An Open-Label, Randomized, Crossover Study to Assess Nicotine Uptake, Tobacco-Related Biomarkers of Exposure, Biomarkers of Potential Harm, and Puff Topography With Use of mybluTM Electronic Cigarettes in Adult Smokers
Phase: NA
Conditions: Healthy Volunteers
Sponsor: Fontem US LLC

An Open-Label, Randomized, Crossover Study to Assess Nicotine Uptake, Tobacco-
Related Biomarkers of Exposure, Biomarkers of Potential Harm, and Puff Topography 
with Use of mybluTM Electronic Cigarettes in Adult Smokers 
 
 
NCT# NCT04429932 
 
 
Study Protocol - 04-Dec-2019 
 
 
 
 

Page 1 
 
 
 
 
 
 
 
 
An Open-Label, Randomized, Crossover Study to Assess Nicotine Uptake, 
Tobacco-Related Biomarkers of Exposure, Biomarkers of Potential Harm, and Puff 
Topography with Use of myblu™ Electronic Cigarettes in Adult Smokers 
 
 
 
 
Sponsor Project No.: NER 01/003 
 
 Project No.: CA22736 
 
 
Final Protocol: 04-Nov-2019 
Amendment 1: 04-Dec-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), and applicable regulatory requirements. All required study documentation will be 
archived as required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Nerudia Ltd. Any viewing 
or disclosure of such information that is not authorized in writing by Nerudia Ltd is strictly 
prohibited. Such information may be used solely for the purpose of reviewing or performing 
this study. 

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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
An Open-Label, Randomized, Crossover Study to Assess Nicotine Uptake, 
Tobacco-Related Biomarkers of Exposure, Biomarkers of Potential Harm, and Puff 
Topography with Use of myblu™ Electronic Cigarettes in Adult Smokers 
 
 
 
 
 
 
 
Clinical Site and Principal Investigator: 
 
 
 
Site Name: 
 
Address: 
 
 
Phone: 
Fax: 
 
 
 
 
 
 
 
 
 
 
 
 
__________________________________ 
_________ 
 
Signature 
Date 
 
 
 
 
 
 
 __________________________________ 
 
 
Printed Name 
 
 
 
 
 
 
 
 
 
 
An additional signature page as a standalone document may be used for the signature of any 
additional clinical sites. 
 

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SYNOPSIS 
Study Objectives 
Primary: 
1. To characterize nicotine uptake following controlled use of 
myblu™ electronic cigarettes (e-cigarettes). 
2. To assess the change-from-baseline differences in the primary 
tobacco-related biomarkers of exposure (BoE) following a 9-day 
use period of myblu™ e-cigarettes. 
Secondary 
1. To assess the change-from-baseline differences in the primary 
tobacco-related BoE following a 14-day use period of myblu™ 
e-cigarettes. 
2. To assess the change-from-baseline differences in the secondary 
tobacco-related BoE following 9-day and 14-day use periods of 
myblu™ e-cigarettes. 
3. To characterize the change in the primary and secondary 
tobacco-related BoE and biomarkers of potential harm (BoPH) 
during a 14-day period of use of myblu™ e-cigarettes and compare 
between exclusive e-cigarette use, exclusive combustible cigarette 
use and dual (combustible cigarette and e-cigarette) use. 
4. To assess the change-from-baseline differences in the primary and 
secondary tobacco-related BoE between Day 9 and Day 14 in 
subjects using myblu™ e-cigarettes, both exclusively and 
alongside use of combustible cigarettes. 
5. To assess change-from-baseline differences in BoPH following 
9-day and 14-day use periods of myblu™ e-cigarettes. 
6. To assess measures of subjective effects associated with use of 
myblu™ e-cigarettes. 
7. To determine puffing topography parameters (puff count, puff 
duration, puff volume, peak puff flow rate, average puff flow rate, 
inter puff interval) following an 8-day use period of myblu™ 
e-cigarettes and assess change-from-baseline differences (if 
applicable). 
8. To assess change-from-baseline differences in physiologic 
endpoints (i.e., blood pressure [BP], heart rate [HR], and 
spirometry) following 9-day and 14-day use periods of myblu™ 
e-cigarettes. 
9. To characterize product use of myblu™ e-cigarettes under 
short-term controlled and ad libitum use conditions. 
10. To assess the safety and tolerability of myblu™ e-cigarettes 
following short-term use. 

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Study Design 
This will be an open-label, randomized, 2-part study in adult smokers. 
All subjects will participate in both study parts. Part 2 will begin 
immediately after Part 1. 
Screening procedures will be performed within 28 days prior to study 
procedures on Day -2. 
Subjects who successfully complete the screening procedures and 
meet the eligibility criteria will be eligible to check in to the clinical 
research unit (CRU) on Day -2 and will complete all subjective effects 
questionnaires for the purpose of familiarization with the questions, 
scales, and computerized tablet. Subjects will also participate in a 
brief trial on Day -2 (approximately 30 minutes) using the myblu™ 
device with a 0% nicotine e-liquid, to familiarize with the use of the 
device. Baseline study assessments, including BoE, BoPH, spirometry 
(Day -1 only), BP, HR, and puff topography (in a subset of 16 subjects 
[2 subjects from each sequence in Part 1] on Day -1 only) will be 
performed on Days -2 through -1, as appropriate. Subjects will 
continue to smoke their usual brand combustible cigarette from 
check-in through Day -1, but will abstain from use of any tobacco- or 
nicotine-containing products for at least 12 hours prior to the start of 
product use on Day 1. Subjects will be randomized to 1 of 8 sequences 
(Part 1) on Day -1. 
Part 1 (Days 1 to 9) 
On Days 1, 3, 5, and 7, subjects will use the study product they are 
assigned to use the following day according to the randomization 
scheme. Subjects will use the assigned study product ad libitum until 
the start of the abstinence period (i.e., at least 12 hours prior to the 
start of the first product use session on the next day). A fully charged 
battery and a fresh pod will be provided on each day. Additional pods 
will be provided as needed. Pods will be weighed within 24 hours 
before the start and after completion of product use on each day. On 
Day 1, puff topography measurements will be performed in the same 
subset of 16 subjects (2 subjects from each sequence in Part 1) for 
1 hour during ab libitum product use. Puff topography should be 
performed within ± 2 hours of the time of the baseline assessment on 
Day -1. 
On Days 2, 4, 6, and 8, subjects will participate in two product use 
sessions on each day, using the assigned study product according to 
the randomization scheme. In the first (controlled) product use 
session, subjects will use the assigned study product under controlled 
conditions (i.e., 10 puffs taken at 30-second intervals, with puffs 
3 seconds in duration). Blood samples for nicotine pharmacokinetic 
(PK) assessment will be collected prior to and for 3 hours following 
the start of the first product use session. Subjects will complete the 
Urge to Smoke questionnaire during and following the first product 

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use session and the Product Liking, Product Evaluation Scale (PES), 
and Future Intent to Use questionnaires following the first product use 
session. Following collection of the last PK blood sample (180-minute 
time point) and completion of the subjective effects questionnaires, 
subjects will start the second (ad libitum) product use session, during 
which they will use the same assigned study product ad libitum (with 
no limits on puff duration or inter-puff interval) until approximately 
23:00. Subjects will complete the Urge to Smoke, Product Liking, 
PES, and Future Intent to Use questionnaires at least 6 hours after the 
start of the second product use session. A fresh pod and fully charged 
device will be provided for each product use session. Pod weights will 
be measured before and after each product use session. On Day 8, puff 
topography measurements will be performed in the same subset of 
16 subjects (2 subjects from each sequence in Part 1) for 1 hour during 
the second (ab libitum) product use session. Puff topography will be 
performed at least 4 hours after the start of the second (ab libitum) 
product use session and should be within ± 2 hours of the time of the 
baseline assessment on Day -1.  
On Day 9, subjects may use all or any of the 4 study products (used 
previously on Days 1 to 8) ad libitum until approximately 23:00. For 
BoE and BoPH assessments, blood samples will be collected on Day 9 
and urine samples will be collected over 24 hours (starting on Day 8 
after completion of the second [ab libitum] product use session). BP 
and HR measurements will be taken throughout the period of 
ad libitum product use. Subjects will complete the Questionnaire on 
Smoking Urges-Brief (QSU-Brief), the Minnesota Tobacco 
Withdrawal Scale-Revised (MTWS-R), and the Penn State 
[Electronic] Cigarette Dependence Index (PSCDI/PSECDI) 
questionnaires at least 6 hours after the start of the ad libitum product 
use session on Day 9. Spirometry measurements will be conducted 
following completion of all subjective effects questionnaires on 
Day 9. Fresh pods and a fully charged device will be provided on 
Day 9 and pod weights will be measured. 
Depending on the availability of topography equipment, puff 
topography may not be performed at all scheduled time points and 
may not be performed for some or all assigned subjects. 
Part 2 (Days 10 to 14) 
Subjects will be randomized to 1 of 3 study arms (Part 2) on Day 10. 
Subjects will use any or all of the 8 study products and/or smoke their 
usual brand combustible cigarettes ad libitum for 5 days (until 
approximately 23:00 on each day) according to the randomization 
scheme. For BoE and BoPH assessments, blood samples will be 
collected on Day 14 and urine samples will be collected over 24 hours 
(starting on Day 13 after the end of product use for that day). On 
Day 14, BP and HR measurements will be taken throughout the period 

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of ad libitum product use/smoking. The QSU-Brief, MTWS-R, and 
PSCDI/PSECDI questionnaires will be completed at least 6 hours 
after the start of the ad libitum product use session on Day 14. 
Spirometry measurements will be conducted following completion of 
all subjective effects questionnaires on Day 14. Product use behavior 
will be assessed by documenting the number of cigarettes smoked, the 
flavor and strength of the myblu™ products, and pod weights, per day, 
as appropriate. On each study day, fresh pods and a fully charged 
device will be provided, as appropriate. 
The CRU will attempt to contact all subjects who used at least one 
study product (including subjects who terminate the study early) using 
their standard procedures approximately 14 days after the last study 
product use to determine if any adverse event (AE) has occurred since 
the last study visit. 
Study Population 
The study population will be comprised of healthy, adult male and 
female smokers, who are between 21 and 65 years of age (inclusive). 
Each subject must self-report smoking an average of 10 or more 
manufactured combustible cigarettes per day (CPD) for at least 
12 months prior to Screening.  
Forty (40) subjects will be expected to complete the study and will 
participate in both study parts. Every attempt will be made to enroll no 
more than 60% of either sex. 
Duration of Study 
Conduct 
The duration of the study from Screening to Day 15 is approximately 
6 weeks. 
Study Products and 
Administration: 
Details of the study products are presented as follows: 
In Part 1, 20 subjects will be randomized to use Products A to D and 
20 subjects will be randomized to use Products E to H. 
Product 
Designation 
Study Product Name 
A 
myblu™ (freebase), Gold Leaf flavor, 2.4% 
B 
myblu™ (freebase), Polar Mint flavor, 2.4% 
C 
myblu™ (freebase), Cherry flavor, 2.4% 
D 
myblu™ (freebase), Vanilla flavor, 2.4% 
E 
myblu™ (freebase), Gold Leaf flavor, 1.2% 
F 
myblu™ (freebase), Polar Mint flavor, 1.2% 
G 
myblu™ (freebase), Menthol flavor, 2.4% 
H 
myblu™ Intense (nicotine salts), Fresh Mint flavor, 
2.4% 

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In Part 2, subjects will be randomized to one of the following arms: 
Arm 
Product Use Description 
I  (myblu™) 
Exclusive use of myblu™ products 
ad libitum 
J  (Combustible) 
Exclusive smoking of usual brand 
combustible cigarettes ad libitum 
K  (Dual Use) 
Smoking of usual brand combustible 
cigarettes (up to 50% of the subject’s 
self-reported CPD) and use of myblu™ 
products ad libitum 
Subjects randomized to Arms I and K may choose to use all or any of 
Products A to H. 
Endpoints, Key 
Assessments, and 
Summarization 
Pharmacokinetics: 
For each first (controlled) product use session on Days 2, 4, 6, and 8, 
plasma nicotine PK parameters (AUC0-180, Cmax, and Tmax) will be 
computed from the individual plasma concentrations for each study 
product. Baseline adjustments will be performed. 
Nicotine concentrations and PK parameters will be listed by subject 
and summarized using descriptive statistics. 
Biomarkers: 
For each of Days -1, 9, and 14, biomarker concentrations will be listed 
by subject and summarized using descriptive statistics. Absolute and 
percent change-from-baseline will be determined for the mass 
excreted and creatinine-adjusted values. 
Primary Biomarkers of Exposure: 
Biomarker 
Matrix 
Chemical Constituent 
Carboxyhemoglobin (COHb) 
Blood 
Carbon monoxide (CO) 
4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL) 
Urine 
4-(methylnitrosamino)-
1-(3-pyridyl)-1-
butanone (NNK) 
3-hydroxypropylmercapturic 
acid (3-HPMA) 
Urine 
Acrolein 
S-phenyl mercapturic acid 
(S-PMA) 
Urine 
Benzene 

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Secondary Biomarkers of Exposure 
Biomarker 
Matrix 
Chemical Constituent 
N-nitrosonornicotine (NNN) 
Urine 
NNN 
2-cyanoethyl-mercapturic 
acid (CEMA) 
Urine 
Acrylonitrile 
Hydroxyethyl mercapturic 
acid (HEMA) 
Urine 
Ethylene oxide 
3-hydroxy-1-
methylpropylmercapturic acid 
(HMPMA) 
Urine 
Crotonaldehyde 
Monohydroxybutenylmercapt
uric acid (MHBMA) 
Urine 
1,3-butadiene 
Hydroxypyrene (1-OHP)  
Urine 
Pyrene 
o-toluidine (o-tol) 
Urine 
Toluidine 
3-hydroxybenzo[a]pyrene (3-
OH B[a]P) 
Urine 
B[a]P 
1-aminonaphthalene (1-AN) 
Urine 
Naphthalene 
2-aminonaphthalene (2-AN) 
Urine 
Naphthalene 
Nicotine equivalents 
Urine 
Nicotine 
Biomarkers of Potential Harm: 
Biomarker 
Matrix 
Biological Effect 
Soluble intracellular adhesion 
molecule (sICAM)  
Blood 
Inflammation 
White blood cells (WBCs) 
Blood 
Inflammation 
High density lipoprotein 
cholesterol (HDL-C) 
Blood 
Inflammation 
Monocyte chemoattractant 
protein 1 (MCP-1) 
Blood 
Inflammation 
Type III isoprostane 8-epi-
prostaglandin F2α 
Urine 
Oxidative stress 

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(8-epi-PGF2α) 
11-dehydrothromboxane B2 
(11-DHTXB2) 
Urine 
Platelet activation 
Subjective Effects: 
Urge to Smoke (Days 2, 4, 6, and 8) 
Responses and derived parameters (Emax, TEmax, and AUEC0-120) 
will be listed by subject and summarized using descriptive statistics.  
Product Liking (Days 2, 4, 6, and 8) 
Responses will be listed by subject and summarized using descriptive 
statistics.  
Product Evaluation (Days 2, 4, 6, and 8) 
Responses will be considered as a 7-point scale, and will be presented 
as factors outlined in Section 7.3.3.3. 
Descriptive statistics of the subscales will be provided by study 
product and product use session. Individual responses will be listed. 
Future Intent to Use (Days 2, 4, 6, and 8) 
Responses recorded as visual analog scale (VAS) scores will be 
treated as bipolar categorical variables (-50 to <0, 0, >0 to 50) and 
summarized by study product using frequency count tables. The 
bipolar score for the Future Intent to Use questionnaire is calculated 
by subtracting 50 from the original VAS score. The bipolar scores will 
also be treated as continuous variables and summarized using 
descriptive statistics. 
QSU-Brief (Days 9 and 14) 
Responses to the QSU-brief will be considered as a 7-point scale and 
treated as a continuous variable and will be presented as two factors as 
outlined in Section 7.3.3.5.  
Descriptive statistics of the subscales will be provided by study day 
and study arm (Part 2 only). Individual responses will be listed. 
MTWS-R (Days 9 and 14) 
The total score to the MTWS-R will be summarized by study day and 
study arm (Part 2 only). 
PSCDI/PSECDI (Days 9 and 14) 
The total score to the PSCDI/PSECDI will be summarized by study 
day and study arm (Part 2 only). 
Puff Topography: 
Topography parameters (puff count, puff duration, puff volume, peak 

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puff flow rate, average flow rate, inter-puff interval) will be listed by 
subject and summarized using descriptive statistics. 
Physiological Endpoints: 
Blood Pressure and Heart Rate 
Unadjusted and change from baseline BP and HR parameters (e.g., 
AUEC0-t, Emax, and TEmax) will be listed by subject and 
summarized using descriptive statistics.  
Spirometry 
Pre- and post-bronchodilator lung function variables (measured and 
percent of predicted forced expiratory volume in 1 second [FEV1], 
measured and percent of predicted forced vital capacity [FVC], 
measured and percent of predicted FEV1:FVC ratio, and measured 
and percent of predicted forced expiratory flow [FEF]25-75%) will be 
listed by subject and summarized using descriptive statistics. 
Product Use Behavior: 
All product use data, including the number of combustible cigarettes 
smoked and the difference in pod weights, will be summarized using 
descriptive statistics.  
Incidence of device malfunction(s) will also be tabulated. 
Safety: 
Screening evaluations will include a full physical examination, vital 
signs measurements, 12-lead electrocardiogram (ECG), clinical 
laboratory tests (serum chemistry, hematology, urinalysis, and 
serology), exhaled CO measurement, urine drug screen, urine/breath 
alcohol screen, and a serum/urine pregnancy test (females only).  
Safety will be monitored on-study through physical examination 
(symptom-driven), vital signs measurements, ECGs, and clinical 
laboratory tests (serum chemistry, hematology, and urinalysis).  
AEs spontaneously reported by the subjects or observed by the 
Investigator or other study personnel will be monitored from the time 
subjects first use a study product until the follow-up.  
AEs will be tabulated and summary statistics for vital signs and 
clinical laboratory tests may be computed and provided, as deemed 
clinically appropriate. 
 

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a: 
Within 28 days prior to study procedures on Day -2. All screening procedures will be completed at the same study site where on-study procedures will be 
performed. 
b: Subjects will be admitted to the CRU on Day -2, at the time indicated by the CRU. 
c: To be performed at least 6 hours after the start of the ad libitum product use session on that day. 
d: To be performed also at the pre-screening visit, if applicable. 
e: To be updated at Check-in as necessary. 
f: 
Symptom-driven physical examinations may be performed at other times, at the Investigator or designee’s discretion. 
g: Samples for serum chemistry will be obtained following a fast of at least 8 hours, however, in case of dropouts or rechecks, subjects may not have fasted for 
8 hours prior to the serum chemistry sample being taken. 
h: To be performed prior to the start of the first product use session. 
i: 
BP and HR will be measured within 2 hours prior to and at every hour after the start of ad libitum product use and throughout the period of ad libitum 
product use. Following completion of ad libitum product use on that day, BP and HR will be measured at 00:00, 03:00, and at least 30 minutes prior to the 
start of product use on the next day (for Day 14, the last measurement will be collected at approximately 06:00 on Day 15). Measurements are to be taken at 
least 15 minutes after the last tobacco- or nicotine-containing product used. When BP and HR measurements are scheduled at the same time or immediately 
after a puff topography session, subjects may not have abstained from tobacco- or nicotine-containing product use for 15 minutes prior to the BP and HR 
measurements. 
j: 
On Day -1, subjects will be randomized to 1 of 8 sequences (Part 1). 
k: Subjects will use the assigned study product under controlled conditions (i.e., 10 puffs taken at 30-second intervals, with puffs 3 seconds in duration). 
l: 
Subjects will continue to exclusively smoke their UBCC from C-I through Day -1, but will abstain from use of any tobacco- or nicotine-containing products 
for at least 12 hours prior to product use on Day 1. On Day -2, subjects will participate in a brief trial (approximately 30 minutes) using the myblu™ device 
with a 0% nicotine e-liquid. 
m: The ad libitum (second) product use session will begin after collection of the last PK blood sample (180-minute time point) and completion of the subjective 
effects questionnaires and will consist of unlimited use of the same assigned study product until approximately 23:00. 
n: Subjects will use the study product they are assigned to use the following day according to the randomization scheme. Subjects will use the assigned study 
product ad libitum until the start of the abstinence period (i.e., at least 12 hours prior to the start of the first product use session on the next day). 
o: The flavor and strength of the myblu™ products, pod weights, and the number of cigarettes smoked, as appropriate, will be documented. 
p: Pods will be weighed within 24 hours before the start and after completion of product use on each day. 
q: The number of inhalations, duration of each inhalation, and reasons for missed puffs will be documented. Pods will be weighed within 24 hours before and 
after each product use session. 
r: 
To be performed following a fast of at least 8 hours, with the exception of blood collection for COHb which will be performed in the afternoon. 
s: 
To be performed approximately 5 minutes prior to the start of the first product use session. 
t: 
To be performed approximately 30 seconds prior the scheduled PK blood draws. 

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u: To be performed approximately 10 minutes prior to the start of the first product use session. 
v: 
Puff topography measurements will be performed over 1 hour and will begin at least 4 hours after the start of the ad libitum product use. The puff 
topography session on Day 8 should be within ± 2 hours of the time of the Day -1 session. Puff topography measurements will be performed following a fast 
of at least 1 hour and will be prior to completing any subjective effects questionnaires during the ad libitum product use session. Depending on the 
availability of topography equipment, puff topography may not be performed at all scheduled time points and may not be performed for some or all assigned 
subjects. 
w: To be perfomed on Day 1 only. 
x: When scheduled during the same product use session, spirometry will be performed after completion of puff topography measurements and subjective 
effects questionnaires. 
y: The CRU will attempt to contact all subjects who used at least one study product (including subjects who terminate the study early) using their standard 
procedures approximately 14 days after the last study product use to determine if any AE has occurred since the last study visit. 
z: 
To be performed prior to discharge or prior to early termination from the study. 
aa: On Day 10, subjects will be randomized to 1 of 3 study arms (Part 2). 
bb: On Day 9, subjects may use all or any of the 4 study products (previously used on Days 1 to 8) ad libitum until approximately 23:00. 
cc: Subjects will use the study product(s) and/or smoke their UBCC ad libitum (until approximately 23:00) for 5 days, according to the randomization scheme. 
dd: Twenty-four (24)-hour urine collection will begin at the start of the overnight abstinence on each of Days -2, 8, and 13. The start time of each urine 
collection should be within ± 1 hour of the start time on Day -2. 
 
 
 
Abbreviations:  AE = Adverse event, BMI = Body mass index, BoE = Biomarkers of exposure, BoPH = Biomarkers of potential harm, BP = Blood pressure, 
C-I = Check-in, Chem = Serum chemistry, CO = Carbon monoxide, COHb = Carboxyhemoglobin, CRU = Clinical research unit, EAS = End of ad libitum 
product use session, ECG = Electrocardiogram, FSH = Follicle-stimulating hormone, FU = Follow-up, HBsAg = Hepatitis B surface antigen, HCV = Hepatitis C 
virus, HIV = Human immunodeficiency virus, HR = Heart rate, I/E = Inclusion/exclusion, MTWS-R = Minnesota Tobacco Withdrawal Scale-Revised, 
PES = Product Evaluation Scale, PK = Pharmacokinetic(s), PSCDI/PSECDI = Penn State [Electronic] Cigarette Dependence Index, QSU-Brief = Questionnaire 
on Smoking Urges-Brief, RR = Respiratory rate, Scr = Screening, T = Temperature, UBCC = Usual brand combustible cigarette. 
 
 

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ABBREVIATIONS 
1-AN 
1-aminonaphthalene 
1-OHP 
Hydroxypyrene 
11-DHTXB2 
11-dehydrothromboxane B2 
2-AN 
2-aminonaphthalene 
3-HPMA 
3-hydroxypropylmercapturic acid 
3-OH B[a]P 
3-hydroxybenzo[a]pyrene 
8-epi-PGF2α 
Type III isoprostane 8-epi-prostaglandin F2α 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC 
Area under the concentration-time curve 
AUC0-180 
Area under the nicotine concentration-time curve from time 0 to 
180 minutes 
AUEC0-120 
Area under the change from baseline score versus time curve from 
time 0 to 120 minutes 
AUEC0-t 
Area under the change from baseline score versus time curve from 
time 0 to time t 
BMI 
Body mass index 
BoE 
Biomarker(s) of exposure 
BoPH 
Biomarker(s) of potential harm 
BP 
Blood pressure 
bpm 
Beats per minute 
°C 
Degree Celsius 
CEMA 
2-cyanoethyl-mercapturic acid 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLIA-88 
Clinical Laboratory Improvement Amendments of 1988 
Cmax 
Maximum measured plasma concentration 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CPD 
Cigarette(s) per day 
CRU 
Clinical research unit 

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CYP 
Cytochrome P450 
DMP 
Data Management Plan 
e-cigarette 
Electronic cigarette 
e-liquid 
Electronic cigarette liquid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
Emax 
Maximum change from baseline score 
°F 
Degree Fahrenheit 
FDA 
Food and Drug Administration 
FEF 
Forced expiratory flow 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FVC 
Forced vital capacity 
g 
Gram 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High density lipoprotein cholesterol 
HEMA 
Hydroxyethyl mercapturic acid 
HIV 
Human immunodeficiency virus 
HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
K2-EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
ln 
Natural logarithm 
m2 
Meters squared 
mAh 
Milliampere hour 
MCP-1 
Monocyte chemoattractant protein 1 
mg 
Milligram 

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MHBMA 
Monohydroxybutenylmercapturic acid 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
MTWS-R 
Minnesota Tobacco Withdrawal Scale-Revised 
ng 
Nanogram 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
NNN 
N-nitrosonornicotine 
o-tol 
o-toluidine 
PES 
Product Evaluation Scale 
PK 
Pharmacokinetic(s) 
ppm 
Parts per million 
PSCDI 
Penn State Cigarette Dependence Index 
PSECDI 
Penn State Electronic Cigarette Dependence Index 
QA 
Quality Assurance 
QSU-Brief 
Questionnaire on Smoking Urges-Brief 
RCF 
Relative centrifugal force 
S-PMA 
S-phenyl mercapturic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
sICAM 
Soluble intracellular adhesion molecule 
SOP 
Standard operating procedure 
TEmax 
Time of the Emax 
Tmax 
Time to reach the maximum measured plasma concentration 
US or USA 
United States of America 
USB 
Universal serial bus 
V 
Volt 
VAS 
Visual analog scale 
WBC 
White blood cell 

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DEFINITION OF TERMS 
Check-in 
Check-in is defined as the time when the subject arrives at the 
CRU 
Concomitant 
medication 
Concomitant medication refers to all medication taken during the 
study conduct period from 28 days prior to Screening through 
discharge. Medications started prior to Screening but which the 
subject continues to take during the study, are considered to be 
concomitant medications 
Randomization 
Assignment of subjects to a specific sequence 
Screening 
Screening is defined as the 28-day period prior to study 
procedures on Day -2, during which subjects will undergo 
screening assessments 
Screening failure 
Any subject who does not meet the entry criteria at Screening or 
Day -2 for study enrollment will be considered a Screening failure 
Sponsor 
‘Sponsor’ refers to Nerudia Ltd 
Subject 
‘Subject’ refers to an individual who participates in the clinical 
study 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL REVISION HISTORY.........................................................................................2 
SPONSOR SIGNATURE PAGE...............................................................................................3 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE..............................................................4 
STUDY CONTACTS ................................................................................................................5 
SYNOPSIS .................................................................................................................................6 
STUDY EVENTS FLOW CHART .........................................................................................14 
ABBREVIATIONS .................................................................................................................19 
DEFINITION OF TERMS.......................................................................................................22 
TABLE OF CONTENTS .........................................................................................................23 
1. 
INTRODUCTION AND BACKGROUND.................................................................27 
1.1 
Background ......................................................................................................27 
1.2 
myblu™ Previous Clinical Experience ............................................................27 
1.3 
Study Purpose ..................................................................................................29 
2. 
STUDY OBJECTIVES AND ENDPOINTS ...............................................................29 
2.1 
Study Objectives ..............................................................................................29 
2.2 
Study Endpoints ...............................................................................................30 
3. 
SUMMARY OF STUDY DESIGN .............................................................................34 
3.1 
Design and Procedures .....................................................................................34 
3.2 
Confinement and Follow-Up ...........................................................................38 
3.3 
End of Study Definition ...................................................................................38 
4. 
STUDY POPULATION ..............................................................................................38 
4.1 
Inclusion Criteria..............................................................................................38 
4.2 
Exclusion Criteria ............................................................................................39 
4.3 
Study Restrictions ............................................................................................42 
4.3.1 
Food and Beverages ..........................................................................42 
4.3.2 
Medications .......................................................................................42 
4.3.3 
Meals/Dietary Considerations ...........................................................42 
4.3.4 
Activity .............................................................................................43 
4.3.5 
Tobacco Use/Considerations.............................................................43 
4.4 
Subject Early Discontinuation or Withdrawal .................................................43 
4.5 
Subject Randomization ....................................................................................44 
5. 
STUDY PRODUCTS/MATERIALS ..........................................................................45 
5.1 
Description of Study Products .........................................................................45 
5.1.1 
Usual Brand Combustible Cigarette .................................................45 

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5.1.2 
myblu™ E-Cigarettes ........................................................................46 
5.2 
Study Product Accountability and Dispensing ................................................46 
6. 
STUDY PROCEDURES .............................................................................................47 
6.1 
Screening..........................................................................................................47 
6.1.1 
Informed Consent..............................................................................47 
6.1.2 
Medical History/Demographic Data/Record of Concomitant 
Medication ........................................................................................47 
6.1.3 
Tobacco/Nicotine Product Use History ............................................47 
6.1.4 
Exhaled Carbon Monoxide ...............................................................48 
6.2 
Check-in and Confinement ..............................................................................48 
6.2.1 
Baseline Assessments (Days -2 and -1) ............................................48 
6.3 
Product Use ......................................................................................................49 
6.3.1 
Days 1, 3, 5, and 7.............................................................................49 
6.3.2 
Days 2, 4, 6, and 8.............................................................................49 
6.3.3 
Day 9 .................................................................................................49 
6.3.4 
Days 10 to 14 ....................................................................................50 
6.4 
Study Assessments ...........................................................................................50 
6.4.1 
Nicotine Pharmacokinetics ...............................................................50 
6.4.2 
Biomarkers Sample Collection .........................................................51 
6.4.2.1 
Blood ............................................................................51 
6.4.2.2 
Urine ............................................................................51 
6.4.2.3 
Future Research............................................................52 
6.4.3 
Subjective Effects Questionnaires ....................................................52 
6.4.4 
Puff Topography ...............................................................................53 
6.4.5 
Spirometry.........................................................................................53 
6.4.6 
Safety Assessments ...........................................................................54 
6.4.6.1 
Physical Examination...................................................54 
6.4.6.2 
Body Weight, Height, and BMI ...................................54 
6.4.6.3 
Electrocardiogram ........................................................54 
6.4.6.4 
Vital Signs ....................................................................54 
6.4.6.5 
Clinical Laboratory ......................................................55 
6.4.7 
Adverse Events .................................................................................56 
6.4.7.1 
Monitoring ...................................................................56 

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6.4.7.2 
Reporting......................................................................56 
6.4.7.3 
Serious Adverse Events ...............................................56 
6.4.7.4 
Pregnancy .....................................................................57 
6.4.7.5 
Smoking Cessation Information...................................57 
7. 
DATA ANALYSIS ......................................................................................................57 
7.1 
Sample Size Estimation ...................................................................................58 
7.2 
Analysis Populations ........................................................................................58 
7.3 
Data Analysis, Summarization, and Statistical Methods .................................58 
7.3.1 
Nicotine Pharmacokinetic Analysis ..................................................58 
7.3.2 
Biomarkers ........................................................................................60 
7.3.2.1 
Urine Nicotine Equivalents ..........................................60 
7.3.2.2 
Calculation of Total Mass Excreted .............................60 
7.3.2.3 
Creatinine Adjustments ................................................60 
7.3.2.4 
Data Summary and Analysis ........................................60 
7.3.3 
Subjective Effects .............................................................................61 
7.3.3.1 
Urge to Smoke Parameters...........................................61 
7.3.3.2 
Product Liking..............................................................61 
7.3.3.3 
Product Evaluation .......................................................61 
7.3.3.4 
Future Intent to Use......................................................62 
7.3.3.5 
QSU-Brief ....................................................................62 
7.3.3.6 
MTWS-R......................................................................62 
7.3.3.7 
Penn State (Electronic) Cigarette Dependence 
Index (PSCDI/PSECDI)...............................................62 
7.3.4 
Puff Topography ...............................................................................62 
7.3.5 
Physiological Endpoints....................................................................63 
7.3.5.1 
Blood Pressure (BP) and Heart Rate (HR)...................63 
7.3.5.2 
Spirometry....................................................................63 
7.3.6 
Product Use Behavior .......................................................................64 
7.3.7 
Safety ................................................................................................64 
8. 
STUDY ADMINISTRATION.....................................................................................64 
8.1 
Ethics................................................................................................................64 
8.1.1 
Institutional Review Board ...............................................................64 
8.1.2 
Ethical Conduct of the Study ............................................................65 

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8.1.3 
Subject Information and Consent......................................................65 
8.2 
Confidentiality .................................................................................................65 
8.3 
Termination of the Study .................................................................................65 
8.4 
Data Quality Assurance ...................................................................................66 
8.5 
Direct Access to Source Data/Documents .......................................................66 
8.5.1 
Monitoring the Study ........................................................................66 
8.6 
Reporting for the Study ....................................................................................67 
8.6.1 
Case Report Forms ............................................................................67 
8.6.2 
Data Coding ......................................................................................67 
8.6.3 
Report Format ...................................................................................67 
8.6.4 
Record Keeping.................................................................................67 
8.7 
Publication Policy ............................................................................................68 
9. 
REFERENCES ............................................................................................................69 
10. 
APPENDICES .............................................................................................................70 
 
 
List of Appendices 
Appendix 1: Urge to Smoke Questionnaire ......................................................................... 71 
Appendix 2: Product Liking Questionnaire ......................................................................... 72 
Appendix 3: Product Evaluation Scale (PES)...................................................................... 73 
Appendix 4: Future Intent to Use Questionnaire ................................................................. 74 
Appendix 5: Questionnaire of Smoking Urges-Brief (QSU-Brief) ..................................... 75 
Appendix 6: Minnesota Tobacco Withdrawal Scale-Revised (MTWS-R).......................... 76 
Appendix 7: Penn State [Electronic] Cigarette Dependence Index (PSCDI/PSECDI) ....... 77 
 
 
List of Tables 
Table 1. Study Events ............................................................................................................. 14 
 
 
List of Figures 
Figure 1. Overall Study Design............................................................................................... 37 
 

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1. INTRODUCTION AND BACKGROUND 
1.1 
Background 
E-cigarettes have become a popular alternative to cigarette smoking and are garnering 
significant attention as potentially reduced exposure products and smoking cessation 
products. E-cigarettes consist of a battery, heating component, and a reservoir (often referred 
to as a pod, cartridge, or tank) containing tobacco-derived nicotine in a solution composed of 
glycerin and/or propylene glycol and flavorings. Upon activation, the heating element heats 
the solution and the consumer inhales the resulting vapor. 
Because e-cigarette use does not involve the combustion of tobacco, it is expected that 
e-cigarette consumers will experience reduced exposure to most biomarkers of tobacco 
exposure compared to combustible cigarettes. Previous studies have shown that switching 
from combustible cigarettes to e-cigarettes with high rates of compliance results in large 
reductions in a number of cigarette smoke toxicants (Cravo 2016, Goniewicz 2017, 
O'Connell 2016, McRobbie 2015, Hecht 2015).  
Therefore, to be of greatest benefit, e-cigarettes must provide smokers with an experience 
that would allow for maximal displacement of combustible cigarettes while at the same time 
not serve as a gateway to other more toxic products for nonsmokers. Key elements that 
contribute to an acceptable initiating experience include the nicotine content in the products 
as well as the response that consumers have in terms of satisfaction and prevention of 
symptoms of withdrawal. 
1.2 
myblu™ Previous Clinical Experience 
One previous clinical study has been conducted with the myblu™ closed system 
(FON-01blu-2018). Fifteen healthy adult smokers enrolled in an open-label, 6-period 
crossover study to characterize nicotine uptake and subjective effects during a 10-puff 
controlled exposure (puffs 3 seconds in duration, taken at approximately 30-second intervals) 
relative to usual brand combustible cigarettes and the blu PRO open system product and to 
determine the potential impact of a nicotine salt e-liquid (with lactic acid). 
Blood samples for plasma nicotine analysis were collected approximately 5 minutes prior to 
and at 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, and 30 minutes following the start of product use. The 
subjective effects questionnaires were completed at approximately 20 minutes following the 
start of each product use and included 6 questions presented on a scale of 1 (not at all) to 7 
(extremely).  
Nicotine overall exposure over 30 minutes (AUC0-30) and peak exposure (Cmax) increased 
with increasing nicotine content in the myblu™ products (16 - 40 mg nicotine), and was 
higher in the 25 mg nicotine salt formulation compared to the non-salt formulation. The time 
to reach maximal plasma nicotine concentrations (Tmax) ranged from approximately 
6.0 - 7.9 minutes following use of myblu™ and blu PRO products with nicotine salts and 
approximately 8.0 minutes following use of myblu™ non-salt formulation. AUC0-30 and 
Cmax of nicotine were lowest following use of blu PRO compared to all other products 
tested. AUC0-30 and Cmax of nicotine was highest following use of cigarette compared to 
any other product tested. Tmax was shorter following use of the five e-cigarette test products 

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compared to the cigarette.  
Arithmetic Mean Baseline Adjusted Plasma Nicotine Concentration-Time Profiles 
Following Fixed Product Use by Product (Linear Scale)
 
Summary of Baseline Adjusted Plasma Nicotine Pharmacokinetics by Study Product 
Parameter 
Product A: 
myblu™ 
25 mg 
Product B: 
myblu™ 25 mg 
(free-base) 
Product C: 
myblu™ 40 mg 
Product D: 
myblu™ 16 mg 
Product E: 
blu PRO 48 mg 
Product F: 
Cigarette 
AUC0-30 
(ng*min/mL) 
125.2 (53.4) 
[n=13] 
98.99 (35.8) 
[n=14] 
190.7 (71.8) 
[n=15] 
118.5 (60.8) 
[n=15] 
84.84 (89.8) 
[n=14] 
324.9 (35.8) 
[n=15] 
Cmax (ng/mL) 
7.576 (80.6) 
[n=13] 
5.048 (49.9) 
[n=14] 
10.27 (83.6) 
[n=15] 
6.510 (76.5) 
[n=15] 
4.845 (108.3) 
[n=14] 
17.81 (49.6) 
[n=15] 
Tmax (min) 
6.033  
(4.58, 16.77) 
[n=13] 
8.034  
(2.28, 15.10) 
[n=14] 
7.900  
(1.97, 15.00) 
[n=15] 
6.967  
(3.98, 15.05) 
[n=15] 
6.908  
(2.35, 15.03) 
[n=14] 
8.050  
(5.00, 15.13) 
[n=15] 
AUC and Cmax are presented as geometric mean and geometric coefficient of variability %, Tmax values are presented as 
median (min, max). 
n: number of observations included in the summary statistics  
 
Product A: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 25 mg 
Product B: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, non-nicotine salt liquid 25 mg 
Product C: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 40 mg 
Product D: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 16 mg 
Product E: blu PRO open system with Purilum Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 48 mg 
Product F: Subject’s usual brand combustible cigarette 
Mean scores for the subjective effects assessments tended to be highest after combustible 
cigarette use and generally followed by myblu™ 40 mg. With the exception of the questions 
“was it enough nicotine?” and “was it too much nicotine?”, the responses following use of 
the 25 mg salt formulation were comparable to the 25 mg non-salt formulation. 
 

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Summary of Subjective Effects Score by Study Product (Safety Population) 
Questions 
Study Products 
A 
B 
C 
D 
E 
F 
n =13 
n =14 
n =15 
n =15 
n =14 
n =15 
Did it make you dizzy? 
2.1 ± 1.32 
1.9 ± 1.73 2.8 ± 1.78 
1.5 ± 0.74 1.7 ± 0.99 
3.7 ± 1.80 
Did it make you nauseous?  
1.2 ± 0.44 
1.3 ± 0.83 1.4 ± 0.91 
1.1 ± 0.26 1.4 ± 0.84 
1.9 ± 1.44 
Did you enjoy it? 
3.5 ± 1.98 
3.5 ± 1.87 4.0 ± 1.36 
3.5 ± 1.46 3.2 ± 1.81 
4.9 ± 1.44 
Did it relieve the urge to smoke? 
3.5 ± 1.98 
3.6 ± 2.10 4.1 ± 1.79 
3.3 ± 1.91 3.1 ± 2.11 
5.5 ± 1.60 
Was it enough nicotine? 
3.1 ± 1.93 
4.0 ± 1.96 4.3 ± 1.79 
3.3 ± 1.99 3.2 ± 2.08 
5.4 ± 1.55 
Was it too much nicotine? 
1.5 ± 0.97 
2.5 ± 2.21 2.2 ± 1.66 
1.7 ± 1.11 1.4 ± 0.63 
2.4 ± 1.55 
Scoring: 1 – Not at all, 2 – Very little, 3 – A little, 4 – Moderately, 5 – A lot, 6 – Quite a lot, 7 – Extremely. 
Scores are presented as mean ± SD. 
n = Number of subjects used in the analysis 
Product A: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 25 mg 
Product B: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, non-nicotine salt liquid 25 mg 
Product C: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 40 mg 
Product D: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 16 mg 
Product E: blu PRO open system with Purilum Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 48 mg 
Product F: Subject’s usual brand combustible cigarette 
Overall, the study products were well-tolerated under the conditions of use in the study. 
There were no serious adverse events (SAEs) reported in the study, and no subjects were 
discontinued due to AEs. Product use emergent AEs were infrequently reported with four 
subjects reporting a total of 10 AEs. Venipuncture site pain was the most frequently reported 
AE, experienced by two subjects. All remaining AEs were experienced by one subject each. 
All AEs were mild in severity, with the exception of moderate insomnia (blu PRO 48 mg). 
The PI considered one AE of headache (myblu™ 25 mg [non-salt formulation]) to be 
possibly related to study product and the remaining nine events unlikely or unrelated. 
1.3 
Study Purpose 
This study is being conducted to evaluate the overall performance of the currently-marketed 
myblu™ e-cigarette device and pods, as assessed by nicotine uptake and consumer 
satisfaction. The endpoints to be assessed are based on the United States (US) Food and Drug 
Administration (FDA) Electronic Nicotine Delivery Systems Draft Guidance for Industry 
(FDA 2019), and the data may be included in future premarket tobacco application 
submissions to the Center for Tobacco Products.  
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
Primary 
1. To characterize nicotine uptake following controlled use of myblu™ e-cigarettes. 
2. To assess the change-from-baseline differences in the primary tobacco-related BoE 
following a 9-day use period of myblu™ e-cigarettes. 

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Secondary 
1. To assess the change-from-baseline differences in the primary tobacco-related BoE 
following a 14-day use period of myblu™ e-cigarettes. 
2. To assess the change-from-baseline differences in the secondary tobacco-related BoE 
following 9-day and 14-day use periods of myblu™ e-cigarettes. 
3. To characterize the change in the primary and secondary tobacco-related BoE and BoPH 
during a 14-day period of use of myblu™ e-cigarettes and compare between exclusive 
e-cigarette use, exclusive combustible cigarette use and dual (combustible cigarette and 
e-cigarette) use. 
4. To assess the change-from-baseline differences in the primary and secondary 
tobacco-related BoE between Day 9 and Day 14 in subjects using myblu™ e-cigarettes, 
both exclusively and alongside use of combustible cigarettes. 
5. To assess change-from-baseline differences in BoPH following 9-day and 14-day use 
periods of myblu™ e-cigarettes. 
6. To assess measures of subjective effects associated with use of myblu™ e-cigarettes. 
7. To determine puffing topography parameters (puff count, puff duration, puff volume, 
peak puff flow rate, average puff flow rate, inter puff interval) following an 8-day use 
period of myblu™ e-cigarettes and assess change-from-baseline differences (if 
applicable). 
8. To assess change-from-baseline differences in physiologic endpoints (i.e., BP, HR, and 
spirometry) following 9-day and 14-day use periods of myblu™ e-cigarettes. 
9. To characterize product use of myblu™ e-cigarettes under short-term controlled and 
ad libitum use conditions. 
10. To assess the safety and tolerability of myblu™ e-cigarettes following short-term use. 
2.2 
Study Endpoints 
Pharmacokinetics: 
For each first (controlled) product use session on Days 2, 4, 6, and 8, plasma nicotine PK 
parameters (AUC0-180, Cmax, and Tmax) will be computed from the individual plasma 
concentrations for each study product. Baseline adjustments will be performed. 
Nicotine concentrations and PK parameters will be listed by subject and summarized using 
descriptive statistics. 

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Biomarkers: 
For each of Days -1, 9, and 14, biomarker concentrations will be listed by subject and 
summarized using descriptive statistics. Absolute and percent change-from-baseline will be 
determined for the mass excreted and creatinine-adjusted values. 
Primary Biomarkers of Exposure: 
Biomarker 
Matrix 
Chemical Constituent 
COHb 
Blood 
CO 
NNAL 
Urine 
NNK 
3-HPMA 
Urine 
Acrolein 
S-PMA 
Urine 
Benzene 
Secondary Biomarkers of Exposure: 
Biomarker 
Matrix 
Chemical Constituent 
NNN 
Urine 
NNN 
CEMA 
Urine 
Acrylonitrile 
HEMA 
Urine 
Ethylene oxide 
HMPMA 
Urine 
Crotonaldehyde 
MHBMA 
Urine 
1,3-butadiene 
1-OHP 
Urine 
Pyrene 
o-tol 
Urine 
Toluidine 
3-OH B[a]P 
Urine 
B[a]P 
1-AN 
Urine 
Naphthalene 
2-AN 
Urine 
Naphthalene 
Nicotine equivalents 
Urine 
Nicotine 

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Biomarkers of Potential Harm: 
Biomarker 
Matrix 
Biological Effect 
sICAM 
Blood 
Inflammation 
WBCs 
Blood 
Inflammation 
HDL-C 
Blood 
Inflammation 
MCP-1 
Blood 
Inflammation 
8-epi-PGF2α 
Urine 
Oxidative stress 
11-DHTXB2 
Urine 
Platelet activation 
Subjective Effects: 
Urge to Smoke (Days 2, 4, 6, and 8) 
Responses and derived parameters (Emax, TEmax, and AUEC0-120) will be listed by subject 
and summarized using descriptive statistics.  
Product Liking (Days 2, 4, 6, and 8) 
Responses will be listed by subject and summarized using descriptive statistics.  
Product Evaluation (Days 2, 4, 6, and 8) 
Responses will be considered as a 7-point scale, and will be presented as factors outlined in 
Section 7.3.3.3. 
Descriptive statistics of the subscales will be provided by study product and product use 
session. Individual responses will be listed. 
Future Intent to Use (Days 2, 4, 6, and 8) 
Responses recorded as VAS scores will be treated as bipolar categorical variables (-50 to <0, 
0, >0 to 50) and summarized by study product using frequency count tables. The bipolar 
score for the Future Intent to Use questionnaire is calculated by subtracting 50 from the 
original VAS score. The bipolar scores will also be treated as continuous variables and 
summarized using descriptive statistics. 
QSU-Brief (Days 9 and 14) 
Responses to the QSU-brief will be considered as a 7-point scale and treated as a continuous 
variable and will be presented as two factors as outlined in Section 7.3.3.5.  
Descriptive statistics of the subscales will be provided by study day and study arm (Part 2 
only). Individual responses will be listed. 

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MTWS-R (Days 9 and 14) 
The total score to the MTWS-R will be summarized by study day and study arm (Part 2 
only). 
PSCDI/PSECDI (Days 9 and 14) 
The total score to the PSCDI/PSECDI will be summarized by study day and study arm 
(Part 2 only). 
Puff Topography: 
Topography parameters (puff count, puff duration, puff volume, peak puff flow rate, average 
puff flow rate, inter-puff interval) will be listed by subject and summarized using descriptive 
statistics. 
Physiological Endpoints: 
Blood Pressure and Heart Rate 
Unadjusted and change from baseline BP and HR parameters (e.g., AUEC0-t, Emax, and 
TEmax) will be listed by subject and summarized using descriptive statistics.  
Spirometry 
Pre- and post-bronchodilator lung function variables (measured and percent of predicted 
FEV1, measured and percent of predicted FVC, measured and percent of predicted 
FEV1:FVC ratio, and measured and percent of predicted FEF25-75%) will be listed by 
subject and summarized using descriptive statistics. 
Product Use Behavior: 
All product use data, including the number of combustible cigarettes smoked and the 
difference in pod weights, will be summarized using descriptive statistics. 
Safety: 
Screening evaluations will include a full physical examination, vital signs measurements, 
12-lead ECG, clinical laboratory tests (serum chemistry, hematology, urinalysis, and 
serology), exhaled CO measurement, urine drug screen, urine/breath alcohol screen, and a 
serum/urine pregnancy test (females only).  
Safety will be monitored on-study through physical examination (symptom-driven), vital 
signs measurements, ECGs, and clinical laboratory tests (serum chemistry, hematology, and 
urinalysis).  
AEs spontaneously reported by the subjects or observed by the Investigator or other study 
personnel will be monitored from the time subjects first use a study product until the 
follow-up.  
AEs will be tabulated and summary statistics for vital signs and clinical laboratory tests may 
be computed and provided, as deemed clinically appropriate.  

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Incidence of device malfunction(s) will also be tabulated.  
3. SUMMARY OF STUDY DESIGN 
3.1 
Design and Procedures 
This will be an open-label, randomized, 2-part study in adult smokers. All subjects will 
participate in both study parts. Part 2 will begin immediately after Part 1. 
Screening procedures will be performed within 28 days prior to study procedures on Day -2. 
Forty (40) adult, male and female, self-affirmed smokers (smoke an average of 10 or more 
manufactured combustible CPD for at least 12 months prior to Screening), who successfully 
complete the screening procedures and meet the eligibility criteria, will be eligible to 
check-in to the CRU on Day -2. Every attempt will be made to enroll no more than 60% of 
either sex. 
Following check-in, subjects will complete all subjective effects questionnaires for the 
purpose of familiarization with the questions, scales, and computerized tablet. Subjects will 
also participate in a brief trial on Day -2 (approximately 30 minutes) using the myblu™ 
device with a 0% nicotine e-liquid, to familiarize with the use of the device. Baseline study 
assessments, including BoE, BoPH, spirometry (Day -1 only), BP, HR, and puff topography 
(in a subset of 16 subjects [2 subjects from each sequence in Part 1] on Day -1 only) will be 
performed on Days -2 through -1, as appropriate. Subjects will continue to smoke their usual 
brand combustible cigarette from check-in through Day -1, but will abstain from use of any 
tobacco- or nicotine-containing products for at least 12 hours prior to the start of product use 
on Day 1. Subjects will be randomized to 1 of 8 sequences (Part 1) on Day -1. 
Part 1 (Days 1 to 9) 
On Days 1, 3, 5, and 7, subjects will use the study product they are assigned to use the 
following day according to the randomization scheme. Subjects will use the assigned study 
product ad libitum until the start of the abstinence period (i.e., at least 12 hours prior to the 
start of the first product use session on the next day). A fully charged battery and a fresh pod 
will be provided on each day. Additional pods will be provided as needed. Pods will be 
weighed within 24 hours before the start and after completion of product use on each day. On 
Day 1, puff topography measurements will be performed in the same subset of 16 subjects 
(2 subjects from each sequence in Part 1) for 1 hour during ab libitum product use. Puff 
topography should be performed within ± 2 hours of the time of the baseline assessment on 
Day -1. 
On Days 2, 4, 6, and 8, subjects will participate in two product use sessions on each day, 
using the assigned study product according to the randomization scheme. In the first 
(controlled) product use session, subjects will use the assigned study product under 
controlled conditions (i.e., 10 puffs taken at 30-second intervals, with puffs 3 seconds in 
duration). Blood samples for nicotine PK assessment will be collected prior to and for 
3 hours following the start of the first product use session. Subjects will complete the Urge to 

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Smoke questionnaire during and following the first product use session and the Product 
Liking, PES, and Future Intent to Use questionnaires following the first product use session. 
Following collection of the last PK blood sample (180-minute time point) and completion of 
the subjective effects questionnaires, subjects will start the second (ad libitum) product use 
session, during which they will use the same assigned study product ad libitum (with no 
limits on puff duration or inter-puff interval) until approximately 23:00. Subjects will 
complete the Urge to Smoke, Product Liking, PES, and Future Intent to Use questionnaires at 
least 6 hours after the start of the second product use session. A fresh pod and fully charged 
device will be provided for each product use session. Pod weights will be measured before 
and after each product use session. On Day 8, puff topography measurements will be 
performed in the same subset of 16 subjects (2 subjects from each sequence in Part 1) for 
1 hour during the second (ab libitum) product use session. Puff topography will be performed 
at least 4 hours after the start of the second (ab libitum) product use session and should be 
within ± 2 hours of the time of the baseline assessment on Day -1. 
On Day 9, subjects may use all or any of the 4 study products (used previously on 
Days 1 to 8) ad libitum until approximately 23:00. For BoE and BoPH assessments, blood 
samples will be collected on Day 9 and urine samples will be collected over 24 hours 
(starting on Day 8 after completion of the second [ab libitum] product use session). BP and 
HR measurements will be taken throughout the period of ad libitum product use. Subjects 
will complete the QSU-Brief, the MTWS-R, and the PSCDI/PSECDI questionnaires at least 
6 hours after the start of the ad libitum product use session on Day 9. Spirometry 
measurements will be conducted following completion of all subjective effects 
questionnaires on Day 9. Fresh pods and a fully charged device will be provided on Day 9 
and pod weights will be measured. 
Depending on the availability of topography equipment, puff topography may not be 
performed at all scheduled time points and may not be performed for some or all assigned 
subjects. 
Part 2 (Days 10 to 14) 
Subjects will be randomized to 1 of 3 study arms (Part 2) on Day 10. Subjects will use any or 
all of the 8 study products and/or smoke their usual brand combustible cigarettes ad libitum 
for 5 days (until approximately 23:00 on each day) according to the randomization scheme. 
For BoE and BoPH assessments, blood samples will be collected on Day 14 and urine 
samples will be collected over 24 hours (starting on Day 13 after the end of product use for 
that day). On Day 14, BP and HR measurements will be taken throughout the period of 
ad libitum product use/smoking. The QSU-Brief, MTWS-R, and PSCDI/PSECDI 
questionnaires will be completed at least 6 hours after the start of the ad libitum product use 
session on Day 14. Spirometry measurements will be conducted following completion of all 
subjective effects questionnaires on Day 14. Product use behavior will be assessed by 
documenting the number of cigarettes smoked, the flavor and strength of the myblu™ 
products, and pod weights, per day, as appropriate. On each study day, fresh pods and a fully 
charged device will be provided, as appropriate. 
Subjects will not be forced to use any tobacco/nicotine products at any time during the study. 

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The overall study design is depicted in Figure 1. 
Safety will be monitored through physical examination (symptom-driven), vital signs 
measurements, ECGs, and clinical laboratory tests (serum chemistry, hematology, and 
urinalysis). 
AEs spontaneously reported by the subjects or observed by the Investigator or other study 
personnel will be monitored from the time of first use of any study product until the 
follow-up. Device malfunctions will also be recorded. 
The safety monitoring practices employed by this protocol (i.e., vital signs, 12-lead ECGs, 
clinical laboratory tests, AE questioning, and physical examinations) are adequate to protect 
the subjects’ safety and should detect all expected emergent AEs. 
Discontinued subjects may be replaced at the discretion of the Sponsor. 

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Figure 1. Overall Study Design 
 
a: 
To be performed within 28 days prior to study procedures on Day -2. 
b: Baseline study assessments will be performed on Days -2 and -1 while subjects continue to smoke their 
usual brand combustible cigarette. 
c: Subjects may use all or any of the 4 study products (i.e., A, B, C, and/or D) ad libitum (Ad lib) until 
approximately 23:00. 
d: Subjects may use all or any of the 4 study products (i.e., E, F, G, and/or H) ad libitum (Ad lib) until 
approximately 23:00.  
e: Subjects will be randomized to 1 of 3 study arms (Part 2) on Day 10 and will use any or all of the 8 study 
products (Products A to H) and/or smoke their usual brand combustible cigarettes ad libitum for 5 days 
according to the randomization scheme. 
f: 
The CRU will attempt to contact all subjects who used at least one study product (including subjects who 
terminate the study early) using their standard procedures approximately 14 days after the last study 
product used.  
g: Subjects will use ad libitum the study product they are assigned to use the following day according to the 
randomization scheme. Subjects will use the assigned study product ad libitum until the start of the 
abstinence period (i.e., at least 12 hours prior to the start of the first product use session on the next day). 
h: Subjects will complete one set of questionnaires for the purpose of familiarization with subjective effects 
questions, appropriate use of the VAS, and use of the computerized tablet system. 
i: 
A total of 16 subjects (2 subjects from each sequence in Part 1) will have puff topography evaluated for 
1 hour during ad libitum product use. 
 

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Study Products in Part 1: 
A 
myblu™ (freebase), Gold Leaf flavor, 2.4% 
B 
myblu™ (freebase), Polar Mint flavor, 2.4% 
C 
myblu™ (freebase), Cherry flavor, 2.4% 
D 
myblu™ (freebase), Vanilla flavor, 2.4% 
E 
myblu™ (freebase), Gold Leaf flavor, 1.2% 
F 
myblu™ (freebase), Polar Mint flavor, 1.2% 
G 
myblu™ (freebase), Menthol flavor, 2.4% 
H 
myblu™ Intense (nicotine salts), Fresh Mint flavor, 2.4% 
Study Arms in Part 2: 
I  (myblu™) 
Exclusive use of myblu™ products ad libitum 
J  (Combustible) 
Exclusive smoking of usual brand combustible cigarettes 
ad libitum 
K  (Dual Use) 
Smoking of usual brand combustible cigarettes (up to 50% of the 
subject’s self-reported CPD) and use of myblu™ products 
ad libitum 
3.2 
Confinement and Follow-Up 
Subjects will be housed at the CRU on Day -2, at the time indicated by the CRU, until after 
completion of all study procedures on Day 15. At all times, a subject may be required to 
remain at the CRU for longer at the discretion of the Investigator or designee. 
The CRU will attempt to contact all subjects who used at least one study product (including 
subjects who terminate the study early) using their standard procedures approximately 
14 days after the last study product use to determine if any AE has occurred since the last 
study visit. 
3.3 
End of Study Definition 
The end of study is defined as the date of the last scheduled study procedure as outlined in 
the Study Events Flow Chart (Table 1). 
4. STUDY POPULATION 
Subjects selected for this study will be identified via standard recruitment methods. 
4.1 
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Healthy, adult, male or female, 21 to 65 years of age, inclusive, at Screening. 

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2. Reports smoking an average of at least 10 manufactured combustible (menthol or 
non-menthol) CPD for at least 12 months prior to Screening. Brief periods of 
non-smoking (e.g., up to ~7 consecutive days due to illness, trying to quit, participation 
in a study where smoking was prohibited) within 60 days prior to Check-in will be 
permitted at the discretion of the Investigator. 
3. Has a positive urine cotinine (≥ 200 ng/mL) at Screening. 
4. Has an exhaled carbon monoxide (CO) > 10 ppm at Screening. 
5. A female subject of childbearing potential must have been using 1 of the following forms 
of contraception and agree to continue using it through completion of the study: 
• hormonal (e.g., oral, vaginal ring, transdermal patch, implant, or injection) 
consistently for at least 3 months prior to Check-in; 
• double barrier method (e.g., condom with spermicide, diaphragm with spermicide) 
consistently for at least 14 days prior to Check-in; 
• intrauterine device for at least 3 months prior to Check-in; 
• a partner who has been vasectomized for at least 4 months prior to Check-in; 
• abstinence beginning at least 14 days prior to Check-in. 
6. A female subject of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to Check-in: 
• hysteroscopic sterilization; 
• bilateral tubal ligation or bilateral salpingectomy; 
• hysterectomy; 
• bilateral oophorectomy;  
or be postmenopausal with amenorrhea for at least 1 year prior to Check-in and 
follicle-stimulating hormone (FSH) levels consistent with postmenopausal status. 
7. Is willing to comply with the requirements of the study, including a willingness to use the 
e-cigarettes. 
8. Provides voluntary consent to participate in this study documented on the signed 
informed consent form (ICF). 
4.2 
Exclusion Criteria 
Subjects may be excluded from the study if there is evidence of any of the following criteria 
at Screening, Check-in, or during the study as noted, in the opinion of the Investigator: 
1. Has a history or presence of clinically significant gastrointestinal, renal, hepatic, 
neurologic, hematologic, endocrine, oncologic, urologic, pulmonary (especially 
bronchospastic diseases and asthma), immunologic, psychiatric, or cardiovascular 

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disease, or any other condition that, in the opinion of the Investigator, would jeopardize 
the safety of the subject or impact the validity of the study results. 
2. Has a clinically significant abnormal finding on the physical examination, medical 
history, vital signs, ECG, or clinical laboratory results, in the opinion of the Investigator. 
3. Has a positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C virus (HCV). 
4. Has previously been diagnosed with any form of cancer, except for basal cell or 
squamous epithelial carcinomas of the skin that have been resected at least 1 year prior to 
Screening. 
5. Has diabetes mellitus that is not controlled by diet/exercise alone, in the opinion of the 
Investigator. 
6. Has had an acute illness (e.g., upper respiratory infection, viral infection) requiring 
treatment within 14 days prior to Check-in. 
7. Has a fever (> 100.5°F/38.05°C) at Screening or Check-in. 
8. Has a body mass index (BMI) > 40 kg/m2 or < 18 kg/m2 at Screening. 
9. Has a history or presence of drug or alcohol abuse within 24 months of Check-in, as 
determined by the Investigator. 
10. Has a systolic blood pressure < 90 mmHg or > 150 mmHg, diastolic blood pressure 
< 40 mmHg or > 95 mmHg, or heart rate < 40 bpm or > 99 bpm at Screening. 
11. Has a post-bronchodilator FEV1 < 50% of predicted at Screening. 
12. Has a post-bronchodilator FEV1 increase ≥ 12% and > 200 mL from pre- to 
post-bronchodilator at Screening. 
13. Is allergic to propylene glycol or glycerin. 
14. Has an estimated creatinine clearance < 70 mL/minute (using the Cockcroft-Gault 
equation) at Screening. 
15. Has a positive urine/breath screen for alcohol or positive urine screen for drugs of abuse 
at Screening or Check-in. 
16. If female, the subject is pregnant, lactating, or intends to become pregnant during the 
time period from Screening through the end of study. 
17. Has taken medication for depression or asthma within 12 months prior to Check-in and 
throughout the study. 
18. Has used prescription anti-diabetic medication and/or insulin therapy within 12 months 
prior to Check-in and throughout the study. 

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19. Has used medications known to interact with cytochrome P450 (CYP) 2A6 (including, 
but not limited to, amiodarone, desipramine, isoniazid, ketoconazole, miconazole, 
phenobarbital, rifampin, tranylcypromine, methoxsalen) within 3 months prior to 
Check-in and throughout the study. 
20. Has used prescription or over-the-counter nonsteroidal anti-inflammatory drugs 
(e.g., aspirin, ibuprofen) within 7 days prior to Check-in and throughout the study. 
Medication listed as part of acceptable birth control methods, hormonal replacement 
therapy, and occasional or seasonal use of over-the-counter products such as analgesics, 
antihistamines, nasal decongestants, and dietary supplements are permitted at the 
discretion of the Investigator in consultation with the Sponsor (refer to Section 4.3.2). 
21. Has used inhalers to treat any medical condition within 3 months prior to Check-in and 
throughout the study. 
22. Use of prescription or over-the-counter bronchodilator medication (e.g., inhaled or oral 
β-agonists) for treatment of any illness within 12 months prior to Check-in and 
throughout the study. 
23. Has used other nicotine-containing products other than manufactured combustible 
cigarettes (e.g., e-cigarettes, roll-your-own cigarettes, bidis, snuff, nicotine inhaler, pipe, 
cigar, chewing tobacco, nicotine patch, nicotine spray, nicotine lozenge, or nicotine gum) 
within 14 days prior to Check-in. 
24. Has used any prescription smoking cessation treatments, including, but not limited to, 
varenicline (Chantix®) or bupropion (Zyban®) within 3 months prior to Check-in. 
25. Is a self-reported puffer (i.e., adult smoker who draws smoke from the cigarette into the 
mouth and throat but does not inhale). 
26. Is planning to quit smoking during the study or postponing a quit attempt in order to 
participate in the study. 
27. Has donated plasma within 7 days prior to Check-in. 
28. Has donated blood or blood products (with the exception of plasma as noted above), had 
significant blood loss, or received whole blood or a blood product transfusion within 
56 days prior to Check-in. 
29. Has participated in a previous clinical study for an investigational drug, device, biologic, 
or tobacco product within 30 days prior to Check-in. 
30. Is or has a first-degree relative (i.e., parent, spouse, sibling, child) who is a current or 
former employee of the tobacco or vaping industry or a named party or class 
representative in litigation with the tobacco or vaping industry. 
31. Is or has a first-degree relative (i.e., parent, spouse, sibling, child) who is a current 
employee of the CRU. 

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32. In the opinion of the Investigator, the subject should not participate in this study. 
4.3 
Study Restrictions 
4.3.1 Food and Beverages 
Foods and beverages containing the following substances should not be consumed as 
indicated below: 
• Alcohol should be avoided for 48 hours prior to Screening and Check-in to avoid 
exclusion for a positive alcohol test and throughout the study. 
• Foods containing poppy seeds should be avoided for 48 hours prior to Screening and 
Check-in to avoid exclusion for a positive urine drug test and throughout the study. 
• Food and beverages containing grapefruit for 14 days prior to Check-in and 
throughout the study. 
• Subjects will be advised to avoid eggplant, meats cooked at high temperatures 
(e.g., barbecued, grilled, pan-fried), cured sandwich meats, bacon, salami, and 
sausages for 48 hours prior to Check-in and throughout the study.  
• Caffeinated beverages will be restricted throughout confinement. 
4.3.2 Medications 
Medication use will be assessed to satisfy the inclusion and exclusion criteria. All 
medications (and reasons for their use) taken from 30 days prior to Check-in through the 
end-of-study will be recorded. Except for those medications noted in the exclusion criteria 
(Section 4.2) and albuterol used during spirometry measurements for this study, prescription 
or over-the-counter medications required to treat a disease or condition are permitted at the 
discretion of the Investigator. Hormonal contraceptives (e.g., oral, vaginal ring, transdermal 
patch, implant, injection) and hormonal replacement therapy are permitted. Occasional or 
seasonal use of over-the-counter products such as analgesics (e.g., acetaminophen), 
antihistamines, nasal decongestants, and dietary supplements are permitted. Exceptions may 
be permitted at the discretion of the Investigator in consultation with the Sponsor, providing 
the medication in question would have no impact on the study. Any exceptions will be 
documented. 
Decisions to use concomitant medications during the study will be made in the best interest 
of the health of the subject. If use of a prohibited medication is required during the study, a 
joint decision will be made by the Investigator and Sponsor to continue or discontinue the 
subject. Any exceptions will be documented and required medications that might impact 
study endpoints should be considered during interpretation of the study results. 
4.3.3 Meals/Dietary Considerations 
For all subjects, meals and snacks will be provided at the appropriate times during 
confinement at the CRU. Each meal and/or snacks served at the CRU will be standardized 
and will be similar in caloric content and composition and will be taken at approximately the 

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same time on each day. When confined in the CRU, subjects will be required to fast from all 
food and drink except water between meals and snacks. 
Subjects will fast for at least 1 hour prior to and for at least 4 hours after the start of each first 
product use session on Days 2, 4, 6, and 8. Subjects will also fast for at least 1 hour prior to 
each puff topography session and for at least 8 hours prior to blood sample collection for 
biomarkers (other than COHb). 
During confinement, water will be allowed ad libitum, except that subjects may not consume 
beverages of any kind (including water) during the first product use session on Days 2, 4, 6, 
and 8, and during each puff topography session. An exception to the water restriction can be 
made if a subject starts coughing uncontrollably while smoking or using the e-cigarettes. 
4.3.4 Activity 
Subjects will be instructed to refrain from abnormal strenuous physical activity which could 
cause muscle aches or injury, including contact sports at any time from 48 hours prior to 
Screening and Check-in, and during confinement. 
During each 24-hour urine collection period, specific measures will be taken to prevent the 
subject from missing a urine collection by strictly controlling and providing access to 
designated restrooms only. Subjects will be asked to void prior to entering the shower. 
4.3.5 Tobacco Use/Considerations 
Except as required by the study, consumption of tobacco- or nicotine-containing products 
will not be permitted from Check-in through discharge. 
4.4 
Subject Early Discontinuation or Withdrawal 
Subjects will be advised that they are free to withdraw from the study at any time. In 
addition, subject participation in this study may be discontinued for any of the following 
reasons: 
• AE 
• Lost to follow-up 
• Non-compliance with study procedures 
• Protocol violation 
• Study terminated by Sponsor, FDA, or other regulatory authorities 
• Withdrawal of consent 
• Investigator’s discretion, including a severe laboratory abnormality or other medical 
condition that indicates to the Investigator that continued participation is not in the 
best interest of the subject 

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Protocol deviations/violations should not lead to subject withdrawal unless they indicate a 
significant risk to the subject’s safety or jeopardize the scientific integrity of the study. 
If premature withdrawal from the study occurs for any reason, the Investigator must 
determine the primary reason and record this information in the electronic case report form 
(eCRF). Additionally, subjects withdrawing after study product administration will undergo 
all discharge safety procedures as feasible and as deemed necessary by the Investigator. 
A subject withdrawn from the study due to any AE or clinically significant abnormal 
laboratory test values will be evaluated by the Investigator or other qualified individual and 
will be treated and/or followed up until the symptoms or values return to normal or 
acceptable levels or until lost to follow-up, as appropriate in the opinion of the Investigator. 
Subjects withdrawing or removed from this study cannot re-enter. 
4.5 
Subject Randomization 
Subjects who complete the study screening assessments and meet all the eligibility criteria 
and are randomized will be assigned a unique randomization identification number on Day -1 
for Part 1 and on Day 10 for Part 2, and will receive study products according to the 
randomization scheme generated by 
 
In Part 1, the sequences to be used in the randomization of Part 1 will be ABDC, BCAD, 
CDBA, DACB, EFHG, FGEH, GHFE, and HEGF. 
In Part 2, subjects will be randomized to 1 of 3 study arms (i.e., I, J, or K). 
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (e.g., Subject No. 101 will replace Subject No. 1). 

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5. STUDY PRODUCTS/MATERIALS 
5.1 
Description of Study Products 
In Part 1, 20 subjects will be randomized to use Products A to D and 20 subjects will be 
randomized to use Products E to H.  
The following study products will be used in Part 1 of this study: 
Product 
Designation Study Product Name 
A 
myblu™ (freebase), Gold Leaf flavor, 2.4% 
B 
myblu™ (freebase), Polar Mint flavor, 2.4% 
C 
myblu™ (freebase), Cherry flavor, 2.4% 
D 
myblu™ (freebase), Vanilla flavor, 2.4% 
E 
myblu™ (freebase), Gold Leaf flavor, 1.2% 
F 
myblu™ (freebase), Polar Mint flavor, 1.2% 
G 
myblu™ (freebase), Menthol flavor, 2.4% 
H 
myblu™ Intense (nicotine salts), Fresh Mint flavor, 2.4% 
In Part 2, subjects will be randomized to one of the following arms: 
Arm 
Product Use Description 
I  (myblu™) 
Exclusive use of myblu™ products ad libitum 
J  (Combustible) 
Exclusive smoking of usual brand combustible cigarettes 
ad libitum 
K  (Dual Use) 
Smoking of usual brand combustible cigarettes (up to 50% of the 
subject’s self-reported CPD) and use of myblu™ products 
ad libitum 
5.1.1 Usual Brand Combustible Cigarette 
Subjects will be required to bring with them to the CRU a sufficient supply (i.e., 2-week 
supply [unopened packs]) of their usual brand combustible cigarettes for personal use 
throughout confinement. 

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5.1.2 myblu™ E-Cigarettes 
myblu™ is a two-piece closed system available in the US market. The myblu™ system is 
comprised of a rechargeable 350 mAh battery and a disposable pod. The pods connect 
directly and contain the mouthpiece, heating element, are pre-filled with e-liquid, and are 
compatible only with myblu™ batteries. During use, a consumer inhales through the 
mouthpiece and a sensor in the battery detects the change in air pressure which activates the 
heating element. The e-liquid heats to an aerosol which the consumer inhales.  
The battery is charged with a micro-USB charger and produces a typical output of 3.7 V 
(maximum 3.9 V). The pods contain 1.5 mL of e-liquid which lasts approximately 200 puffs, 
depending on individual use behaviors. Each e-liquid contains a mixture of glycerin, 
propylene glycol, nicotine freebase, and a proprietary blend of flavors.  
5.2 
Study Product Accountability and Dispensing 
All myblu™ e-cigarettes (devices and all e-liquids including the 0% nicotine e-liquid) will be 
provided by the Sponsor. The CRU staff will coordinate shipping of e-cigarettes from the 
Sponsor. The staff will document the date each shipment was received and recorded in the 
inventory records. The CRU staff will document and reconcile the total number of products 
shipped to the CRU, the total number of products dispensed during the study, and the total 
number of products remaining at the end of clinical conduct. Subjects will bring a 2-week 
supply (unopened packs) of their usual brand combustible cigarettes for personal use at 
designated times throughout confinement in the CRU. 
All products will be stored in a locked, limited-access area at the CRU and kept at controlled 
room temperature (defined as 20 - 25°C [68 - 77°F], with excursions permitted to 15 - 30°C 
[59 - 86°F]). Humidity is recorded but not controlled. 
Study products for dispensing (including usual brand combustible cigarettes) to subjects will 
be prepared by the study staff according to instructions provided by the Sponsor. Individual 
study product dispensing records will be maintained by the CRU staff for each subject. Care 
should be taken when repackaging the study products for use at the CRU to avoid exposure 
to air and moisture to the extent possible. The pharmacy will maintain records of the number 
of cigarettes dispensed for each subject. 
The study staff will document the start time and stop time of each product use session. A 
fresh pod and fully charged device will be used for each product use session and each 
product use day (as applicable). The number of cigarettes smoked will be documented on 
Days -2 and -1, and on Days 10 through 14 for subjects in Arms J and K. The flavor and 
strength of the myblu™ products will be documented as appropriate. Pod weights will be 
documented in grams to 4 decimal places. 
Subjects will smoke their usual brand combustible cigarettes and use each assigned product 
only in designated areas of the CRU. 
Opened and unopened packages of e-cigarettes and components will be returned to the 
Sponsor or destroyed at the direction of the Sponsor. Unopened packages of subject’s own 

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brand combustible cigarettes will be returned to the subjects; opened packages will be 
destroyed. All returns or destruction of study products will be documented. 
6. STUDY PROCEDURES 
6.1 
Screening 
Potential subjects will undergo Screening procedures to ensure that they meet the 
requirements for inclusion in the study within 28 days prior to study procedures on Day -2. 
Screening procedures will be performed as delineated in the Study Events Flow Chart 
(Table 1). 
Pre-screening procedures, if applicable, will be performed as delineated in the Study Events 
Flow Chart (Table 1). 
6.1.1 Informed Consent 
All prospective subjects will have the study explained by the Investigator or his/her designee 
and will be required to read, sign, and date an Institutional Review Board (IRB)-approved 
ICF prior to completion of screening or other study procedures. This consent form will 
provide the subjects in non-technical terms with the purpose of the study, procedures to be 
carried out, and potential hazards. The subjects will be assured that they may withdraw from 
the study at any time without jeopardizing medical care related to or required as a result of 
study participation. Subjects will be given a copy of their signed ICF. 
6.1.2 Medical History/Demographic Data/Record of Concomitant Medication 
Medical history and socio-demographic data, including name, sex, age (each subject must 
show proof of age with government-issued identification [e.g., driver’s license]), race, 
ethnicity, address, and phone number will be recorded at Screening for each subject. 
Additional data including social security number or tax identification number will be 
recorded at Check-in. 
Any concomitant medications taken from 30 days prior to Check-in through discharge will 
be recorded. 
6.1.3 Tobacco/Nicotine Product Use History 
Subjects will be required to report previous tobacco-product and nicotine-product use 
histories to satisfy the study inclusion and exclusion criteria.  
Details of the subject’s usual brand combustible cigarette, including the brand, brand style, 
flavor, cigarette length, and amount of daily use will be recorded at Screening and updated at 
Check-in as necessary. A color photocopy or photograph of the subject’s usual brand 
combustible cigarette package will be taken by the CRU staff at Check-in. 

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6.1.4 Exhaled Carbon Monoxide 
Exhaled CO levels will be measured using a Bedfont Micro+ Smokerlyzer or similar device, 
at Screening. 
6.2 
Check-in and Confinement 
Subjects will check in to the CRU on Day -2 at a time specified by the CRU. Check-in 
procedures will be performed as delineated in the Study Events Flow Chart (Table 1).  
After check-in, subjects will complete one set of questionnaires for the purpose of 
familiarization with subjective effects questions, appropriate use of the VAS, and use of the 
computerized tablet system. Data collected from the training session will not be used for any 
analysis.  
Subjects will also participate in a brief trial on Day -2 (approximately 30 minutes) using the 
myblu™ device with a 0% nicotine e-liquid, to familiarize with the use of the device. 
Instructions on the proper use of the myblu™ products will be provided prior to use. 
Subjects will have their personal belongings thoroughly checked during Check-in. All 
subjects will be required to shower and will receive clean articles of clothing prior to the start 
of the first study product use on Day 1.  
Subjects will be confined from Check-in on Day -2 through completion of scheduled study 
events on Day 15. 
A subject may be required to remain at the CRU for longer at the discretion of the 
Investigator or designee. 
6.2.1 Baseline Assessments (Days -2 and -1) 
Subjects will continue to smoke their usual brand combustible cigarette from Check-in 
through Day -1, but will abstain from use of any tobacco- or nicotine-containing products for 
at least 12 hours prior to the start of product use on Day 1.  
The number of usual brand combustible cigarettes smoked per day will be documented. 
Baseline assessments will be performed as delineated in the Study Events Flow Chart 
(Table 1). Urine samples will be collected for biomarkers over a 24-hour period from the 
start of the overnight abstinence on Day -2. On Day -1, blood samples for biomarkers will be 
collected, BP and HR measurements will be taken throughout the period of ad libitum 
smoking, and spirometry will be performed.  
Subjects will be randomized to 1 of 8 sequences on Day -1 and 2 subjects from each 
sequence will have puff topography measurements (Section 6.4.4) performed on Day -1. 

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6.3 
Product Use 
6.3.1 Days 1, 3, 5, and 7 
On Days 1, 3, 5, and 7, subjects will use the study product they are assigned to use the 
following day according to the randomization scheme. Subjects will use the assigned study 
product ad libitum until the start of the abstinence period (i.e., at least 12 hours prior to the 
start of the first product use session on the next day).  
Each subject will be provided with a fully charged battery and a fresh pod on each day. 
Additional pods will be provided as needed. The clinic staff will document the time each 
product is dispensed. Pods will be weighed within 24 hours before the start and after 
completion of product use on each day. Products that stop functioning should be replaced as 
soon as possible, with the failure documented and the pod weighed within 24 hours. 
6.3.2 Days 2, 4, 6, and 8 
On Days 2, 4, 6, and 8, subjects will participate in two product use sessions on each day.  
During the first product use session on each day, subjects will use the assigned e-cigarette 
under controlled conditions by taking 10 puffs at 30-second intervals, with puffs 3 seconds in 
duration. During the second product use session on each day, subjects will use the same 
assigned e-cigarette ad libitum with no limits on puff duration or inter-puff interval. 
The first product use session will start following an abstention from use of any tobacco- or 
nicotine-containing products for at least 12 hours. The second product use session will begin 
following collection of the last PK blood sample (180-minute time point) and completion of 
the subjective effects questionnaires, and will end at approximately 23:00.  
Subjects will be provided with a fully charged battery and a fresh pod for each product use 
session. The clinic staff will document the time the product is dispensed, the start and stop 
time of each product use session, the number of inhalations (first product use session only), 
the duration of each inhalation (first product use session only), and reasons for missed puffs 
during the first product use session. Pods will be weighed within 24 hours before and after 
each product use session. Products that stop functioning should be replaced as soon as 
possible, with the failure documented and the pod weighed within 24 hours. No product use 
of any kind will be allowed between the first and second product use sessions.  
6.3.3 Day 9 
Subjects may use all or any of the 4 study products (used previously on Days 1 through 8) 
ad libitum until approximately 23:00.  
Each subject will be provided with a fully charged battery and will be assigned a fresh pod of 
each of the 4 study products. The clinic staff will document the time each product is 
dispensed. Pods will be weighed within 24 hours before the start and after completion of 
product use on Day 9. Products that stop functioning should be replaced as soon as possible, 
with the failure documented and the pod weighed within 24 hours.  

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6.3.4 Days 10 to 14 
Subjects randomized to Arm I (myblu™) will exclusively use any or all of the 8 study 
products ad libitum until approximately 23:00 on each day.  
Subjects randomized to Arm J (Combustible) will exclusively smoke their usual brand 
combustible cigarette ad libitum until approximately 23:00 on each day. 
Subjects randomized to Arm K (Dual Use) will be allowed to smoke their usual brand 
combustible cigarette ad libitum (up to 50% of their self-reported CPD) and use any or all of 
the 8 study products ad libitum until approximately 23:00 on each day. 
Subjects assigned to Arms I and K will be provided with a fully charged battery and will be 
assigned a fresh pod of each e-liquid on each day. 
The clinic staff will document the time each study product/combustible cigarette is 
dispensed. As applicable, pods will be weighed within 24 hours before the start and after 
completion of product use on each day, with the weights documented in grams to 4 decimal 
places. Products that stop functioning should be replaced as soon as possible, with the failure 
documented and the pod weighed within 24 hours. The number of combustible cigarettes 
smoked on each day will be documented, as applicable.  
6.4 
Study Assessments 
All study assessments will take place at the times delineated in the Study Events Flow Chart 
(Table 1) unless otherwise noted below. 
When scheduled during the same product use session on the same day, the following study 
procedures will be performed in the order indicated below, with regard to the prescribed 
time: 
a. Puff topography 
b. Blood pressure and heart rate 
c. Subjective effects questionnaires 
d. Spirometry 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
6.4.1 Nicotine Pharmacokinetics 
On each of Days 2, 4, 6, and 8, a 4 mL blood sample for plasma nicotine analysis will be 
drawn into a plastic K2-EDTA (lavender top) vacutainer tube at the time points delineated in 
the Study Events Flow Chart (Table 1). Allowable deviation windows for PK sampling are:  
± 30 seconds for samples collected from 3 - 15 minutes, ± 1 minute for samples collected 
from 20 - 60 minutes, and ± 3 minutes for all other samples. 

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PK blood samples will be collected by direct venipuncture or through an intravenous catheter 
port as determined by the clinical staff.  
Additional blood (typically up to approximately 1 mL) may be drawn between the blood 
draws during the first 15 minutes for the purpose of keeping the needle patent, if required. 
The blood from the 1 mL draws will be discarded. In total, approximately 192 mL of blood 
will be drawn from each subject during the entire study for nicotine PK analysis. 
The blood samples collected for plasma nicotine analysis may be kept at room temperature 
prior to centrifugation, and will be centrifuged at approximately 1000 to 1300 RCF at ~5°C 
for approximately 10 minutes, within 60 minutes from collection. After centrifugation, the 
plasma will be transferred to two methanol prewashed 3.5 mL polypropylene screw cap 
tubes, properly labeled, and then stored at -20°C (± 10°C) or below (within 120 minutes from 
collection) until analysis. 
Samples will be analyzed using a validated liquid chromatography coupled to tandem mass 
spectrometry detection analytical method with the appropriate quality controls in accordance 
with FDA Good Laboratory Practice regulations (Title 21 Code of Federal Regulations 
[CFR] Part 58). 
6.4.2 Biomarkers Sample Collection 
6.4.2.1 Blood 
Blood samples for COHb in whole blood (2 x 4 mL), sICAM in plasma (1 x 4 mL), WBCs in 
whole blood (1 x 4 mL), HDL-C in serum (1 x 3.5 mL), and MCP-1 in serum (1 x 3.5 mL), 
will be collected at the time points delineated in the Study Events Flow Chart (Table 1). 
Samples for COHb will be collected in the afternoon and samples for the other biomarkers 
will be collected following an overnight fast of at least 8 hours.  
Up to approximately 69 mL of blood will be required for the planned biomarker assessments 
during the entire study. 
Detailed instructions for collection, processing, and shipping of blood samples will be 
provided separately. 
6.4.2.2 Urine 
Urine for biomarker measurements will be collected over a 24-hour period on the days 
indicated in the Study Events Flow Chart (Table 1). Each 24-hour urine collection will begin 
at the start of abstinence from tobacco- or nicotine-containing products and will end at the 
same time ± 30 minutes the following day. The start time of each urine collection should be 
within ± 1 hour of the start time on Day -2. 
Subjects will be instructed as to urine collection methods. Subjects will be instructed to 
attempt to void prior to the beginning and at the end of each interval. All urine must be 
collected during the entire 24-hour interval. The start and stop time of each 24-hour interval 
and the total weight of the collection will be documented. The weight of the 24-hour urine 

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collection containers will be documented prior to the collection (tare weight) and following 
completion of the collection. 
Urine will be refrigerated during the collection interval. Collections for each subject will be 
pooled periodically into one labeled container throughout the interval and the total weight (g) 
will be measured and recorded at the end of the 24-hour interval. Any missed voids will be 
documented, including the reason for missing. Aliquots will be prepared as noted in the 
following chart: 
Biomarker 
Number of Aliquots/ 
Volume Required 
Container 
Type 
Nicotine equivalents 
1-OHP  
8-epi-PGF2α  
11-DHTXB2   
Creatinine (for adjustment) 
2 aliquots of 5 mL each 
polypropylene  
NNAL / NNN   
MHBMA   
3-HPMA / CEMA / HMPMA   
S-PMA  
HEMA 
1-AN / 2-AN  
o-tol 
3-OH-B[a]P 
2 aliquots of 10 mL each UV shielded 
polypropylene 
All aliquots will be prepared within 120 minutes from the end of the collection interval and 
will be stored at -20 ± 10°C until shipped for analysis. 
Detailed instructions for collection, processing, and shipping of urine samples will be 
provided separately. 
6.4.2.3 Future Research 
No additional analysis is planned to be performed on the blood or urine samples for possible 
future research. Any additional research on these samples unspecified by this protocol will 
require approval from the subjects. 
6.4.3 Subjective Effects Questionnaires 
The Urge to Smoke (VAS), Product Liking (VAS), PES (7-point scale), Future Intent to Use 
(VAS), QSU-Brief, MTWS-R, and PSCDI/PSECDI questionnaires will be completed using a 
computerized tablet device. All relevant software and staff training specific to the electronic 
questionnaires will be provided by the vendor. Any electronic device used must meet all 
regulatory requirements, including FDA 21 CFR Part 11. 
All questionnaires will be completed at the time points delineated in the Study Events Flow 
Chart (Table 1). 

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When scheduled at the same time as a PK blood draw, the Urge to Smoke questionnaire will 
be completed approximately 30 seconds prior to the scheduled blood draw (except for the 
one scheduled at Time 0, which will be performed approximately 10 minutes prior to the start 
of the first product use session), and all other questionnaires will be completed within 
approximately 2 minutes after the scheduled blood draw, as applicable. 
6.4.4 Puff Topography 
Puff topography will be evaluated during ad libitum product use on the days indicated in the 
Study Events Flow Chart (Table 1). Subjects will engage in a 1-hour ad libitum product use 
with their usual brand combustible cigarette (Day -1) or the assigned study product (Days 1 
and 8), using the topography device (SPA-M). The topography session should start at least 
4 hours after the start of the ad libitum product use of that day. 
The puff topography session on Days 1 and 8 should be within ± 2 hours of the time of the 
Day -1 session. 
The topography device will be monitored to ensure the device is actively recording during 
each session. 
Additional details and instructions for puff topography procedures will be provided 
separately. 
Depending on the availability of topography equipment, puff topography may not be 
performed at all scheduled time points and may not be performed for some or all assigned 
subjects. 
6.4.5 Spirometry 
Subjects will undergo lung function testing at Screening to affirm eligibility (FEV1, 
FEV1:FVC ratio) and as a safety endpoint (FEV1, FVC, FEV1:FVC ratio, and forced 
expiratory flow [FEF]25-75%) on the days indicated in the Study Events Flow Chart 
(Table 1).  
Spirometry measurements will be conducted in accordance with the 2005 American Thoracic 
Society / European Respiratory Society Joint Task Force on the standardization of spirometry 
(Miller 2005). The spirometry predicted values will be standardized by the Third National 
Health and Nutrition Examination Survey predicted set. Personnel performing spirometry 
tests must receive appropriate training and the spirometer must be kept calibrated as 
recommended by the manufacturer. 
The spirometry tests should be performed in a sitting position following at least 15 minutes 
of rest and at least 1 hour from the last combustible cigarette smoked or last myblu™ product 
use. Spirometry must be performed after exhaled CO measurements when these events are to 
be performed on the same day. Multiple measurements may be attempted, but no more than 
8 test maneuvers should be performed during a test session. If a subject shows signs of 
fatigue during repeated testing, testing will be halted and further attempts will only be 
allowed at the Investigator’s discretion. 

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The subjects will be instructed on how to correctly perform spirometry tests by appropriately 
trained personnel prior to the measurements being recorded. Spirometry measurements will 
be performed before and after administration of a short-acting bronchodilator (albuterol). 
Following acceptable pre-bronchodilator measurements, subjects will be administered 4 puffs 
from an albuterol metered-dose inhaler at approximately 30 second intervals (~360 µg total 
dose assuming 90 µg per puff) using a spacer and a 5-second breath hold after each puff. 
Post-bronchodilator measurements will be made approximately 10 - 15 minutes following the 
last albuterol puff.  
The CRU will be responsible for procuring sufficient supplies to perform the spirometry 
measurements, including quantities of albuterol and any additional materials for its 
administration, and for keeping accurate documentation of accountability, 
dispensing/administration, and disposal of these items as appropriate. 
6.4.6 Safety Assessments 
Safety assessments in addition to those below may be obtained as necessary at the discretion 
of the Investigator. In the case of an early subject withdrawal, discharge safety assessments 
should be collected to the extent possible. 
6.4.6.1 Physical Examination 
A standard physical examination assessing the general physical well-being will be performed 
at Screening. A symptom-driven physical examination will be conducted at other times as 
deemed appropriate by the Investigator (Table 1). 
6.4.6.2 Body Weight, Height, and BMI 
Body weight and body height will be measured as delineated in the Study Events Flow Chart 
(Table 1). BMI will be recorded as kg/m2. 
6.4.6.3 Electrocardiogram 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart (Table 1). 
ECGs will be taken following resting in the supine position for at least 5 minutes. All ECG 
tracings will be reviewed by the Investigator or a qualified designee. 
6.4.6.4 Vital Signs 
Single measurements of vital signs (respiratory rate, HR, BP, and oral temperature) will be 
performed as outlined in the Study Events Flow Chart (Table 1). Additional vital signs may 
be taken at any other times, if deemed necessary. 
BP and HR measurements will be taken following a rest period of at least 5 minutes in a 
seated position. Vital signs are to be measured at least 15 minutes after the last tobacco- or 
nicotine-containing product used. When BP and HR measurements are scheduled at the same 
time or immediately after a puff topography session, subjects may not have abstained from 

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tobacco- or nicotine-containing product use for 15 minutes prior to the BP and HR 
measurements. 
On Days 2, 4, 6, 8, and 10 through 12, vital signs measurements will be taken within 2 hours 
prior to the start of the first product use session. 
6.4.6.5 Clinical Laboratory 
All clinical laboratory tests (with the exception of the urine cotinine test) will be conducted 
by a laboratory accredited by the Centers for Medicare and Medicaid Services (Clinical 
Laboratory Improvement Amendments of 1988 [CLIA-88]) or at the study site using 
CLIA-waived kits or procedures. Values for the clinical laboratory parameters are to be 
within the laboratory normal ranges or deemed not clinically significant in the opinion of the 
Investigator. All tests listed below will be performed as delineated in the Study Events Flow 
Chart (Table 1). Up to approximately 50 mL of blood will be drawn from each subject during 
the entire study for clinical laboratory tests. 
Serum Chemistry 1 
Urinalysis 2  
Additional Tests 
• 
Albumin 
• 
Alkaline phosphatase 
• 
Alanine aminotransferase 
• 
Aspartate 
aminotransferase 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Glucose 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid  
 
Hematology 
• 
Hematocrit 
• 
Hemoglobin 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count 
with differential 
 
• 
Bilirubin 
• 
Blood 
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Nitrite 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
• 
Serology 
o HIV 
o HBsAg 
o HCV 
• 
Serum/urine pregnancy 
test 3  
• 
Serum FSH 4  
• 
Urine cotinine  
• 
Urine drug screen 
o Amphetamines 
o Cannabinoids 
o Cocaine 
o Opiates 
• 
Urine/breath alcohol 
1 Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, subjects may not have fasted for 8 hours prior to the serum chemistry sample being 
taken. 
2  A microscopic examination for red blood cells, white blood cells, bacteria, and casts will be 
performed if an abnormality is noted in leukocyte esterase, protein, blood, or nitrite. 
3  Human chorionic gonadotropin (females only). 
4  For postmenopausal females only. 

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6.4.7 Adverse Events 
An AE is any untoward medical occurrence associated with the use of the study product, 
whether or not considered study product-related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a study product, whether or not related to the study 
product. 
6.4.7.1 Monitoring 
The subjects will be instructed to inform the Investigator or staff of any AEs and intercurrent 
illnesses experienced during the study. Additionally, a specific inquiry regarding AEs will be 
conducted prior to each product use and at discharge (or upon early withdrawal). The inquiry 
will be posed in a non-specific manner using open-ended questions so as not to bias the 
response (e.g., How are you feeling today?). 
A subject who has any clinically significant AE or clinically significant abnormal laboratory 
test value will be evaluated by the Investigator or other qualified individual and will be 
treated and/or followed up until the symptoms or values return to normal or acceptable levels 
(as appropriate in the opinion of the Investigator), or until the subject is lost to follow-up. 
Where appropriate, medical tests and examinations will be performed to document resolution 
of the event(s). 
6.4.7.2 Reporting 
All AEs occurring during this clinical trial after the subject has received the first study 
product must be recorded on the eCRF, including the date and time of onset, action taken, 
outcome (resolved, improved, unchanged, worse, fatal, or unknown/lost to follow-up), 
duration, relationship to product administration, and severity for each event. AEs will be 
listed. 
Events captured between Screening and the first study product use will be documented as 
baseline signs and symptoms. 
The Investigator will review each event and assess its relationship to product administration 
as unrelated, unlikely, possibly, probably, or likely. 
In addition, each sign or symptom reported will be graded on a 3-point severity scale using 
mild, moderate, or severe. 
6.4.7.3 Serious Adverse Events 
A serious adverse event (SAE) is any AE that in the view of either the Investigator (or 
designee) or Sponsor, results in any of the following outcomes: death, a life threatening AE, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be 
life threatening, or require hospitalization may be considered serious when, based upon 

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appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the above definition. 
Life threatening is defined as an AE that in the view of the Investigator (or designee) or 
Sponsor, its occurrence places the subject at immediate risk of death. It does not include an 
AE that, had it occurred in a more severe form, might have caused death. 
Unexpected is defined as an AE that is not consistent with the known risk information 
associated with the study product. 
All SAEs, whether or not considered study-related, must be reported by telephone and by fax 
or e-mail to the Sponsor within 24 hours of the CRU’s learning of the SAE or, at the latest, 
on the following workday. The Sponsor’s representative to contact about this study is 
provided in the list of study contacts and on the Sponsor signature page. The Investigator 
must also inform the IRB, in compliance with GCP reporting guidelines, and the site monitor 
of any SAE. 
6.4.7.4 Pregnancy 
A pregnancy occurring in a female study subject during the study will be documented in the 
clinical conduct study report to the IRB. Pregnancy itself is not an AE. The Investigator or 
designee will discontinue the pregnant subject from the study and will advise her to seek 
prenatal care and counseling from her primary care provider. Advice given will be 
documented in the subject’s source document. 
The CRU staff will request the pregnant subject to notify the CRU of the outcome of the 
pregnancy (e.g., birth, loss, termination). To help ensure this, the CRU staff will follow up 
with the subject until the end of pregnancy, if in compliance with the CRU’s standard 
operating procedures (SOPs) and with the subject’s consent. This request and the subject’s 
response will be documented in the subject’s source document. 
6.4.7.5 Smoking Cessation Information 
At Screening and prior to discharge from the study (or upon early termination), all subjects 
will be advised that to reduce the health effects of smoking, the best thing to do is to quit, and 
will be encouraged to contact a qualified medical professional for advice on smoking 
cessation. 
7. DATA ANALYSIS 
Data will be handled and processed according to 
 and/or the site’s SOPs, as 
appropriate, which are written based on the principles of GCP. A brief description of the 
statistical analysis is included below, detailed methodology for all summary and statistical 
analyses of the data collected in this trial will be documented in a statistical analysis plan 
(SAP) prepared by 
 and agreed upon by the Sponsor. The SAP may modify the plans 
outlined in the protocol; however, any major modifications of the primary endpoints and/or 
their analysis will also be reflected in a protocol amendment. If deemed appropriate, 

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additional statistical analyses other than those described in this section may be performed and 
included in the plan. 
7.1 
Sample Size Estimation 
The sample size chosen for this study was selected without statistical considerations. It has 
been determined adequate to meet the study objectives. 
7.2 
Analysis Populations 
7.2.1 Safety Population 
The Safety Population will include all subjects who have successfully completed eligibility 
requirements after checking in to the CRU and used at least one study product. 
7.2.2 Outcomes Population 
The Outcomes Population is a subset of the safety population and will consist of subjects 
who used a study product and have evaluable PK, biomarkers, subjective effects, BP, HR, 
spirometry, or topography data. This population will be used in the summary and analysis of 
PK, subjective effects, topography, biomarkers, spirometry, and product use, and all 
available data will be included in the summary tables to the extent possible. 
7.3 
Data Analysis, Summarization, and Statistical Methods 
SAS software (version 9.3 or higher) will be used for all data presentation and summarization 
including summary tables, graphs, and data listings. In general, all data will be listed by 
subject and time point and summarized by study product, time point, and sex using 
descriptive statistics appropriate for the endpoint. Figures will be used to display the data 
graphically. 
Missing data will not be imputed. Where individual data points are missing because of 
dropouts or other reasons, the data will be considered missing at random and summarized 
based on reduced denominators.  
7.3.1 Nicotine Pharmacokinetic Analysis 
Individual nicotine concentrations will be adjusted for baseline nicotine (“baseline-adjusted”) 
and all PK parameters will be calculated based on the adjusted concentrations. Baseline 
adjustment will be performed by subtraction of the pre-existing nicotine concentration from 
each nicotine concentration obtained after test product administration in that period/day for 
each subject using the following equation: 
Ct  = Ct unadjusted – [C0 · e-Kel· t1] 
where Ct is the adjusted concentration at time t, Ct unadjusted is the observed concentration at 
time t, C0 is the pre-product use concentration (-5 minutes), Kel = 
ln (2)
t½ , t½ is 2 hours 
(average nicotine half-life), t is the actual sampling time since product administration, and t1 

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is the actual sampling time since the time of the pre-product use sample. Any resulting 
negative concentration values following the baseline adjustment will be set to 0. 
Nicotine PK parameters will be determined from the adjusted individual subject plasma 
concentration-time profiles by applying a non-compartmental approach using appropriate 
validated PK software (e.g., Phoenix® WinNonlin® version 6.3 or higher).  
For each study product and each first product use session on Days 2, 4, 6, and 8, the 
following PK parameters will be calculated from the baseline-adjusted nicotine 
concentration-time data: 
AUC0-180 
Area under the nicotine concentration-time curve from time 0 (defined as the 
start of the first product use session) to the 180-minute time point as 
calculated by the linear trapezoidal method 
Cmax 
Maximum baseline-adjusted plasma concentration. 
Tmax 
Time to reach the maximum baseline-adjusted plasma concentration. If the 
maximum value occurs at more than one time point, Tmax is defined as the 
first time point with this value. 
Plasma concentrations below the limit of quantitation will be set to one-half of the lower 
limit of quantitation for the calculation of descriptive statistics of unadjusted plasma nicotine 
concentrations and for the calculation of baseline-adjusted nicotine concentrations. 
Nicotine concentrations and PK parameters will be listed by subject and summarized by 
study product, by sex and overall using descriptive statistics. 
7.3.1.1 Analysis of Variance 
A linear mixed model for analysis of variance will be performed on the log-transformed PK 
parameters Cmax and AUC following the first product use session on each of Days 2, 4, 6, 
and 8. The model will include sequence, study product, and period as fixed effects and 
subject-nested-within-sequence as a random effect. Sequence will be tested using 
subject-nested-within-sequence as the error term. Geometric least-squares means (LSM) and 
95% confidence intervals (CIs) will be provided for the PK parameters of Cmax and AUC by 
study product. Geometric LSM ratio, 95% CIs of geometric LSM ratio, and p-values will be 
provided for the study product comparisons in Cmax and AUC. The comparisons of interest 
will include each of the study products compared to each other. 
The above statistical analyses will be performed using the appropriate SAS procedure.  
Non-parametric analysis (Wilcoxon Signed Rank test) will be performed for the comparisons 
of Tmax.  
Details of the statistical methods will be provided in the SAP. 

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7.3.2 Biomarkers 
Biomarker concentrations reported as below the limit of quantitation (BLQ) will be reported 
as “BLQ” in the listings and set to one-half of the limit of quantitation for summarization and 
statistical analysis.  
The following variables will be determined and summarized for each urine biomarker. 
• Measured concentration  
• Total biomarker mass excreted per 24 hours 
• Creatinine-adjusted excretion level 
Absolute and percent change-from-baseline will be determined for the mass excreted and 
creatinine-adjusted values. The total urine biomarker mass excreted per 24 hours 
change-from-baseline value will be used as the primary variable in the statistical analysis.  
7.3.2.1 Urine Nicotine Equivalents 
Nicotine equivalents will be calculated as the molar sum of nicotine and 5 major nicotine 
metabolites. Values of individual components reported as BLQ will be set to one-half of the 
limit of quantitation prior use in the calculation below. Missing urine data will not be 
imputed. 
Nicotine equivalents (µg/mL) = 
(nicotine [ng/mL]/162.23 [mg/mmol] + nicotine-gluc 
(ng/mL)/338.36 [mg/mmol] + cotinine [ng/mL]/176.22 [mg/mmol] + cotinine-gluc 
[ng/mL]/352.34 [mg/mmol] + trans-3'-hydroxycotinine [ng/mL]/192.22 [mg/mmol] + trans-
3'-hydroxycotinine-gluc [ng/mL]/368.34 [mg/mmol]) x 162.23 (mg/mmol) x 1 µg/1000 ng 
7.3.2.2 Calculation of Total Mass Excreted 
Urine biomarker concentrations will be converted into biomarker quantities excreted in 
24 hours by multiplying the measured concentration by the total weight (i.e., 1 kilogram = 
1 liter) of urine produced by the subject during the 24-hour period. 
7.3.2.3 Creatinine Adjustments 
Urine creatinine will be measured and used to adjust the values of the primary and secondary 
urine BoE and BoPH as follows. 
      Biomarker            = 
Biomarker (units) x 100 
(unit/g creatinine) 
       
creatinine (mg/dL) 
7.3.2.4 Data Summary and Analysis 
Comparisons of the Day 9 primary BoE change-from-baseline values between study products 
and comparisons of the Day 14 primary BoE change-from-baseline values between study 
arms will be made using a linear mixed model analysis of variance (ANOVA).  

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An approach similar to that used for the primary endpoints will be used to make Day 9 and 
Day 14 change-from-baseline comparisons between study products and study arms for the 
applicable secondary BoE, BoPH, physiologic endpoints, and subjective measure endpoints 
as described in the SAP.  
Comparisons of the primary and secondary BoE change-from-baseline values at each time 
point between study products and study arms will also be made using a linear mixed model 
ANOVA. 
The comparisons of interest will include each of study products compared to each other 
(Part 1) and comparisons between study arms (Part 2). 
7.3.3 Subjective Effects 
7.3.3.1 Urge to Smoke Parameters 
The following parameters will be calculated for the urge to smoke assessments: 
Emax 
The maximum change from baseline VAS score 
(VASpre-use - VASpost-use). 
TEmax 
Time of the Emax. If the maximum value occurs at more than one time point, 
TEmax will be defined as the first time point with this value. 
AUEC0-120 
The area under the change from baseline VAS score versus time curve from 
time 0 to 120 minutes, calculated using the linear trapezoidal method with 
linear interpolation using actual sample times. 
Responses and derived parameters will be listed by subject and summarized by study 
product, by sex and overall using descriptive statistics. 
An appropriate statistical method, similar to the PK analysis detailed above, will be used to 
compare Urge to Smoke parameters (no data transformation). 
7.3.3.2 Product Liking 
Responses will be listed by subject and summarized by study product, by sex and overall 
using descriptive statistics. 
7.3.3.3 Product Evaluation 
Product Evaluation will be considered as a 7-point scale. Responses will be presented as the 
following factor scores:  
a) Satisfaction: average of the response scores from questions 1, 2, 3, and 12; 
b) Psychological reward: average of the response scores from questions 4 to 8; 
c) Aversion: average of the response scores from questions 9, 10, 16, and 18; 

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d) Relief: average of items 11, 13, 14, 15, and reversed for item 20 (i.e., not at all = 7, 
extremely = 1); 
e) Items 17, 19, 21 will be summarized as individual item scores. 
Descriptive statistics of the subscales will be provided by study product, by sex and overall. 
Individual responses will be listed by subject. 
7.3.3.4 Future Intent to Use  
Responses recorded as VAS scores will be treated as bipolar categorical variables (-50 to <0, 
0, >0 to 50) and summarized by study product, by sex and overall using frequency count 
tables. The bipolar score for the Future Intent to Use questionnaire is calculated by 
subtracting 50 from the original VAS score.  
The bipolar scores will also be treated as continuous variables and summarized by study 
product, by sex and overall using descriptive statistics. 
7.3.3.5 QSU-Brief 
QSU-Brief will be considered as a 7-point scale. Responses will be presented as the 
following factor scores:  
• Factor 1 (anticipation of pleasure from smoking) - average of items 1, 3, 6, 7, and 10 
• Factor 2 (relief of nicotine withdrawal) - average of items 2, 4, 5, 8, and 9 
Descriptive statistics of the subscales will be provided by study product, study arm (as 
applicable), study day, and by sex and overall. Individual responses will be listed by subject. 
7.3.3.6 MTWS-R 
Total scores will be listed by subject and summarized by study product, study arm (as 
applicable), study day, and by sex and overall using descriptive statistics. 
7.3.3.7 Penn State (Electronic) Cigarette Dependence Index (PSCDI/PSECDI) 
Total scores will be listed by subject and summarized by study product, study arm (as 
applicable), study day, and by sex and overall using descriptive statistics. 
7.3.4 Puff Topography 
The following topography parameters will be assessed: 
• Puff count 
• Puff duration 
• Puff volume 
• Peak puff flow rate 

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• Average puff flow rate 
• Inter-puff interval 
Topography parameters will be listed by subject and summarized by study product, study 
day, overall and by sex, usual brand cigarette flavor (non-menthol or menthol), age, number 
of years smoking, CPD, and time point using descriptive statistics. 
An appropriate statistical method, similar to the PK analysis detailed above, will be used to 
compare topography parameters. 
7.3.5 Physiological Endpoints 
7.3.5.1 Blood Pressure (BP) and Heart Rate (HR) 
The following parameters will be calculated from the BP and HR measurements: 
AUEC0-t 
The area under the change from baseline versus time curve from time 0 to the 
last measureable time point, calculated using the linear trapezoidal method 
with linear interpolation using actual sample times. 
Emax 
The maximum change from baseline. 
TEmax 
Time of the Emax. If the maximum value occurs at more than one time point, 
TEmax will be defined as the first time point with this value. 
An ANOVA will be performed on the natural log (ln)-transformed AUEC0-t and Emax, 
using the appropriate statistical procedure. Ninety (90)% CIs for the ratios will be obtained 
for the difference between the comparison of interest LSMs resulting from the analyses on 
the ln-transformed AUEC0-t and Emax. 
The potential relationship between BP and HR change from baseline and plasma nicotine 
concentrations may be assessed. 
Unadjusted and change from baseline BP and HR parameters will be listed by subject and 
summarized by study product, study arm (as applicable), study day, and by sex and overall 
using descriptive statistics.  
7.3.5.2 Spirometry 
The following pre- and post-bronchodilator lung function variables will be listed by subject 
and summarized by study day, study arm (as applicable), and by sex and overall using 
descriptive statistics:  
• Measured and percent of predicted FEV1 
• Measured and percent of predicted FVC 
• Measured and percent of predicted FEV1:FVC ratio 
• Measured and percent of predicted FEF25-75% 

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An appropriate statistical method, similar to the PK analysis detailed above, may be used to 
compare spirometry parameters. 
7.3.6 Product Use Behavior 
The number of puffs and duration of each puff (first product use session), and the difference 
in pod weights before and after each product use session (first and second product use 
sessions) will be listed by subject and summarized by study product, product use session, 
study arm (as applicable), study day, and by sex and overall using descriptive statistics. 
The amount of nicotine delivery for each study product may be estimated using an 
appropriate method to correct for nicotine strength. If estimated, the amount of nicotine 
delivery will be listed by subject and summarized using descriptive statistics. 
Correlation analyses may be performed to determine the potential relationship between puff 
topography parameters and pod weight change. 
7.3.7 Safety 
Safety data including single vital signs assessments, ECGs, and clinical laboratory results 
will be listed and summarized by subject and time point as appropriate. 
All AEs captured in the database will be listed in by-subject data listings. However, only 
study product use-emergent AEs will be summarized. A study product use-emergent AE is 
defined as an AE that is starting or worsening at the time of or after the first study product 
use. 
Frequencies of subjects with study product use-emergent AEs, regardless of relationship to 
study product will be summarized and sorted by system organ class. Frequencies of subjects 
with study product use-emergent serious AEs will be likewise summarized. Frequencies of 
study product use-emergent AEs will be summarized by severity and relationship to study 
product. 
Changes in physical examinations (if any) will be described in the text of the final report. 
All concomitant medications recorded will be listed by subject. 
Incidence of device malfunction(s) will be tabulated. 
8. STUDY ADMINISTRATION 
8.1 
Ethics 
8.1.1 Institutional Review Board 
This protocol will be reviewed by the IntegReview IRB, and the study will not start until the 
IRB has approved the protocol or a modification thereof. The IRB is constituted and operates 
in accordance with the principles and requirements described in the US Code of Federal 

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Regulations (21 CFR Part 56). The IRB is compliant to International Council for 
Harmonisation (ICH) guidelines, and may be reached at: 
IntegReview IRB 
3815 S. Capital of Texas Hwy, Suite 320 
Austin, Texas 78704, USA 
Tel.:  +1 512 817-1130 
Fax:  +1 512 697-0085 
Email:  clientservices@integreview.com 
8.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration 
of Helsinki, GCP, and the ICH harmonized tripartite guideline regarding 
GCP (E6 Consolidated Guidance, April 1996). 
8.1.3 Subject Information and Consent 
The purpose of the study, the procedures to be carried out, and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign, and 
date an ICF summarizing the discussion prior to Screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their signed ICF. 
8.2 
Confidentiality 
All clinical sites and vendors will have signed confidentiality agreements with 
 By 
signing this protocol, the Investigator and 
 staff will regard all information provided 
by the Sponsor and all information obtained during the course of the study as confidential. 
Neither the clinical site nor 
 will supply to the Sponsor any subject names, initials, 
date of birth (except year), or other personal identifiers (HIPAA 2015). All such information 
appearing on any study document must be redacted before a copy of the document is 
supplied to the Sponsor. The photocopied government-issued ID to verify subject age will be 
kept separate from other source documentation and not provided to the Sponsor. Study 
findings stored on a computer will be stored in accordance with local data protection laws. 
As required, in the case of an event where medical expenses are the responsibility of the 
Sponsor, personal information i.e., full name, social security details etc. may be released to 
the Sponsor. The subjects will be informed during the consenting process that representatives 
of the Sponsor, IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in the strictest confidence and in accordance with local data protection laws. 
8.3 
Termination of the Study 
The Investigator reserves the right to terminate the study in the interest of subject welfare. 

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The Sponsor reserves the right to suspend or terminate the study at any time. 
8.4 
Data Quality Assurance 
Data management activities will be detailed in the Data Management Plan (DMP). Each 
vendor involved with this study will adhere to Good Documentation Practices and their 
standard operating procedures covering their respective activities relevant to participation in 
this study. The Investigator will ensure that all data related to the conduct of this study at 
his/her site is attributable, legible, contemporaneous, original, accurate, enduring, and readily 
accessible. 
Standard operating procedures are available for all activities performed at 
 relevant 
to the quality of this study. Designated personnel of 
 will be responsible for 
implementing and maintaining quality assurance (QA) and quality control systems to ensure 
that the study is conducted, and that data are reported in compliance with the study protocol, 
GCP and Good Laboratory Practice requirements as well as applicable regulatory 
requirements and local laws, rules and regulations relating to the conduct of the clinical 
study.  
The Clinical Study Report will be audited by the QA department and the QA audit certificate 
will be included in the study report. 
8.5 
Direct Access to Source Data/Documents 
All clinical sites and vendors will ensure that the Sponsor, IRB and inspection by domestic 
and foreign regulatory authorities will have direct access to all study-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing 
(ICH[E6][R2] 5.1.2 & 6.10). In the event that other study-related monitoring should be done 
by other parties, they will be required to sign a confidentiality agreement prior to any 
monitoring and auditing.  
8.5.1 Monitoring the Study 
The responsible study monitor or Sponsor’s designee will contact and visit the Investigator as 
necessary, and he/she will be allowed, upon request, to inspect and verify all records of the 
study (e.g., source document, ICFs, eCRFs, regulatory documents) in a manner consistent 
with GCP and all other applicable state and federal law. 
It will be the study monitor’s responsibility to inspect the source documents to verify the 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered in the eCRF. The monitor will verify that each subject has consented in writing prior 
to any study procedures being performed. Where the terms of the Informed Consent, GCP, 
and all other applicable state and federal law permit, the monitor should have access to 
laboratory test reports and other subject records needed to verify the entries on the eCRF. 
The Investigator (or his/her designee) agrees to cooperate with the monitor to ensure that any 
issues detected in the course of these monitoring visits are resolved. 

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In addition, the Sponsor’s internal auditors (or designee) and government inspectors may 
evaluate the study and must be allowed access to eCRFs, source documents, and other study 
files. 
The Investigator must notify the Sponsor (or designee) promptly of any inspections of the 
study or activities related to the study scheduled by regulatory authorities, allow the Sponsor 
(or designee) to be present, and promptly forward copies of inspection reports to the Sponsor 
(or designee).  
8.6 
Reporting for the Study 
8.6.1 Case Report Forms 
eCRFs will be completed for each screened subject whether or not he/she has completed the 
study. The Investigator will assure complete and accurate entries on the forms. All eCRFs 
will be reviewed and signed by the Investigator. The final signed eCRFs are provided to the 
Sponsor in the format as decided upon between 
 and the Sponsor (e.g., compact disc, 
flash drive, secure file transfer protocol). This will be documented in the DMP (if 
applicable). 
8.6.2 Data Coding 
AEs will be coded using MedDRA®. Concomitant medications will be coded using the 
World Health Organization Drug Dictionary. Each dictionary version will remain the same 
throughout the trial. Coding will be completed by qualified members of the 
 staff. 
8.6.3 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the 
ICH M2 Expert Working Group), the final report will be written according to the 
ICH E3 Guideline (Structure and Content of Clinical Study Reports). 
8.6.4 Record Keeping 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by the clinical site and/or 
 (as appropriate) until at least 
5 years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region or at least 5 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period however if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. It is the 
responsibility of the Sponsor to inform the Investigator/Institution as to when these 
documents no longer need to be retained. 

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8.7 
Publication Policy 
All unpublished information given to 
 by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
information. 

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9. REFERENCES 
Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges 
(QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001;3(1):7-16. 
Cravo AS, Bush J, Sharma G, Savioz R, Martin C, Craige S, Walele T. A randomized, 
parallel group study to evaluate the safety profile of an electronic vapour product over 
12 weeks. Regul Toxicol Pharmacol. 2016;81(Suppl 1):S1-S14. 
Food and Drug Administration:  Center for Tobacco Products (CTP). Guidance for Industry:  
Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems 
(Jun 2019). Available at:  https://www.fda.gov/media/127853/download. 
Foulds J, Veldheer S, Yingst J, Hrabovsky S, Wilson SJ, Nichols TT, Eissenberg T. 
Development of a questionnaire for assessing dependence on electronic cigarettes among a 
large sample of ex-smoking e-cigarette users. Nicotine Tob Res. 2015;17(2):186-192. 
Goniewicz ML, Gawron M, Smith DM, Peng M, Jacob P 3rd, Benowitz NL. Exposure to 
nicotine and selected toxicants in cigarette smokers who switched to electronic cigarettes: a 
longitudinal within-subjects observational study. Nicotine Tob Res. 2017;19(2):160-167. 
Hatsukami DK, Zhang Y, O’Connor RJ, Severson HH. Subjective responses to oral tobacco 
products: scale validation. Nicotine Tob Res. 2013;15(7):1259-64. 
Hecht SS, Carmella SG, Kotandeniya D, Pillsbury ME, Chen M, Ransom BW, Vogel RI, 
Thompson E, Murphy SE, Hatsukami DK. Evaluation of toxicant and carcinogen metabolites 
in the urine of e-cigarette users versus cigarette smokers. Nicotine Tob Res. 
2015;17(6):704-709. 
McRobbie H, Phillips A, Goniewicz ML, Smith KM, 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). 
2015;8(9):873-878. 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, 
van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas 
D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of 
spirometry. Eur Respir J. 2005;26:319-338. 
O’Connell G, Graff DW, D'Ruiz CD. Reductions in biomarkers of exposure (BoE) to 
harmful or potentially harmful constituents (HPHCs) following partial or complete 
substitution of cigarettes with electronic cigarettes in adult smokers. Toxicol Mech Methods. 
2016;26(6):443-454. 
U.S. Department of Health and Human Services. National Institutes of Health. HIPAA 
Privacy Rule. Information for Researchers. Guidance Regarding Methods for 
De-identification of Protected Health Information in Accordance with the Health Insurance 
Portability and Accountability Act (HIPAA) Privacy Rule (06Nov2015). Available at:  
https://www.hhs.gov/hipaa/for-professionals/privacy/special-topics/de-
identification/index.html.  
 

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10. APPENDICES 
Appendix 1. Urge to Smoke Questionnaire 
Appendix 2. Product Liking Questionnaire 
Appendix 3. Product Evaluation Scale (PES) 
Appendix 4. Future Intent to Use Questionnaire 
Appendix 5. Questionnaire of Smoking Urges-Brief (QSU-Brief) 
Appendix 6. Minnesota Tobacco Withdrawal Scale-Revised (MTWS-R) 
Appendix 7. Penn State [Electronic] Cigarette Dependence Index (PSCDI/PSECDI) 
 
 

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Appendix 3: Product Evaluation Scale (PES)  
(Hatsukami 2013) 
Please mark the number that best represents how using the product made you feel. 
 
1. Was it satisfying? 
2. Did it taste good? 
3. Did you enjoy the sensations in your mouth? 
4. Did it calm you down? 
5. Did it make you feel more awake? 
6. Did it make you feel less irritable? 
7. Did it help you concentrate? 
8. Did it reduce your hunger for food? 
9. Did it make you dizzy? 
10. Did it make you nauseous? 
11. Did it immediately relieve your craving for a cigarette? 
12. Did you enjoy it? 
13. Did it relieve withdrawal symptoms? 
14. Did it relieve the urge to smoke? 
15. Was it enough nicotine? 
16. Was it too much nicotine? 
17. Was it easy to use? 
18. Were there bothersome side effects? 
19. Were you comfortable using the product in public? 
20. Did you still have a craving for a cigarette after using the product? 
21. Are you concerned that you would become dependent on this product? 
---------------------------------------------------------------- 
Scale: 1 = not at all, 2 = very little, 3 = a little, 4 = moderately, 5 = a lot, 6 = quite a lot, 
7 = extremely 
 
Four multi-item subscales will be derived from "Satisfaction" (items 1, 2, 3, and 12); 
"Psychological Reward" (items 4 through 8); "Aversion" (items 9, 10, 16, and 18); and 
"Relief" (items 11, 13, 14, 15, and reversed for item 20) and single items 17, 19, and 21 will 
be summarized. 
 

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Appendix 5: Questionnaire of Smoking Urges-Brief (QSU-Brief) 
(Cox 2001) 
 
 
 
Factor 1 (anticipation of pleasure from smoking): average of items 1, 3, 6, 7, and 10. 
Factor 2 (relief of nicotine withdrawal): average of items 2, 4, 5, 8, and 9. 
 
 

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Appendix 6: Minnesota Tobacco Withdrawal Scale-Revised (MTWS-R) 
 
Note:  The DSM-5 and craving items from the MTWS have been included here. Please see 
http://www.med.uvm.edu/behaviorandhealth/research/minnesota-tobacco-withdrawal-scale.  
 
Please rate yourself for the period of the last 24 hours. 
 
1. Angry, irritable, frustrated  
0   1   2   3   4 
2. Anxious, nervous  
0   1   2   3   4 
3. Depressed mood, sad  
0   1   2   3   4 
4. Difficulty concentrating  
0   1   2   3   4 
5. Increased appetite, hungry, weight gain  
0   1   2   3   4 
6. Insomnia, sleep problems, awakening at night  
0   1   2   3   4 
7. Restless  
0   1   2   3   4 
8. Desire or craving to smoke  
0   1   2   3   4 
---------------------------------------------------------------- 
Scale: 0 = none, 1 = slight, 2 = mild, 3 = moderate, 4 = severe 
 

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Appendix 7: Penn State [Electronic] Cigarette Dependence Index (PSCDI/PSECDI) 
(Foulds 2015) 
Note: For the PSECDI, substitute the underlined word with the words in square brackets. 
 
1. How many cigarettes [times] per day do you usually smoke [use your electronic 
cigarette]? ([assume that one “time” consists of approximately 15 puffs or lasts 
approximately 10 minutes]) 
(Scoring: 0–4 times/day = 0, 5–9 = 1, 10–14 = 2, 15–19 = 3, 20–29 = 4, 30+ = 5) 
2. On days that you can smoke [use your electronic cigarette] freely, how soon after you 
wake up do you smoke your first cigarette of the day [first use your electronic cigarette]? 
(Scoring: 0–5 mins = 5, 6–15 = 4, 16–30 = 3, 31–60 = 2, 61–120 = 1, 121+ = 0) 
3. Do you sometimes awaken at night to have a cigarette [use your electronic cigarette]? 
(Scoring: Yes = 1, No = 0) 
4. If yes, how many nights per week do you typically awaken to smoke [use your electronic 
cigarette]? 
(Scoring: 0–1 nights = 0, 2–3 nights = 1, 4+ nights = 2) 
5. Do you smoke [use an electronic cigarette] now because it is really hard to quit? 
(Scoring: Yes = 1, No = 0) 
6. Do you ever have strong cravings to smoke [use an electronic cigarette]? 
(Scoring: Yes = 1, No = 0) 
7. Over the past week, how strong have the urges to smoke [use an electronic cigarette] 
been? 
(Scoring: None/Slight = 0, Moderate/Strong= 1, Very Strong/Extremely Strong = 2) 
8. Is it hard to keep from smoking [using an electronic cigarette] in places where you are not 
supposed to? 
(Scoring: Yes = 1, No = 0) 
When you haven’t used tobacco [an electronic cigarette] for a while or when you tried to 
stop smoking [using]… 
9. Did you feel more irritable because you couldn’t smoke [use an electronic cigarette]? 
(Scoring: Yes = 1, No = 0) 
10. Did you feel nervous, restless, or anxious because you couldn’t smoke [use an electronic 
cigarette]? 
(Scoring: Yes = 1, No = 0) 
Total scoring: 0 - 3 = not dependent, 4 - 8 = low dependence, 9 - 12 = medium dependence, 
13+ = high dependence.