1) the rewarding effects of CC will be disrupted because subjects 
will already have attained fairly high peak nicotine concentrations immediately before smoking the 
cigarette. This reduces the rewarding effect of smoking, in part from receptor desensitization that 
occurs following nicotine exposure, which reduces the response to a subsequent dose of nicotine, and in 
part from satiating the drive to smoke; 2) the use of the JUUL will become associated with the same 
cues that elicit smoking, thereby promoting the substitution of JUUL use for CC use; and 3) ad libitum 
nicotine intake from the JUUL and its rewarding effects will be maximized because, unlike CC, they will 
be experienced after a period of nicotine deprivation. Thus, despite a lower per-puff nicotine dose 
relative to CC, the pharmacologic impact and reinforcing effect will be maximized. The study will 
evaluate two flavors (Menthol and Virginia Tobacco), randomly assigned, to determine if flavor 
assignment (similar to the subjects’ usual brand of CC or different than the subjects usual brand CC) has 
an effect on the success of this reconditioning procedure. 
1.3 STUDY DESIGN 
 
Figure 4 - Timeline 
 STUDY OBJECTIVES AND ENDPOINTS 
2.1 SWITCHING FROM CC TO THE JUUL 
We will assess the effects of devaluation on switching from CCs to the JUUL, assessed by self-reported 
consumption of both products, and expired air carbon monoxide levels (CO). 
Scr
V7
WK9
WK10
WK12
Complete Switch to JUUL
Into to JUUL
WK11
WK1
WK2
WK3
WK4
V6
WK6
WK7
WK8
V2
WK5
V3
V4
V5
Figure 3 – Satisfaction Ratings 
Satisfaction ratings over one week of cigarette devaluation. 

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2.2 MEASUREMENT OF SMOKING REWARD 
Smoking reward will be measured using the modified Cigarette Evaluation Questionnaire (mCEQ). 
Changes in rewarding effects over the first week will be correlated with e-cigarette use and subsequent 
reductions in CC smoking over the full 12-week study period. 
 INVESTIGATIONAL PLAN 
3.1 OVERALL STUDY DESIGN AND PLAN 
This small-scale, open-label study (N= 50) will evaluate a reward devaluation strategy in which smokers 
use the JUUL e-cigarette immediately before any combustible cigarettes. The outcome of this strategy 
will be compared to the following benchmarks. Results will fall into one of the following two categories: 
3.1.1 Complete switching rate of 48% 
If this reconditioning procedure achieves at least a 40% (20/50 or 10/25 for matched or unmatched 
flavor) switching rate tested at visit 7, it will be viewed as having considerable promise, and will be 
advanced to larger-scale (~N=200) randomized controlled clinical trials (RCTs) to provide a rigorous 
evaluation of its efficacy and effectiveness. These trials may include both double-blind efficacy trials and 
unblinded, pragmatic, real-world effectiveness trials. Future trials will be submitted to the Institutional 
Review Board (IRB) as new protocols.  
3.1.2 Switching Thresholds Not Achieved 
If the above switching rate threshold is not met, the reward devaluation procedure will be considered 
unpromising, and additional studies will not be run.  
3.2 RECONDITIONING INSTRUCTIONS 
The JUUL will be dispensed, and subjects will be instructed to use the JUUL as often as they like. They 
will also be instructed to use JUUL immediately before each CC to relieve their craving as much as 
possible before smoking their usual brand. The JUUL will also be the first product that they are 
instructed to use each morning. Smokers will be told to try to completely substitute JUUL for CCs by the 
end of the first week of use. Subjects will be questioned by study staff to ensure that they understand 
these instructions.  
3.3 GENERAL STUDY PROCEDURES 
During the product use period, daily text messaging will be used to assess JUUL and CC use, as well as to 
obtain a brief assessment of associated subjective rewarding effects (appendix 13). Self-reported 
compliance with the instruction to pair each CC with JUUL use will be assessed. At each session, expired 
air CO will be measured along with blood pressure, heart rate, respiratory rate and body weight. 
Participants will also complete questionnaires rating subjective effects of smoking and JUUL use. 
Subjects will be given enough JUUL e-cigarette pods to last until their next scheduled session, along with 
an extra 4 days’ worth to allow for flexibility in case sessions need to be rescheduled. JUUL usage will be 
tracked not only by self-reported number of occasions used, but also by pod counts (empty and full) and 
determination of residual levels of partially used pods. 

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3.4 STUDY AND SESSION DURATIONS 
The total duration for a subject will be approximately 12-13 weeks. This will allow for a grace period for 
scheduling the first study session and completing the 12-week product use period.  
The Screening Session will last approximately two hours and the Laboratory Sessions (V2 – V7) will each 
last approximately one hour.  
 STUDY POPULATION 
4.1 SELECTION OF STUDY POPULATION 
4.1.1 Inclusion Criteria 
Each subject must meet all of the following inclusion criteria before enrollment at V2: 
Inclusion Criteria 
1. Has signed the ICF and is able to understand the information provided in the ICF. 
2. Is 21 to 65 years of age (inclusive) at screening.  
3. Smokes ≥ 10 commercially available CCs per day (no brand restrictions), for the last 12 months. 
4. Expired air CO reading of at least 10 ppm as assessed at the screening session. 
5. Interested in switching to an electronic cigarette. 
6. Willing and able to comply with the requirements of the study. 
7. Owns a smart phone with text message and data capabilities compatible with necessary surveys. 
4.1.2 Exclusion Criteria 
Potential subjects who show or report indications of or self-report a diagnosis of conditions listed below 
may be excluded from the study. If the study physician determines, through the course of pre-screening, 
a physical exam, medical history, current medications, ECG, or laboratory finding(s), that an individual 
has one of the conditions listed below or reveals other information that may jeopardize the subjects’ 
safe study participation, then they may be excluded. For medical conditions that do not appear below, 
the subject may be enrolled if the study physician does not feel that the medical condition would 
jeopardize data validity or safe study participation. 
Exclusion Criteria 
1. Is unhealthy or cannot participate in the study for any reason (e.g., medical, psychiatric, and/or 
social reason) as judged by the Investigator or designated medical staff based on all available 
assessments from the screening period (e.g., safety laboratory, vital signs, physical examination, 
ECG, concomitant medications and medical history).   
2. PHQ-9 score greater than 9, or a score greater than 0 on item #9 (“Thoughts that you would be 
better off dead, or of hurting yourself in some way”) at screening. 

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Exclusion Criteria 
3. Planned use of an FDA-approved smoking cessation product during the study. 
4. High Blood Pressure (systolic >150 mm Hg, diastolic >95 mm Hg) at screening.  
5. Body mass index (BMI) less than 15.0 kg/m2 or greater than 40.0 kg/m2. 
6. Coronary heart disease, structural cardiac disease (including, but not limited to valvular heart 
disease or cardiac murmurs), cardiac dysrhythmias, syncope, cardiac chest pain, or history of 
heart attack or heart failure. 
7. 
Has received psychotherapy or behavioral treatments within 30 days of screening, or during the 
study.   
8. 
Taking antidepressants or psychoactive medications (e.g. antipsychotics, benzodiazepines, 
hypnotics). 
9. 
Use of any of these products in the past 30 days:   
a. Illegal drugs (or if the urine drug screen is positive for cocaine, THC, amphetamines, 
methamphetamines, or opiates); 
b. Experimental (investigational) drugs that are unknown to subject;  
c. Chronic opiate use. 
10. Use of smokeless tobacco (chewing tobacco, snuff), cigars (except for “Black & Mild” cigars or 
Cigarillos), pipes, hookah, e-cigarettes, nicotine replacement therapy or other smoking cessation 
treatments within 14 days of screening. 
11. Pregnant or nursing (by self-report) or positive pregnancy test. 
12. Subject enrollment numbers met. 
4.1.3 Women of Childbearing Potential 
Pregnant or breastfeeding women will be excluded from the study. All females will undergo a serum 
pregnancy test at screening and a urine pregnancy test at every visit. Heterosexually active females of 
childbearing potential (not post-menopausal) must agree to use medically acceptable contraceptives 
during the course of the trial. Medically acceptable contraceptives include: (1) surgical sterilization (such 
as a tubal ligation, hysterectomy, or Essure), (2) approved hormonal contraceptives (such as birth 
control pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used 
with a spermicide, or (4) an intrauterine device (IUD).  Contraceptive measures such as Plan BTM, sold for 
emergency use after unprotected sex, are not acceptable methods for this study. Female participants 
will be encouraged in the consent form to notify study staff if they believe a change in their pregnancy 
status has occurred during the trial.  
Post-menopause is defined as the time after which a woman has experienced 12 consecutive months of 
amenorrhea (lack of menstruation).  

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4.2 RECRUITMENT STRATEGIES 
Subjects will be selected through an IRB approved generic recruitment advertisements which are 
designed to recruit subjects into the volunteer database for future smoking and tobacco related 
research at the Rose Research Center. For this database, many of the subjects have provided basic 
smoking history data, along with demographic information, which will allow for screening and selection 
of potentially interested subjects. 
Subjects who call in will be screened into the volunteer database, and if they pre-qualify, will be offered 
the option to prescreen for this protocol. 
Subjects will be contacted only with IRB approved appropriate materials and information, submitted 
along with this protocol. These documents will include a brief description of the study and information 
on how to prescreen for participation. Subjects will be contacted by phone, email and/or text messages 
which prompt interested subjects to prescreen through an electronic screen form. 
4.2.1 
Pre-Screening 
Pre-screening will be completed prior to the screening visit (V1) for all subjects. Participants will be 
provided with a set of IRB approved questions directly related to the inclusion and exclusion criteria. 
Based upon the outcome of these questions, potential participants may be scheduled for a screening 
visit (V1). 
4.3 SUBJECT RETENTION IN THE STUDY 
All candidates who schedule a screening visit (V1) will receive a series of email, text, and/or telephone 
reminders; candidates are also permitted, through these communications, to confirm, cancel, or 
reschedule their appointments. 
4.4 DISCONTINUATION OF SUBJECTS FROM STUDY 
Discontinued subjects will include both subjects who withdraw from the study (subject’s decision) and 
subjects who are discontinued from the study (following Investigator’s decision). A subject can only be 
discontinued from the study after randomization at visit 2. Subjects that are not randomized are 
considered screen failures. 
Subjects will be informed that they are free to withdraw from the study at any time. Subjects should be 
questioned for the reason for withdrawal from the study, although they are not obliged to disclose this 
information.  
Subjects discontinued from the study cannot re-enter the study.  
4.4.1 
Subjects will be discontinued from the study for any of the following reasons: 
• Withdrawal of informed consent. 
• Any adverse effect or condition that would jeopardize continued safe study participation. 
• Pregnancy test is positive (for female subjects).  
• Discontinuation is considered to be in the best interest of the subject, or for other subjects 
participating in the study, as judged by the Investigator. 

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4.4.2 
Subjects may be discontinued from the study for any of the following reasons on the judgment of 
the Investigator: 
• No-show to appointments and unable to reschedule within the visit window. 
• The misuse or abuse of study related equipment. 
• Noncompliance to study procedures. 
4.5 LOST TO FOLLOW-UP 
For subjects lost to follow-up, a reasonable number of attempts to contact the subject (including written 
correspondence and/or phone calls) will be made and documented in the source documents. The date 
of the last contact (e.g. last visit, last phone call) will be recorded in the source document. When the 
PI(s) or designee(s) declare(s) a subject is lost to follow-up, the lost to follow-up date will be recorded 
and will correspond to the date of the end of study (EOS) of the subject.  
4.6 VIOLATION OF INCLUSION/EXCLUSION CRITERIA 
Subjects who, after signing the ICF, do not meet the inclusion and exclusion criteria will not be enrolled 
in the study and will be considered screen failures. Re-screening for the study is not permitted. 
4.7 SUBJECT COMPENSATION 
There will be a payment of $25 for the Screening Session (V1) and $75 at the completion of each study 
session V2 through V7. Subjects will also receive an additional payment of $5/day for responding to daily 
text messages during the 12-week product use period. 
If subjects are asked by study staff to return to the center to complete or redo parts of the screening in 
situations of equipment malfunctions or other circumstances that are beyond the subjects’ control, 
subjects may be reimbursed for mileage. 
Subjects who decide to withdraw from the study will be paid for the part of the study they have 
completed.  
4.8 SESSION AND RESPONSE WINDOWS 
4.8.1 
V2 Session Window 
Participants may attend V2 up to 30 days post Screening Session (V1).  
4.8.2 
All other visit Windows 
Participants may attend sessions up to four-calendar day’s pre or post the scheduled visit. 
4.8.3 
SMS Response Window 
The SMS response window will be open until the next SMS message is sent.  

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 JUUL E-CIGARETTE DEVICE AND PODS 
5.1 DESCRIPTION OF JUUL 
The JUUL is a breath-actuated, rechargeable closed e-cigarette system. Each JUUL pod is pre-filled with 
0.7 mL of e-liquid. The e-liquid ingredients include: glycerol, propylene glycol, flavor, nicotine (5% by 
weight), and benzoic acid. 
5.2 DESCRIPTION OF JUUL PODS 
Each JUUL Pod contains 0.7mL with 5% nicotine by weight, approximately equivalent to one pack of 
cigarettes or 200 puffs. Multiple flavors are available, but this study will focus on “Virginia Tobacco” and 
“Menthol” flavored pods, with subjects randomly assigned to one of these flavors (see Section 1.3 
regarding randomization scheme). At Visit 2, subjects will be allowed to use the two different flavors ad 
libitum, presented in counterbalanced order (randomly assigned), with a 10-minute period between 
each trial use. Research staff will inquire whether the subjects are willing and able to use the JUUL 
(either flavor) during the study, to determine eligibility, and prior to randomization of flavor assignment.  
Subjects will be provided with enough pods of their assigned flavor to use during the study (150% of 
reported usage, with each pod approximately equivalent to one pack of cigarettes). JUUL Pods are 
sealed system cartridges for use in the JUUL e-cigarette. Each pod is contained in tamper resistant 
blister packs of four pods. 
5.3 PRODUCT USE TIMEFRAME 
The maximum amount of time the JUUL will be in use will be for twelve weeks, plus up to an additional 
four days (to allow for the scheduling window). Subjects will be instructed on how to use the JUUL e-
cigarette prior to dispensing. 
5.4 ACCOUNTABILITY AND COMPLIANCE 
5.4.1 
Dispensing Product 
The JUUL will be dispensed by the Investigator or designated study staff, as per study design. Subjects 
will be dispensed pods initially at 150% based on their daily smoking habits as reported at baseline (one 
pod per pack of cigarettes smoked per day). Subjects may come into the office between visits to get 
additional supplies if needed. Each dispensation and collection of the product will be recorded. 
5.4.2 
Storage and Accountability 
All JUUL products will be stored in a locked, limited-access area at the study site and kept at a controlled 
room temperature (defined as 20 - 25C [68 - 77F], with excursions permitted to 15 - 30C [59 - 86F]). 
JUUL products should not be exposed to extreme heat or cold.  
5.4.3 
Compliance 
Compliance will be ensured by strict distribution of the product and collection of devices (used and 
unused) which will be documented in appropriate logs.  

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 STUDY PROCEDURES AND ACTIVITIES 
Personnel performing study assessments must have appropriate and documented training. An overview 
of all study assessments is shown in the schedule of events (Section 7.7). Study personnel will adhere to 
standard operating procedures (SOPs) for all activities. Appropriate medical advice will be provided by 
qualified staff (licensed providers) to the subject in case of any medical findings requiring health care. 
6.1 INFORMED CONSENT AND GUIDANCE 
Prior to any study assessments being performed, the subject will be asked to provide their written 
consent to participate in the study on an informed consent form (ICF). All assessments must start after 
the time of ICF signature by the subject for study participation. 
Designated staff, under the supervision of the Principal Investigator, will obtain informed consent from 
each participant. The person obtaining consent provides the participants with a printed document that 
explains the procedures and risks. Designated staff will answer any questions. A signed copy of the 
informed consent form will be given to each participant. Participants are informed that they may 
withdraw from participation in the study at any time without penalty.  
Because of the nature of this study and the number of questionnaires that subjects are expected to 
complete, we do not recruit potential subjects who do not read, are blind, or who do not 
read/understand English. We are not equipped to validate alternate versions of our questionnaires, 
most of which are not published. Questionnaires cannot be administered orally by a translator or by 
technicians to illiterate or blind subjects because the data obtained would not be comparable to self-
administered questionnaires. 
6.2 SAFETY LABORATORY AND OTHER ASSESSMENTS 
An overview of all assessments is provided in the schedule of events (Section 6.4). 
Non-fasting blood samples and urine samples will be collected by qualified and trained site personnel. 
Subjects should be in a seated position during blood collection. 
The maximal total volume of blood drawn for each subject will be around 30 mL for clinical chemistry, 
hematology, and serum pregnancy (for females). 
Samples for clinical chemistry, hematology, and serum pregnancy test will be sent to LabCorp for 
analysis. Urinalysis will also be performed by LabCorp. 
The results of the clinical chemistry, hematology and urine analysis safety panel will not routinely be 
given to subjects to send or be sent to their physician to include in their medical record. However, if the 
subject’s laboratory results are clinically relevant (including positive pregnancy tests), the research 
medical staff will send the subject a copy of the laboratory results. Subjects who are accepted into the 
study but need medical follow-up due to minor abnormalities in laboratory results (at any session) will 
also receive a copy of the laboratory results. 
6.2.1 
Safety Laboratory  
Safety laboratory includes clinical chemistry, hematology, and urinalysis and will be assessed at Visit 1. 

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6.2.1.1 
Clinical Chemistry 
Clinical Chemistry 
Sodium  
Chloride 
Potassium  
Carbon dioxide 
Blood urea nitrogen (BUN) 
Creatinine  
Glucose 
Calcium 
Total protein 
Albumin  
Bilirubin 
Alkaline phosphatase (AP) 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
6.2.1.2 
Hematology 
Hematology 
Red blood cell (RBC) count  
WBC count  
Hemoglobin  
Differential white blood cell (WBC) count  
Hematocrit 
Platelet count  
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular hemoglobin (MCH) 
 
6.2.2 
Urine Samples 
Urine samples will be collected for the urine drug screen (at screening session), urine pregnancy test (at 
all sessions except screening), and safety urinalysis (at screening session). The urine drug screen and 
pregnancy tests will be performed by study personnel at the study site. The urine sample collected for 
urinalysis will be sent to LabCorp for testing. 
In case of any positive pregnancy test, the Investigator or designee will inform the participant about the 
risks associated with smoking during pregnancy. 
In the event of a positive urine drug test for cocaine, THC, opiates, amphetamines, or 
methamphetamines at the screening visit (V1), subjects are notified that they have been excluded from 
study participation because of a positive drug test. 
Urinalysis 
pH 
Red blood cell traces 
Bilirubin 
Protein 
Glucose 
Specific gravity 
Nitrite 
WBC Esterase 
Table 1 - Urinalysis Assessments 
Drug Screening 
Amphetamine 
Cocaine 
THC 
Methamphetamine 

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Opiates 
Table 2 - Drug Screening 
6.2.3 
Serum Pregnancy Test 
Serum pregnancy test will be performed during the screening visit for all females. 
Serum Pregnancy Test 
Quantitative human chorionic gonadotropin (HCG) test 
6.2.4 
Urine Pregnancy Test 
The urine pregnancy test will be performed by study personnel on site for all females at each visit 
(except screening). 
6.2.5 
Electrocardiogram (ECG) 
ECG recording will be performed as per the site’s standard operating procedures. A standard 12-lead 
ECG will be recorded after the subject has rested for at least 5 minutes in a supine position.  
The following parameters will be documented: heart rate, PR interval, QRS interval, QT interval, and QTc 
interval. Every ECG has to be assessed as normal, abnormal – not clinically significant, or abnormal – 
clinically significant. 
ECG print-outs will be interpreted by a qualified physician or licensed medical provider. Any print-outs of 
ECGs on thermo-sensitive paper must be photocopied and stapled together for inclusion in the source 
documents and signed by the Investigator or designee.  
6.2.6 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse rate, temperature and respiratory rate), will be 
measured in sitting position after the subject has rested for at least 5 minutes. After two minutes of 
standing, a second blood pressure reading (systolic and diastolic) and pulse rate will be obtained at the 
screening visit (V1). 
6.2.7 
Physical Examination 
A complete physical examination, including auscultation and palpation will be performed. A complete 
physical examination will include review of general appearance, hair and skin, head, eyes, ears, nose and 
throat, neck, chest, abdomen, dentition, cardiovascular, musculoskeletal and neurological systems. The 
physical examination is to be conducted by a designated fully trained representative. 
Appropriate medical recommendations will be provided to the subject if any medical findings requiring 
health care are identified. 
6.2.8 
AE/SAE Reporting 
Any adverse events (such as cough, sore throat, nausea) since the last session or during the laboratory 
sessions will be assessed. AEs/SAEs will be assessed using face-to-face interviews at the indicated time 
points, and spontaneous reporting from the time of ICF signature until the EOS for the subject. 
6.2.9 
Questionnaires 
The questionnaires will be administered to the subjects using paper questionnaires and/or an electronic 
data collection system. The results of questionnaires will be transcribed into the Case Report Form (CRF) 
as needed.  

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6.2.9.1 
mCEQ – The modified Cigarette Evaluation Questionnaire  
The Cigarette Evaluation Questionnaire was initially developed in the PI's laboratory and used in 
numerous studies to assess the effects of pharmacological treatments on the rewarding effects of 
cigarette smoking. The mCEQ (Appendix 8) is a widely used and validated questionnaire that will be used 
to assess the degree to which subjects experience the reinforcing of smoking, providing five subscale 
scores: smoking satisfaction (satisfying, tastes good, enjoy smoking), psychological rewards (calms 
down, more awake, less irritable, helps concentrate, reduces hunger), aversion (dizziness, nauseated), 
enjoyment of respiratory tract sensations (single-item assessment), craving reduction (single-item 
assessment). Subjects will be asked to assess the 12 items of the questionnaire on a 7-point scale, 
ranging from “not at all” to “extremely”. 
6.2.9.2 
Smoking History Questionnaire 
The Smoking History (Appendix 7) is a questionnaire designed to help assess the subject’s current and 
past smoking habits. This questionnaire will be used to check eligibility criteria. 
6.2.9.3 
Registration Form 
The Registration form (Appendix 3) is an internal questionnaire designed to collect demographic 
information about subjects. 
6.2.9.4 
FTND -- The Fagerström Test for Nicotine Dependence 
The Fagerström Test for Nicotine Dependence (Appendix 11) is a six-item questionnaire developed by 
Karl-Olov Fagerström and is used to determine an individual’s level of nicotine dependence. The scores 
obtained on the test allow the classification of nicotine dependence in three different levels: mild (0-3 
points), moderate (4-6 points), and severe (7-10 points). 
6.2.9.5 
PHQ-9 -- The Patient Health Questionnaire 
The PHQ-9 (Appendix 2) is used to screen for depression and is used to help determine eligibility. 
6.2.9.6 
Reasons to Smoke 
The Reasons to Smoke questionnaire (Appendix 12) is used to determine the most important reasons to 
smoke for each subject. 
6.2.9.7 
ABOUT – Assessment of Behavioral Outcomes 
The ABOUT questionnaire (Appendix 9) is a self-report instrument that measures dependence in a 
directly comparable way across different tobacco- and nicotine-containing products.  
6.2.9.8 
Employment History 
The Employment History (Appendix 10) is an internal questionnaire designed to collect information 
about a subjects’ social economic status. 
6.2.10 Expired Air CO Breath Test  
Subjects will exhale into the Vitalograph CO monitor for determination of CO breath levels. This will be 
performed at each visit. 
6.2.11 Medical History and Concomitant Disease 
Relevant medical history and concomitant disease will be documented at the screening visit (V1). 
Medical history is defined as any condition that started and ended prior to screening. A concomitant 

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disease is defined as any condition that started prior to screening and is still ongoing at V1 (this may also 
include findings detected during the screening visit (V1)). 
6.2.12 Prior and Concomitant Medication 
All medication taken 30 days prior to the screening visit (V1) and during the study will be documented. 
Medications which are stopped before the screening visit (V1) will be considered as prior medication. 
Medications which are started prior to the screening visit (V1) and which are still being taken by the 
subject during the study, as well as medications that are initiated after the screening visit (V1) will be 
considered as concomitant medications. This applies to both prescription and over-the-counter products 
(e.g., vitamins). 
Records of prior and concomitant medications taken include the drug name (preferably both generic 
and trade name), route of administration, dose/unit, frequency of use, indication, the start and, if 
applicable, the stop date. Any therapy changes (including changes of regimen) during the study have to 
be documented. 
6.2.13 Demographics 
Sex, date of birth, race and ethnicity will be recorded for each subject. 
6.2.14 Body Height and Body Weight 
Body weight will be measured at each visit. Height and weight will be measured at screening, and body 
mass index (BMI) will be calculated. 
6.3 JUUL PRODUCT USE PERIOD 
During the 12-week product use period, daily text messaging will be used to assess JUUL and CC use, as 
well as to obtain a brief assessment of the associated subjective rewarding effects and craving. Self-
reported compliance with the protocol (instruction to pair each CC with JUUL use) will also be assessed.  
6.4 6-MONTH FOLLOW-UP 
Participants who complete the study, will be contacted six months after the complete switch day 
utilizing an automated SMS messaging system, to ascertain their current smoking status and use of e-
cigarettes. 

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6.5 SCHEDULE OF EVENTS 
 
Figure 5 - Schedule of Events 
 RISK / BENEFIT INFORMATION 
7.1 POTENTIAL RISKS 
Continuing to smoke carries significant health risks; however, the participants in the studies will have 
expressed no intention to quit smoking within the brief study duration, and hence will not be exposed to 
significant additional risks.  

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7.1.1 
Use of JUUL 
The common risks associated with e-cigarette use include coughing, dry mouth, throat irritation, sore 
throat and shortness-of-breath. 
7.1.2 
Nicotine Toxicity 
The e-cigarette may deliver less of various tobacco smoke constituents than participants’ usual brands 
of cigarettes, and in some cases, may deliver more nicotine. However, participants control their nicotine 
intake and many studies have shown that smokers effectively limit their nicotine intake from cigarettes 
to avoid symptoms of nicotine toxicity (e.g., nausea, vomiting, sweating, headache, dizziness, jittery, 
palpitations, or in the case of extreme cases of nicotine overdose, convulsions, respiratory paralysis and 
death). 
7.1.3 
Tobacco Withdrawal 
To the extent that nicotine or other tobacco smoke constituent intake is reduced or eliminated, 
participants may experience tobacco withdrawal symptoms, including craving, difficulty concentrating, 
mood disturbance and increased appetite/weight gain.  
7.1.4 
Blood Draw 
The risks associated with venipuncture are minimal and include momentary discomfort and/or bruising. 
Infection, bruising, excess bleeding, clotting, and fainting are also possible, although unlikely. 
7.2 PROTECTION AGAINST RISKS 
The risks to which participants will be exposed are comparatively minor, because it is unlikely when 
using the e-cigarette that they will be exposed to higher levels of toxicants than when smoking their 
cigarettes. Smokers are very experienced in regulating their nicotine intake to avoid excessive amounts 
[10]. Additionally, participants will be screened medically and monitored throughout the study. 
Study participants will receive detailed instructions on the use of the tobacco products distributed to 
them, in order to minimize the possibility of misuse. JUUL e-cigarette cartridges are sealed systems. 
Subjects will be instructed to keep all nicotine/tobacco products away from children and pets. 
Participants will be instructed to report any side effects to study staff, who will communicate these 
reports to the medical staff. The most appropriate course of action will be determined, which may 
include options for termination of exposure to study-related clinical materials (e.g., e-cigarettes). 
Participants will, however, be reminded that they have the option to withdraw from the study at any 
time and will be referred to local quit-smoking resources if interested at the end of the study. Subjects 
will also be given a 24-hour emergency contact number in the event that side effects or adverse events 
occur between sessions. 

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 QUALITY CONTROL AND QUALITY ASSURANCE 
8.1 TRAINING OF STAFF 
The Investigator or designee will ensure that appropriate training relevant to the study is provided to all 
staff involved in the study, and that any new information relevant to the performance of this study is 
forwarded in a timely manner to the staff.  
8.2 AUDITS AND INSPECTIONS 
Good Clinical Practice regulations require independent inspections of clinical program activities. Such 
inspections may be performed at any time before, during and/or after the study. 
Authorized representatives of regulatory agencies and/or an IRB may perform audits or inspections, 
including source data verification. The purpose of an audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these activities 
were conducted, and data were recorded, analyzed and accurately reported according to the protocol, 
ICH/GCP guidelines and all applicable regulatory requirements.  
The Investigator and study staff are responsible for maintaining a comprehensive and accurate filing 
system of all study-related documentation that will be suitable for inspection at any time by regulatory 
agencies. By signing this protocol, the Investigator or designee understands and agrees to provide access 
to the necessary documentation and files. 
 REPORTING OF ADVERSE EVENTS 
9.1 DEFINITIONS 
9.1.1 
Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence that may present during 
participation in the study and which may or may not have a causal relationship with study procedures 
and/or products tested in this study. An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to the 
study procedures and/or products. 
Any increase in the severity and/or the frequency of a concomitant disease is considered an AE. 
9.1.2 
Serious Adverse Event 
A Serious Adverse Event is any adverse event that: 
• results in death; 
• is life-threatening; 
• results in inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability / incapacity; 
• results in a congenital anomaly / birth defect; 

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• requires immediate medical or surgical intervention. 
Important medical events that may not result in death, be life-threatening, nor require hospitalization 
may be considered an SAE, when, based on appropriate medical judgment, an SAE may jeopardize the 
subject, or the subject may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definitions. 
The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
Any pre-planned hospitalizations that are known at the time of signing the ICF will not be recorded as an 
SAE; however, they will be recorded as AE only. Any AE that occurs during this pre-planned 
hospitalization will be considered according to the above definitions. 
9.2 COLLECTION OF SAFETY EVENTS FROM SUBJECTS 
Information recorded when collecting AE will include: verbatim description of the AE, seriousness 
assessment, start and stop dates and times, circumstances leading up to the event, clinical elements 
such as clinical course, specific vital signs and test results that may explain the pathophysiology of the 
event, as well as alternative explanations to its occurrence, the action taken with the investigation 
product due to the AE, the subject`s disposition in the study after the occurrence of the AE, and the final 
outcome of the AE. 
Any exacerbation/worsening or increased frequency of an AE or pre-existing condition shall be 
evaluated and recorded. 
AEs should be collected using face-to-face interviews with the subject.  
Whenever a medically meaningful diagnosis is available to comprise a set of reported signs and/or 
symptoms, it should be preferentially provided as the AE or SAE term, rather than the individual signs 
and/or symptoms. Otherwise, each one of those signs and/or symptoms should be reported separately 
as event terms. 
9.2.1 
Period of Collection 
All existing health conditions identified during the Screening Period will be recorded as concomitant 
disease and the subject’s eligibility will be reviewed. Any AEs which occur during the screening session 
will be captured by the study site staff and assessed by the Investigator or designee in order to establish 
relationship or relatedness in respect to study products or procedures. 
Any new, clinically relevant, abnormal finding detected during the study or worsening of a pre-existing 
condition/concomitant disease will be documented as an AE and/or SAE. 
All ongoing AEs at the end of study participation will be followed-up by the Investigator or designee until 
they have improved, resolved, stabilized (i.e., no worsening of condition), or until an acceptable 
explanation has been found. The Investigator or designee will refer the subject to their General 
Practitioner for follow up of those AE when appropriate. 

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9.3 ASSESSMENT OF ADVERSE EVENTS 
9.3.1 
Intensity of Adverse Events 
For each AE, the intensity will be graded on a 3-point intensity scale: 
• Mild:  The AE is easily tolerated and does not interfere with daily activity. 
• Moderate: The AE interferes with daily activity, but the subject is still able to function. 
• Severe: The AE is incapacitating and requires medical intervention. 
9.3.2 
Relationship to Study Procedures 
In general, all AEs and/or SAEs will be assessed by the Investigator or designee as either ‘related’ or ‘not 
related’.  
• Not related: The temporal relationship of the clinical event to study procedures makes a 
causal relationship unlikely, or, concomitant medication, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the observed event. 
• Related: The temporal relationship of the clinical event to study procedures makes a causal 
relationship possible, and concomitant medication, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the observed event. 
9.4 FOLLOW-UP OF NON-SERIOUS AND SERIOUS ADVERSE EVENTS 
Any non-serious AE that is ongoing during the safety follow-up period will be actively followed-up by the 
Investigator during that period until it has improved, resolved, stabilized (i.e., no worsening of the 
condition), or an acceptable explanation has been found (e.g., a chronic condition). 
All SAE will be followed up by the Investigator or designee, despite their continuation after the EOS, until 
their improvement, resolution, stabilization (i.e., no worsening of the condition), or an acceptable 
explanation has been found (e.g., a chronic condition). 
9.5 REPORTING OF SAFETY EVENTS 
The Principal Investigator will report all serious adverse events relating to the study in an expedited 
manner to the Advarra Institutional Review Board (IRB) office and all applicable regulatory authorities in 
accordance with standard operating procedures. 
9.6 REPORTING AND FOLLOW-UP OF PREGNANCIES 
All subjects who are determined to be pregnant after enrollment (V2) will be discontinued from the 
study. This subject’s data will be censored, and that subject will be replaced. Advice on the risk of 
smoking and smoking cessation will be provided by the study staff and subjects will be referred to the 
respective health care facility/health care provider for further support. 
The Investigator or designee is responsible for informing the IRB of any pregnancy that occurs during the 
study and its outcome, according to local regulations. 

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9.7 ADVERSE EVENT LEADING TO DISCONTINUATION 
If a subject is discontinued from the study because of an AE, the Investigator or designee will follow up 
until the AE(s)/SAE(s) has/have improved, resolved, stabilized (i.e., no worsening of condition), or until 
an acceptable explanation has been found. 
 DATA MANAGEMENT 
10.1 DATA COLLECTION PROCEDURES 
The results from the clinical assessments will be recorded in the source data file by the Investigator or 
their authorized designee and then captured in the case report forms (CRFs), unless specified otherwise 
in the final protocol. Trained study personnel will be responsible for capturing the data from the 
observations, tests, and assessments specified in the protocol and in the source documents and 
transferring the data to the CRFs. 
The Investigator has ultimate responsibility for the collection and reporting of all data related to the 
clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring, and available when required. Any corrections made to source documents 
must be clearly recorded, without obscuring the original values and be accompanied by the date of 
change, reason for change, and identification of the person making the change. CRF data will be verified 
against the source documents at the study site by appropriate staff. Instances of missing or unclear data 
will be discussed with the Investigator for resolution. 
10.2 PROTOCOL DEVIATIONS / NONCOMPLIANCE 
Protocol deviations are defined as deviations from the study procedures described in this document, 
whether intentional or unintentional, that may affect the subject (their rights, safety, or well-being) or 
affect the data (completeness, accuracy or reliability). 
Noncompliance that meets the above definition must be reported to the IRB within 10 days of becoming 
aware of the noncompliance. 
10.3 DATA CAPTURE 
All data are collected from subjects using paper documents or an electronic data capture system. All 
applicable data, as specified in the protocol, will be transferred to the database or applicable Case 
Report Forms. 
10.3.1 Salesforce.com 
Data will be collected for recruitment and screening purposes as stated within the IRB generic 
recruitment protocol. Unrelated to that protocol, pre-screening questionnaires will be attached to 
potential participant’s records on whether they qualify or are disqualified for this study. Questionnaires 
utilized for this study will be permanently attached to that potential volunteer’s record unless that 
information is requested to be removed by the participant. 

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Salesforce acts as a database for potential study participants and will retain responses to general 
demographic and lifestyle questions, which could help determine prequalification status for specific 
study participation. 
Salesforce.com utilizes some of the most advanced technology for internet security available today. 
Access to the site is accomplished using industry standard Secure Socket Layer (SSL) technology. 
Information is protected using both server authentication and data encryption, ensuring that the data 
are safe, secure, and available only to registered users at Rose Research Center (RRC). Data are 
completely inaccessible to other groups. 
Salesforce.com provides each RRC user a unique user name and password that must be entered at each 
login. Salesforce.com issues a session "cookie" only to record encrypted authentication information for 
the duration of a specific session. The session "cookie" does not include the username or password of 
the user. Salesforce.com does not use "cookies" to store other confidential user and session 
information, but instead implements more advanced security methods based on dynamic data and 
encoded session IDs. In addition, salesforce.com is hosted in a secure server environment that uses a 
firewall and other advanced technology to prevent interference or access from outside intruders. 
Salesforce.com also offers the ability to allow only specific IP ranges to log in to the system. This ability 
alongside double authentication methods keep the system up to date with some of the most advanced 
security measures in place on the internet today. 
10.3.2 Medrio 
All smoking behavioral and self-report measures will be captured initially using Medrio. Medrio is an 
electronic data collection system that records and performs analysis and reporting of data. Participant 
data will be kept within Medrio’s secure servers and may only be transmitted for a secure (SSL) 
download to our local server. Medrio’s servers are protected by high-end firewall systems, with 
vulnerability scans performed regularly. All services have quick failover points with redundant hardware, 
and complete encrypted backups are performed regularly. Medrio uses Transport Layer Security (TLS) 
encryption (SSL or HTTPS) for all transmitted internet data. All information collected within Medrio is 
compliant with 21 CFR 11 requirements. 
10.4 DATA HANDLING 
Data of all subjects enrolled including screening failures and AEs during the study (from the time of 
informed consent to the end of the study of the subject) will be captured in the source documents. 
 DATA ANALYTIC APPROACH 
Data will be inspected for outliers and if sufficiently extreme (using Chauvenet's criterion [11]) will be 
censored from the data analysis. An alpha criterion of 0.05 will be used in all comparisons; one-tailed 
testing will be conducted because there will only be interest in advancing the devaluation procedure to 
larger confirmatory studies if it helps, rather than hinders, complete switching to e-cigarettes. Statistical 
consulting will be provided by leading experts in the field, Daniel J. Bauer, Ph.D. and Patrick J. Curran, 
Ph.D. Statistical analyses will be organized around evaluating hypotheses for the two main Specific Aims, 
as follows. 

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11.1 PRIMARY OUTCOME MEASURE 
11.1.1 The effect of cigarette devaluation on switching from CC to the JUUL. 
The primary outcome measure will be biochemically verified complete switching from CC to JUUL during 
weeks 9-12, i.e., self-report of no smoking confirmed by an expired air CO reading of <5 ppm. As 
described in Section 3.1, based on the proportion of participants who complete switching to JUUL, this 
reward devaluation procedure will be studied in further randomized clinical trials.   
11.2 SECONDARY OUTCOME MEASURE 
11.2.1 To correlate any changes in cigarette reward with subsequent switching behavior. 
Latent curve models (LCMs; aka longitudinal mixed models, multilevel growth models) will be used to 
characterize changes in the two primary scales of the mCEQ questionnaire, assessing smoking 
satisfaction and psychological reward, over the first week of the study period. Random effects will be 
included for both intercepts and slopes, to allow for within-condition individual differences in initial 
levels and rates of reduction for these outcomes. Preliminary graphical analyses will be conducted to 
evaluate the tenability of linear change. If change is nonlinear, either a transformation will be used to 
linearize the relationship, or the model will be modified to accommodate curvature. We will evaluate 
the assumption of normality for the random effects and error by inspecting the distributions of the 
estimated values. 
These LCMs will then be explored to evaluate the extent to which changes in subjective reward mediate 
the effect of the devaluation procedure on switching. Specifically, the individual intercepts and slopes 
for reward ratings will be used as predictors of switching from CC to JUUL. We predict that the cigarette 
devaluation procedure will lead to a decrease in reward ratings of CC, and that subjects showing the 
greatest decreases on these outcomes will show the highest probability of successfully switching from 
CC to the JUUL (i.e., greatest reduction in CC use and greatest increase in JUUL use).  
 ETHICS AND REGULATIONS 
12.1 IRB APPROVAL 
The protocol, informed consent document and relevant supporting information must be submitted to 
the IRB for review and must be approved before the study is initiated. In addition, any subject 
recruitment materials must be approved by the IRB prior to being used.  
Any change to the protocol must be submitted to the IRB for review and approval before 
implementation. A protocol change intended to eliminate an apparent immediate hazard to subjects 
may be implemented immediately provided the reviewing IRB are notified within 10 working days. 
12.2 ETHICAL CONDUCT OF THE STUDY 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [12] and is consistent with applicable regulatory principles of ICH/GCP. 

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The Investigator agrees to conduct the clinical study in compliance with the protocol and approved by 
the IRB. 
12.3 GCP AND REGULATORY REQUIREMENTS 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with Good Clinical Practice and applicable regulatory 
requirements. The study must be conducted in accordance with the regulations of the United States 
Food and Drug Administration (FDA) as described in 21 CFR 50 and 56, applicable laws and the IRB 
requirements.  
12.4 SUBJECT INFORMATION AND CONSENT 
It is the responsibility of the investigator to provide each subject with full and adequate verbal and 
written information using the IRB approved informed consent document, including the objective and 
procedures of the study and the possible risks involved before inclusion in the study. Informed consent 
must be obtained prior to performing any study-related procedures.  
The signed and personally dated original and completed ICF(s) must be kept by the Investigator and filed 
in the Investigator study file at the site or with the subject’s files and a copy must be given to the 
subject. The subject will be informed that if they withdraw from the study, the data collected until the 
point of discontinuation will be maintained as part of the study data, and that all samples collected 
prior to withdrawal will be analyzed, unless specifically requested by the subject in writing. 
12.5 AMENDMENT TO INFORMED CONSENT FORM 
If a protocol amendment is required, an amendment may be required to the ICF. If revision of the ICF is 
necessary, the Investigator or designee will ensure that the documents have been reviewed and 
approved by the IRB before subjects are informed and sign the amended ICF. 
 ADMINISTRATIVE CONSIDERATIONS 
13.1 SUBJECT CONFIDENTIALITY 
All information obtained during the conduct of the study with respect to the subjects' state of health will 
be regarded as confidential. A statement to this effect will be written in the information provided to the 
subject. An agreement to disclose any such information will be obtained from the subject in writing and 
signed by the subject, in compliance with all local and national data protection and privacy legislation. 
Study records that identify subjects will be kept confidential as required by law. Except when required 
by law, subjects will not be identified by name, social security number, address, telephone number, or 
any other direct personal identifier in study records disclosed outside of Rose Research Center. For 
records disclosed outside of Rose Research Center, subjects will be assigned a unique code number. The 
key to the code will be kept separate from the locked file where the study records are stored. 

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13.2 RECORD RETENTION 
All records of data, in any form, will be maintained by Rose Research Center as required by ICH/GCPs. 
Essential documents will be retained for at least 15 years after completion of the study. 
Appropriate measures will be taken to prevent accidental or premature destruction of these documents. 

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 REFERENCES 
1.  Carter, B.D., Abnet, C.C., Feskanich, D., Freedman, N.D., Hartge, P., Lewis, C.E., Ockene, J.K., 
Prentice, R.L., Speizer, F.E., Thun, M.J., Jacobs, E.J.: Smoking and Mortality — Beyond Established 
Causes. N. Engl. J. Med. 372, 631–640 (2015). doi:10.1056/NEJMsa1407211 
2.  Ward, B.W.: Early Release of Selected Estimates Based on Data From the 2015 National Health 
Interview Survey (05/2016). 120 (2015) 
3.  Centers for Disease Control and Prevention (US), National Center for Chronic Disease Prevention 
and Health Promotion (US), Office on Smoking and Health (US): How Tobacco Smoke Causes 
Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the 
Surgeon General. Centers for Disease Control and Prevention (US), Atlanta (GA) (2010) 
4.  Geiss, O., Bianchi, I., Barrero-Moreno, J.: Correlation of volatile carbonyl yields emitted by e-
cigarettes with the temperature of the heating coil and the perceived sensorial quality of the 
generated vapours. Int. J. Hyg. Environ. Health. 219, 268–277 (2016). 
doi:10.1016/j.ijheh.2016.01.004 
5.  McRobbie, H., Phillips, A., Goniewicz, M.L., Smith, K.M., Knight-West, O., Przulj, D., Hajek, P.: Effects 
of Switching to Electronic Cigarettes with and without Concurrent Smoking on Exposure to Nicotine, 
Carbon Monoxide, and Acrolein. Cancer Prev. Res. Phila. Pa. 8, 873–878 (2015). doi:10.1158/1940-
6207.CAPR-15-0058 
6.  Tayyarah, R., Long, G.A.: Comparison of select analytes in aerosol from e-cigarettes with smoke 
from conventional cigarettes and with ambient air. Regul. Toxicol. Pharmacol. RTP. 70, 704–710 
(2014). doi:10.1016/j.yrtph.2014.10.010 
7.  Nides, M.A., Leischow, S.J., Bhatter, M., Simmons, M.: Nicotine blood levels and short-term smoking 
reduction with an electronic nicotine delivery system. Am. J. Health Behav. 38, 265–274 (2014). 
doi:10.5993/AJHB.38.2.12 
8.  McRobbie, H., Bullen, C., Hartmann-Boyce, J., Hajek, P.: Electronic cigarettes for smoking cessation 
and reduction. Cochrane Database Syst. Rev. CD010216 (2014). 
doi:10.1002/14651858.CD010216.pub2 
9.  Goniewicz ML, Smith DM, Edwards KC, et al. Comparison of Nicotine and Toxicant Exposure in Users 
of Electronic Cigarettes and Combustible Cigarettes. JAMA Netw Open. 2018;1(8):e185937. 
doi:10.1001/jamanetworkopen.2018.5937 
10.  Delnevo, C.D., Giovenco, D.P., Steinberg, M.B., Villanti, A.C., Pearson, J.L., Niaura, R.S., Abrams, D.B.: 
Patterns of Electronic Cigarette Use Among Adults in the United States. Nicotine Tob. Res. Off. J. 
Soc. Res. Nicotine Tob. 18, 715–719 (2016). doi:10.1093/ntr/ntv237 
11.  Pincus, R.: Barnett, V., and Lewis T.: Outliers in Statistical Data. 3rd edition. J. Wiley & Sons 1994, 
XVII. 582 pp., £49.95. Biom. J. 37, 256–256 (1995). doi:10.1002/bimj.4710370219 
12. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving 
Human Subjects. JAMA. 310, 2191–2194 (2013). doi:10.1001/jama.2013.281053 
 
 

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Appendix 1 – Medical History Form 
 

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Appendix 2 – Patient Health Questionnaire (PHQ-9) 
 
 
 

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Appendix 3 – Registration Form 
 
 
 

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Appendix 4 – Research Payment Verification Form 
 
 
 

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Appendix 5 – Review of Systems 
 

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Appendix 6 – Session Payment Form 
 
 
 

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Appendix 7 – Smoking History  

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Appendix 8 – modified Cigarette Evaluation Questionnaire (mCEQ) 

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Appendix 9 – Assessment of Behavioral OUTcomes (ABOUT) 
 

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Appendix 10 – Employment History 
 

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Appendix 11 – Fagerström Test for Nicotine Dependence (FTND) 
 
 
 
 

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Appendix 12 – Reasons to Smoke 
 
 
 
 

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Appendix 13– SMS Daily Survey 
 
 
 
 

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Appendix 14 – JUUL Flavor Assessment Questionnaire 
 
 

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Appendix 15 – 6 Month Follow up Survey