Nicotine Uptake and Abuse Liability Assessments of 5 Blu Disposable Electronic Cigarettes in Comparison to a Combustible Cigarette
Phase: NA
Conditions: Healthy Volunteers
Sponsor: Fontem US LLC

NICOTINE UPTAKE AND ABUSE LIABILITY ASSESSMENTS OF 
5 BLU DISPOSABLE ELECTRONIC CIGARETTES IN COMPARISON 
TO A COMBUSTIBLE CIGARETTE  
 
 
NCT05457634 
 
 
 
 
Study Protocol - FINAL (v0 Original): 13 Jul 2021  
 
 
 
 

Page 1 
 
 
 
 
 
NICOTINE UPTAKE AND ABUSE LIABILITY ASSESSMENTS OF 
5 BLU DISPOSABLE ELECTRONIC CIGARETTES IN COMPARISON 
TO A COMBUSTIBLE CIGARETTE 
 
 
 
Study No.: Fontem-PK-01 
 
 
 
Protocol Version 0 (Original): 13 July 2021 
 
 
 
 
 
 
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 Fontem US LLC.  Any 
viewing or disclosure of such information that is not authorized in writing by Fontem US 
LLC is strictly prohibited. Such information may be used solely for the purpose of reviewing 
or performing this study. 

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SPONSOR SIGNATURE PAGE 
 
Nicotine uptake and abuse liability assessments of 5 blu disposable 
electronic cigarettes in comparison to a combustible cigarette 
 
 
 
Sponsor 
Representative: 
 
Senior Clinical Research Manager 
Imperial Brands Science 
121 Winterstoke Road 
Bristol 
BS3 2LL 
UK 
 
On behalf of: 
Fontem US LLC 
714 Green Valley Road 
Greensboro, NC 27408 US 
 
 
 
 
 
 
 
 
 
__________ 
_________ 
Date 
 
 
 
 
 
 
 
 
 
 
26 July 2021

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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Nicotine uptake and abuse liability assessments of 5 blu disposable 
electronic cigarettes in comparison to a combustible cigarette 
 
 
 
 
 
 
 
 
 
 
Clinical Site and Principal Investigator: 
 
  
 
President, LA Clinical Trials, LLC 
847 N. Hollywood Way, Suite 103 
Burbank, CA 91505 US 
Tel: +1 818-526-7645  
Fax: +1 818-526-7641  
Email: 
 
 
  
 
  
 
  
 
 _
______________ 
_________ 
 S
Date 
 
 
 
 
 
 
23JUL2021

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STUDY CONTACTS 
 
Clinical Site 
LA Clinical Trials, LLC 
847 N. Hollywood Way, Suite 103 
Burbank, CA 91505, US 
Tel: +1 818-526-7645  
Fax: +1 818-526-7641  
Bioanalytical Laboratory 
Celerion 
621 Rose Street 
Lincoln, NE 68502 US 
 
 

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SYNOPSIS 
Title 
Nicotine uptake and abuse liability assessments of 5 blu disposable 
electronic cigarettes in comparison to a combustible cigarette 
Objectives 
Primary objectives: 
• To determine the pharmacokinetics (PK) of nicotine absorption 
into the blood of subjects when they use the blu disposable 
e-cigarette with varying flavors in each study arm compared to 
when they smoke a combustible cigarette.  
• To characterize subjective effects after use of the study products 
and a combustible cigarette.   
Secondary objectives: 
• 
To compare puff topography when subjects smoke a combustible 
cigarette versus use of the blu disposable e-cigarette.  
• 
To evaluate overall safety in subjects using the blu disposable e-
cigarette.  
Phase of study 
Phase I 
Endpoints 
Primary endpoints: 
• Baseline-adjusted plasma nicotine Cmax0-120, Cavg0-120, Tmax0-120, 
AUC0-120, Cmax120-180, Tmax120-180, AUC120-180, Cavg120-180, 
AUC0-180 
• Ratio of Cmax120-180/Cmax0-120 
• Ratio of Cavg120-180/Cavg0-120 
• Subjective effects measures: 
o Product liking assessment  
o Intent to Use Product Again assessment 
o Urge to Smoke Questionnaire 
o Product Evaluation Scale (PES) 
• Mass change of blu disposable e-cigarettes during puffing 
Secondary endpoints: 
• Puff topography (e.g., count, duration, volume, flow rate, and 
inter-puff interval) 
Safety Endpoints: 
• Heart rate and blood pressure during product use sessions 
• Adverse events (AE)/Serious adverse events (SAE) 
Study design 
This will be a part-randomized, open-label abuse liability assessment 
(ALA) and puffing topography study of nicotine-containing products 
carried out in 20 healthy adult volunteers who smoke combustible 
cigarettes. 
Subjects will attend the study site for a Screening Visit (Visit 1) within 
14 days of entry into the study.  At this visit, following informed consent, 
subjects will complete a nicotine use history questionnaire and also 
undergo a brief, observed trial use session with one of the blu disposable 
e-cigarettes they will use during the study.  A nasal swab will be used to 
collect a sample of mucus that will be used to test for a COVID-19 

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antigen.  Blood and urine samples for laboratory assessments will be 
collected, and an alcohol breath test will be conducted.  Medical history 
will be reviewed, exhaled carbon monoxide (eCO) will be measured, an 
ECG will be conducted, and vital signs will be assessed.  Those who 
satisfy the inclusion/exclusion criteria will be entered into the study. 
Subjects will attend the study site 6 times (Visits 2-7) during the main 
study for ALA and puff topography assessments.  Prior to each visit, 
subjects will be required to refrain from using any nicotine-containing 
products for a period of at least 12 hours before study product use.   
During their second visit (Visit 2), the subjects will smoke their usual 
brand cigarette during 2 use sessions.  In the first session, subjects will 
smoke a single combustible cigarette of their usual brand by taking 
10 puffs, 30 seconds apart.  Blood samples (5 mL) will be obtained for 
plasma nicotine analysis at -5, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, and 
120 minutes relative to the first puff on the cigarette.  Blood pressure and 
heart rate will be recorded at -10 (baseline), 8, 60, and 120 minutes.  
Subjects will be asked to complete several subjective effects 
questionnaires at various points either before, during, or after product 
use.  
In the second session, which will begin immediately after the 120 minute 
blood draw and after all questionnaires have been completed, subjects 
will be allowed to take ad libitum puffs on their usual brand cigarette for 
a period of 60 minutes (1 hour) while puffing topography measurements 
are made with a CReSS Pocket device.  Subjects may use as many 
cigarettes as they like.  Blood samples for nicotine PK analysis will be 
drawn at 135, 150, 165, and 180 minutes relative to the first puff on the 
cigarette at the visit (i.e., at 15, 30, 45, and 60 minutes of the ad lib 
session).  Blood pressure and heart rate will be recorded at 180 minutes.  
Subjective effects questionnaires will also be completed at specified time 
points.  
At the end of Visit 2, subjects will be randomized into a product use 
sequence for testing the investigational products (blu disposable 
e-cigarettes). Subjects will be provided with a supply of their assigned 
product to use at home for the day before their next visit 
(familiarization).   
Subjects will then visit the study site on 5 subsequent occasions 
(Visits 3-7); at each visit, the subjects will use their assigned 
blu disposable e-cigarette during 2 use sessions (standardized and ad lib, 
same as at Visit 2).  Study procedures during the 2 use sessions will be 
the same as at Visit 2, and subjects will be provided with a supply of 
their assigned product for familiarization before their next visit through 
Visit 6. 
Study site 
This study will be carried out as a single-center study in the United 
States.  

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Study products 
 
Product 
Flavor 
Nicotine Strength 
A 
 
2.4% 
B 
 
2.4% 
C 
 
2.4% 
D 
 
2.4% 
E 
 
2.4% 
F 
Subject’s Usual Brand Combustible Cigarette 
 
Use regimen 
• During individual visits, there will be 2 use sessions. 
• During the defined use session (first session), subjects will be 
asked to smoke a single cigarette or use the assigned blu 
disposable e-cigarette by taking 10 puffs over a period of 
4.5 minutes.  Total time for this session is 120 minutes.   
• The second use session is an hour-long ad libitum puffing session 
with no restrictions. 
Subjects 
• 20 male or female current cigarette smokers who may also be 
occasional users of e-cigarettes.  
• Aged between 21 and 65 years of age and deemed healthy during 
pre-study screening.  
Inclusion/ 
Exclusion 
Criteria 
The key inclusion criteria are: 
• Subjects must be current smokers (≥10 per day) of factory-made 
combustible cigarettes (eCO >10 ppm at screening) for at least 
6 continuous months before Visit 1 and may be occasional users 
of e-cigarettes.   
• Subjects have urine cotinine >200 ng/mL at Screening  
The key exclusion criteria are: 
• Subjects who, in the judgment of the study physician, have recent 
or active COVID 19 infection, based on results from COVID-19 
screening, body temperature ≥100.4°F, and/or laboratory test 
results suggestive of recent exposure to SARS-CoV-2. 
• Subjects who have an acute illness (e.g., upper respiratory tract 
infection, viral infection) requiring treatment in the 4 weeks prior 
to Visit 1. 
• Subjects with significant abnormalities in their clinical laboratory 
evaluations or electrocardiogram.  
• Subjects who have used any nicotine or tobacco product other 
than e-cigarettes or factory-made combustible cigarettes in the 
14 days prior to Visit 1.  
• Subjects who are self-reported or observed (during the trial 
session at Visit 1) non-inhalers during ENDS/cigarette use.   
• Subjects who have used any prescription or over-the-counter 
smoking cessation treatments, including, but not limited to any 
form of nicotine replacement therapy (NRT), varenicline, or 
bupropion within 30 days prior to Visit 1. 

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• Subject has a history or diagnosis of adult asthma, COPD 
(including emphysema and chronic bronchitis), or use of an 
inhaler within the past 3 months.   
• Subject has an active respiratory infection at time of the 
Screening Visit.  
Duration of 
Study 
Screening duration: approximately 14 days. 
Study duration: approximately 3 weeks.  
Blood Sampling 
Total blood draw volume is expected to be 510 mL for each subject 
during the study. 
Post-Study 
Tests 
A post-study follow-up will be performed with all subjects 5 to 7 days 
after their last study site visit, which will be conducted via a telephone 
call with the subjects. A full physical examination and safety assessments 
will be conducted only if indicated after review by the study physician.  
Safety Data 
On-study safety evaluations will include measurement of heart rate and 
blood pressure at the start, during, and at the end of each study site visit, 
temperature checks before each study site visit, and pregnancy tests in 
female subjects at the start of each product use visit.   
AEs reported by the subjects or observed by study personnel will be 
monitored from the time a subject uses the first investigational 
product/own brand cigarette (Visit 2) until the end of the study and will 
be reported by subjects at the follow-up.  Any concomitant medications 
taken in the 30 days prior to Visit 1 through follow-up will also be 
recorded. 
Bioanalysis 
Nicotine analysis will be performed at an appropriate analytical 
laboratory using validated methods.  
Statistics 
Since this study is the first to examine the nicotine PK in subjects using 
these blu disposable e-cigarettes, no formal power calculations will be 
performed.  A summary of statistical analysis plans follows. 
Analysis of Nicotine Pharmacokinetics: 
Pharmacokinetic parameters of plasma nicotine levels will be calculated 
using non-compartmental methods.  Plasma concentrations and the 
computed plasma PK parameters will be listed for each study product 
and subject.   
Plasma nicotine levels will be plotted as mean concentration in relation 
to time, with 95% confidence intervals of the mean for each product at 
each time point.   
The following PK parameters will be calculated; all parameters will be 
baseline adjusted using the value at time -5 minutes:  
• Cmax0-120 = Maximum plasma concentration during defined use 
session 
• Tmax0-120 = Time of maximum plasma concentration during 
defined use session 
• AUC0-120 = Area under the plasma concentration-time curve from 
time 0 to 120 minutes during defined use session 
• Cavg0-120 = Average concentration from 0 to 120 minutes defined 
as AUC0-120/120 minutes. 

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• Cmax120-180 = Maximum plasma concentration during the 
ad libitum puffing session 
• Tmax120-180 = Time of maximum plasma concentration during the 
ad libitum puffing session 
• AUC120-180 = Area under the plasma concentration-time curve 
from time 120 minutes to 180 minutes during the ad libitum 
puffing session 
• Cavg120-180 = Average concentration from 120 to 180 minutes 
defined as AUC120-180/60 minutes. 
• AUC0-180 = Area under the plasma concentration-time curve from 
time 0 minutes to 180 minutes during both puffing sessions 
• Ratio of Cmax120-180/Cmax0-120 = ratio of these two parameters 
• Ratio of Cavg120-180/Cavg0-120 = ratio of these two parameters 
A one-way or repeated measures analysis of variance will be conducted 
on Cmax0-120 and AUC0-120 to assess for statistical differences between 
the Usual Brand combustible cigarette and the blu disposable 
e-cigarettes.  Significance based on a Dunnett’s multiple comparison 
assessment will be reported.   
 
Analysis of Subjective Effects Measures: 
Where applicable, responses to the questionnaires recorded as Visual 
Analog Scale (VAS) scores or Likert scales will be treated as continuous 
variables and summarized descriptively by study product and time point 
for each questionnaire item using means, standard deviations (SD), 
medians, and ranges. 
The maximum response (Emax) and time to maximum response (Tmax) 
will be determined for the Urge to Smoke questionnaire. 
 
Analysis of Puff Topography Data: 
Summary statistics of the puff topography parameters will be presented 
including means, SD, medians, and ranges.  
 
Analysis of Safety Data: 
Safety data will be descriptively summarized by study product.  
Individual data will be provided in listings.  AEs and incidence of device 
events and malfunction/misuse will be tabulated, and summary statistics 
for vital signs may be computed and provided, as deemed appropriate. 
 

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STUDY EVENTS FLOW CHART 
 
Screening  
Product use phase  
(Visits 2 to 7) 
Follow-up 
phone call/visit 
 
Visit 1 
Informed consent 
X 
 
 
Socio-demographic data 
X 
 
 
Biochemistry, hematology, and urinalysis  
X 
 
 
Urine drugs of abuse screen 
X 
 
 
Urine cotinine level (must be >200 ng/mL) 
X 
 
 
Alcohol breath test 
X 
 
 
Inclusion/exclusion criteria 
X 
X 
 
Urine pregnancy test1 
X 
X 
 
Electrocardiogram2 
X 
 
 
Prior/concomitant medications 
X 
X 
X 
COVID-19 screening3 
X 
X 
 
SARS-CoV-2 (coronavirus) rapid (10 minute) antigen test 
X 
 
 
Nicotine use history4 
X 
 
 
Exhaled carbon monoxide level (must be >10 ppm) 
X 
 
 
Medical history  
X 
 
 
Vital signs, height, and weight5  
X 
 
 
Study product trial use session 
X 
 
 
Randomization 
 
X (Visit 2 only) 
 
Test product use 
 
X6 
 
At-home familiarization period7 
 
X 
 
Compliance check8 
 
X 
 
Blood draws for nicotine pharmacokinetics 
 
X9 
 
Heart rate and blood pressure measurements 
 
X10 
 
Product liking, urge to smoke, intent to use product again questionnaires, and Product 
Evaluation Scale (PES)  
 
X 
 
Puff topography assessments 
 
X 
 
Mass change measurements 
 
X 
 
Adverse events 
 
X 
X 
Post-study assessments 
 
 
 
Telephone call to subjects11 
 
 
X 
Safety assessments (vital signs, biochemistry, hematology, and urinalysis) and physical exam12 
 
 
X 
1Female subjects of child-bearing potential, at Visit 1 and before any product use.  
2Single 12-lead ECG will be taken following resting in the supine position for at least 5 minutes. 

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3Subjects will be queried for symptoms of COVID-19 at each encounter (both in person and telephone reminder calls for visits).  In addition, at each study site 
visit, body temperature will be assessed before allowing the subject to enter the clinic.  If the subject has a COVID-19 vaccination card, a copy of it will be 
obtained for the subject’s study record; however, being vaccinated is not a requirement to enter the study. 
4Fagerström Test for Nicotine Dependence and nicotine use history questionnaires.   
5Blood pressure and heart rate.   
6Subjects must abstain from any nicotine-containing products for at least 12 hours prior to product use visits.  
7The day prior to their study site visit to use that product; for blu disposable only. 
8Exhaled CO <15 ppm.  
9 -5, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 135, 150, 165, and 180 minutes. 
10Before any product use; during and after product use sessions. 
11Between 5 and 7 days after the last study site visit.  
12Symptom driven, if indicated and requested by the study physician following post-study telephone call. 
 

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ABBREVIATIONS 
AE 
Adverse event 
AUC 
Area under the nicotine concentration-time curve  
BMI 
Body mass index 
bpm 
Beats per minute 
C 
Degree Celsius 
CFR 
Code of Federal Regulations 
CLIA-88 
Clinical Laboratory Improvement Amendments of 1988 
Cmax 
Maximum measured plasma concentration 
CO 
Carbon monoxide 
CPD 
Cigarette(s) per day 
CRF 
Case report form 
CRU 
Clinical research unit 
CTP 
Center for Tobacco Products 
CYP 
Cytochrome P450 
e-cigarette 
Electronic cigarette 
e-liquid 
Electronic cigarette liquid 
ECG 
Electrocardiogram 
Emax 
Maximum reduction from baseline VAS score 
ENDS 
Electronic nicotine delivery systems 
F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
FTND 
Fagerström Test for Nicotine Dependence 
g 
Gram 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IRB 
Institutional Review Board 
K2-EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
m2 
Meters squared 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
Milligram 

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mL 
Milliliter 
mmHg 
Millimeters of mercury 
PES 
Product Evaluation Scale 
PK 
Pharmacokinetic(s) 
PMTA 
Premarket Tobacco Product Application 
ppm 
Parts per million 
QA 
Quality Assurance 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
SOP 
Standard operating procedure 
Tmax 
Time to reach the maximum measured plasma concentration 
US  
United States  
VAS 
Visual analog scale 

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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ..............................................................................................2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE .............................................................3 
STUDY CONTACTS ................................................................................................................4 
SYNOPSIS .................................................................................................................................5 
STUDY EVENTS FLOW CHART .........................................................................................10 
ABBREVIATIONS .................................................................................................................12 
TABLE OF CONTENTS .........................................................................................................14 
1. 
INTRODUCTION AND BACKGROUND ................................................................18 
1.1 
Background ......................................................................................................18 
1.2 
Study Purpose ..................................................................................................18 
2. 
STUDY OBJECTIVES AND ENDPOINTS ...............................................................18 
2.1 
Study Objectives ..............................................................................................18 
2.2 
Study Endpoints ...............................................................................................19 
3. 
SUMMARY OF STUDY DESIGN .............................................................................19 
3.1 
Design and Procedures .....................................................................................19 
3.2 
Follow-Up ........................................................................................................20 
3.3 
End of Study Definition ...................................................................................20 
4. 
STUDY POPULATION ..............................................................................................20 
4.1 
Inclusion Criteria .............................................................................................21 
4.1.1 
Screening Visit ..................................................................................21 
4.1.2 
Visits 2 to 7 .......................................................................................21 
4.2 
Exclusion Criteria ............................................................................................21 
4.2.1 
Screening Visit ..................................................................................21 
4.2.2 
Visits 2 to 7 .......................................................................................22 
4.3 
Study Restrictions ............................................................................................22 
4.3.1 
Food and Beverages ..........................................................................22 
4.3.2 
Nicotine .............................................................................................23 
4.3.3 
Medications .......................................................................................23 
4.3.4 
Tobacco Use/Considerations ............................................................23 
5. 
CRITERIA FOR PREMATURE DISCONTINUATION OF STUDY PRODUCT 
USE OR SUBJECT WITHDRAWAL FROM STUDY ..............................................23 
5.1 
Premature Discontinuation (Drop Out) from Study Product Use ....................23 
5.2 
Replacement of Subjects ..................................................................................24 
6. 
SUBJECT IDENTIFICATION AND BLINDING ......................................................24 
7. 
STUDY PRODUCTS/MATERIALS ..........................................................................24 

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7.1 
Description of Study Products .........................................................................24 
7.2 
Study Product Accountability ..........................................................................25 
7.3 
Study Product Use and Mass Change ..............................................................25 
8. 
VISIT DURATION AND WINDOWS .......................................................................26 
8.1 
Visit 1 (Screening) ...........................................................................................26 
8.2 
Visits 2 to 7 (Combustible Cigarette Smoking and ENDS Use) .....................26 
8.3 
Post-study Assessments ...................................................................................26 
9. 
STUDY PROCEDURES .............................................................................................26 
9.1 
Informed Consent.............................................................................................26 
9.2 
Demographic Data ...........................................................................................26 
9.3 
Clinical Laboratory Assessments .....................................................................26 
9.4 
SARS-CoV-2 (Coronavirus) ............................................................................27 
9.5 
Urine Screen for Drugs of Abuse and Alcohol Breath Test ............................27 
9.6 
Inclusion/Exclusion Criteria ............................................................................27 
9.7 
Urine Pregnancy Test .......................................................................................28 
9.8 
COVID-19 Screening.......................................................................................28 
9.9 
Electrocardiogram ............................................................................................28 
9.10 
Medical History and Record of Concomitant Medication ...............................28 
9.11 
Tobacco/Nicotine Product Use ........................................................................28 
9.11.1 
Nicotine Use History Questionnaire .................................................28 
9.11.2 
Fagerström Test for Nicotine Dependence Questionnaire ................28 
9.11.3 
Exhaled Carbon Monoxide ...............................................................28 
9.11.4 
Urinary Cotinine ...............................................................................29 
9.12 
Vital Signs, Height, and Weight ......................................................................29 
9.13 
Trial of Study Products ....................................................................................29 
9.14 
Product Use Sessions (Visits 2 to 7) ................................................................29 
9.14.1 
Defined Product Use Session ............................................................29 
9.14.2 
Ad libitum Product Use Session ........................................................29 
9.14.3 
Nicotine Pharmacokinetics ...............................................................30 
9.14.4 
Puff Topography ...............................................................................30 
9.14.5 
Mass Change .....................................................................................30 
9.14.6 
Subjective Effects Questionnaires ....................................................30 
9.14.6.1 
Urge to Smoke Questionnaire ......................................30 
9.14.6.2 
Product Evaluation Scale (PES)...................................31 
9.14.6.3 
Product Liking Questionnaire ......................................31 
9.14.6.4 
Intent to Use Product Again Questionnaire .................31 
9.15 
Safety Assessments ..........................................................................................31 

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9.15.1 
Adverse Events .................................................................................31 
9.15.1.1 
Adverse Event Monitoring ...........................................31 
9.15.1.2 
Reporting......................................................................31 
9.15.1.3 
Serious Adverse Events ...............................................32 
9.15.2 
Pregnancy ..........................................................................................32 
9.15.3 
Smoking Cessation Information .......................................................32 
9.16 
Blood Sample Collection .................................................................................33 
10. 
DATA ANALYSIS ......................................................................................................33 
10.1 
Sample Size Estimation ...................................................................................33 
10.2 
Analysis Populations ........................................................................................33 
10.2.1 
Safety Population ..............................................................................33 
10.2.2 
Outcomes Population ........................................................................33 
10.2.3 
Pharmacokinetic Subpopulation .......................................................33 
10.3 
Data Analysis, Summarization, and Statistical Methods .................................34 
10.3.1 
Nicotine Pharmacokinetic Analysis ..................................................34 
10.3.2 
Subjective Effects Measures .............................................................35 
10.3.3 
Puff Topography ...............................................................................35 
10.3.4 
Mass Loss..........................................................................................36 
10.3.5 
Safety ................................................................................................36 
11. 
STUDY ADMINISTRATION.....................................................................................36 
11.1 
Ethics................................................................................................................36 
11.1.1 
Institutional Review Board ...............................................................36 
11.1.2 
Ethical Conduct of the Study ............................................................36 
11.1.3 
Subject Information and Consent......................................................36 
11.2 
Termination of the Study .................................................................................37 
11.3 
Data Quality Assurance ...................................................................................37 
11.4 
Direct Access to Source Data/Documents .......................................................37 
11.4.1 
Monitoring the Study ........................................................................37 
11.5 
Reporting for the Study ....................................................................................38 
11.5.1 
Case Report Forms ............................................................................38 
11.5.2 
Report Format ...................................................................................38 
11.5.3 
Record Keeping ................................................................................38 
11.6 
Confidentiality .................................................................................................38 
11.7 
Publication Policy ............................................................................................39 
12. 
REFERENCES ............................................................................................................40 
13. 
APPENDICES .............................................................................................................42 

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13.1 
Appendix 1. COVID-19 Screening ..................................................................42 
13.2 
Appendix 2. Nicotine Use and Subjective Effects Questionnaires ..................44 
13.2.1 
Nicotine use history questionnaire ....................................................44 
13.2.2 
Fagerström Test for Nicotine Dependence .......................................46 
13.2.3 
Product liking questionnaire .............................................................47 
13.2.4 
Urge to smoke questionnaire ............................................................48 
13.2.5 
Intent to use product again questionnaire .........................................49 
13.2.6 
Product Evaluation Scale ..................................................................50 
 
 
 
List of Tables 
Table 1: Study Products ........................................................................................................... 24 
 
 

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1. INTRODUCTION AND BACKGROUND 
1.1 
Background 
Fontem US LLC is undertaking clinical studies to evaluate electronic nicotine delivery 
systems (ENDS) to provide an alternative to combustible cigarettes for smokers.  Upon user 
inhalation, an e-liquid solution containing nicotine, glycerol, propylene glycol, and flavor 
agents is heated and delivered into the lungs via an aerosol.  
The objective of ENDS products is to provide sufficiently satisfying alternatives to cigarette 
smoking.  According to the National Academies of Sciences, Engineering, and Medicine, 
“There is conclusive evidence that completely substituting e-cigarettes for combustible 
tobacco cigarettes reduces users’ exposure to numerous toxicants and carcinogens present in 
combustible tobacco cigarettes” [1].  
Over the past several years, a number of pharmacokinetic (PK)/pharmacodynamic studies of 
ENDS have been published.  Very early devices showed very little, if any, nicotine 
absorption, compared with the typical 15 ng/mL Cmax achieved almost immediately after 
smoking a combustible cigarette after 12 hours of abstinence [2, 3].  Through innovation, 
nicotine delivery has improved, with Cmax after acute use (typically 10 puffs or 5 minutes) 
following 12 hours of overnight abstinence from smoking or vaping ranging from 25% to 
near 100% of combustible cigarettes from some devices and e-liquid nicotine concentrations 
[4-10].  Puff topography parameters, including puff duration, puff volume, and flow rate have 
also been investigated [11-18]. 
1.2 
Study Purpose 
This study is being conducted to assess the abuse liability and puffing topography of 
blu disposable e-cigarettes in adult combustible cigarette smokers.  Nicotine uptake, 
subjective effects, and puff topography will be evaluated and compared with subjects’ usual 
brand combustible cigarette.  It is anticipated that the results from this study will provide 
evidence that the blu disposable e-cigarettes relative to subjects’ usual brand combustible 
cigarettes are appropriate for the protection of the public health, and will therefore support a 
Premarket Tobacco Product Application (PMTA) submission to the Center for Tobacco 
Products (CTP) at the Food and Drug Administration (FDA).  The FDA’s PMTA guidance 
for ENDS (FDA 2019) suggests that applicants include, in addition to other information, 
results from studies addressing topography and use patterns and an assessment of abuse 
liability. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
Primary objectives: 
• To determine the PK of nicotine absorption into the blood of subjects when they use 
the blu disposable e-cigarette with varying flavors in each study arm compared to 
when they smoke a combustible cigarette.  
• To characterize subjective effects after use of the study products and a combustible 
cigarette.   
 

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Secondary objectives: 
• 
To compare puff topography when subjects smoke a combustible cigarette versus use 
of the blu disposable e-cigarette.  
• 
To evaluate overall safety in subjects using the blu disposable e-cigarette. 
 
2.2 
Study Endpoints 
Primary endpoints: 
• Baseline-adjusted plasma nicotine Cmax0-120, Cavg0-120, Tmax0-120, AUC0-120, 
Cmax120-180, Tmax120-180, AUC120-180, Cavg120-180, AUC0-180 
• Ratio of Cmax120-180/Cmax0-120 
• Ratio of Cavg120-180/Cavg0-120 
• Subjective effects measures: 
o Product liking assessment  
o Intent to Use Product Again assessment 
o Urge to Smoke Questionnaire 
o Product Evaluation Scale (PES) 
• Mass change of blu disposable e-cigarettes during puffing 
 
Secondary endpoints: 
• Puff topography (e.g., count, duration, volume, flow rate, and inter-puff interval) 
 
Safety endpoints: 
• Heart rate and blood pressure during product use sessions 
• Adverse events (AE)/Serious adverse events (SAE) 
 
3. SUMMARY OF STUDY DESIGN 
3.1 
Design and Procedures 
This will be a part-randomized, open-label abuse liability assessment (ALA) and puffing 
topography study of nicotine-containing products carried out in 20 healthy adult volunteers 
who smoke combustible cigarettes. 
Subjects will be queried for symptoms of COVID-19 at each encounter (both in person and 
during telephone reminder calls for visits) (Section 13.1).  In addition, at each study site visit, 
body temperature will be assessed before allowing the subject to enter the clinic.   
Subjects will attend the study site for a Screening Visit (Visit 1) within 14 days of entry into 
the study.  At this visit, following informed consent, subjects will complete a nicotine use 
history questionnaire and also undergo a brief, observed trial use session with one of the 
blu disposable e-cigarettes they will use during the study.  A nasal swab will be used to 
collect a sample of mucus that will be used to test for a COVID-19 antigen.  Blood and urine 
samples for laboratory assessments will be collected, and an alcohol breath test will be 
conducted.  Medical history will be reviewed, exhaled carbon monoxide (eCO) will be 
measured, an ECG will be conducted, and vital signs will be assessed.  Those who satisfy the 
inclusion/exclusion criteria will be entered into the study. 

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Subjects will attend the study site 6 times (Visits 2-7) during the main study for ALA and 
puff topography assessments.  Prior to each visit, subjects will be required to refrain from 
using any nicotine-containing products for a period of at least 12 hours before study product 
use.   
During their second visit (Visit 2), the subjects will smoke their usual brand cigarette during 
2 use sessions.  In the first session, subjects will smoke a single combustible cigarette of their 
usual brand by taking 10 puffs, 30 seconds apart.  Blood samples (5 mL) will be obtained for 
plasma nicotine analysis at -5, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, and 120 minutes relative to 
the first puff on the cigarette.  Blood pressure and heart rate will be recorded 
at -10 (baseline), 8, 60, and 120 minutes.  Subjects will be asked to complete several 
subjective effects questionnaires at various points either before, during, or after product use.  
In the second session, which will begin immediately after the 120 minute blood draw and 
after all questionnaires have been completed, subjects will be allowed to take ad libitum puffs 
on their usual brand cigarette for a period of 60 minutes (1 hour) while puffing topography 
measurements are made with a CReSS Pocket device.  Subjects may use as many cigarettes 
as they like.  Blood samples for nicotine PK analysis will be drawn at 135, 150, 165, and 
180 minutes relative to the first puff on the cigarette at the visit (i.e., at 15, 30, 45, and 
60 minutes of the ad lib session).  Blood pressure and heart rate will be recorded at 
180 minutes.  Subjective effects questionnaires will also be completed at specified time 
points.  
At the end of Visit 2, subjects will be randomized into a product use sequence for testing the 
investigational products (blu disposable e-cigarettes); see Section 7.1 for information about 
study products.  Subjects will be provided with a supply of their assigned product to use at 
home for the day before their next visit (familiarization).   
Subjects will then visit the study site on 5 subsequent occasions (Visits 3-7); at each visit, the 
subjects will use their assigned blu disposable e-cigarette during 2 use sessions (standardized 
and ad lib, same as at Visit 2).  Study procedures during the 2 use sessions will be the same 
as at Visit 2, and subjects will be provided with a supply of their assigned product for 
familiarization before their next visit through Visit 6. 
3.2 
Follow-Up  
Between 5 and 7 days after the last study site visit (Visit 7), a post-study follow-up will be 
performed, which will be conducted via a telephone call with the subjects.  A full physical 
examination and safety assessments will be conducted only if indicated, after review by the 
study physician. 
3.3 
End of Study Definition 
The end of study is defined as the date of the follow-up call or the physical examination and 
safety assessments, if indicated.  
4. STUDY POPULATION 
Subjects selected for this study will be identified via standard recruitment methods. 

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4.1 
Inclusion Criteria 
4.1.1 Screening Visit 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Healthy males or females within the ages of 21 to 65 years, inclusive.  
2. Subjects will have a body mass index (BMI) of 18.5 to 35.0 kg/m2, inclusive, and a 
body weight exceeding 52 kg (males) or 45 kg (females).  
3. Subjects must be current smokers (≥10 per day) of factory-made combustible 
cigarettes (eCO >10 ppm at screening) for at least 6 continuous months before Visit 1, 
and may be occasional users of e-cigarettes.   
4. Urine cotinine >200 ng/mL.  
5. Subject demonstrates understanding of the study and willingness/consent to 
participate as evidenced by voluntary written informed consent and has received a 
signed and dated copy of the consent form. 
6. Subject understands and is willing, able, and likely to comply with all the study 
procedures and restrictions. 
7. Subject is in good general health in the opinion of the investigator, with no clinically 
significant and relevant abnormalities of medical history. 
8. Subject has a seated systolic blood pressure ≤160 mmHg, diastolic blood pressure 
≤95 mmHg, and heart rate ≤100 bpm.  
9. Females of childbearing potential are, in the opinion of the investigator, practicing a 
reliable method of contraception. 
 
4.1.2 Visits 2 to 7 
10. Abstinence from all forms of nicotine for 12 hours before the start of each product use 
visit, confirmed by an exhaled breath CO reading ≤15 ppm. 
 
4.2 
Exclusion Criteria 
4.2.1 Screening Visit 
Subjects will be excluded from the study if there is evidence of any of the following criteria 
at Screening or during the study, in the opinion of the investigator: 
1. Subjects who, in the judgment of the study physician, have recent or active 
COVID-19 infection, as evidenced by the following: 
a. Endorsement of symptoms that could indicate COVID-19 during screening 
(Section 13.1) and/or 
b. Body temperature ≥100.4°F and/or  
c. Laboratory test results suggestive of active or recent exposure to SARS-CoV-2 
(Section 9.4). 
2. Subjects who have participated in another clinical study within 30 days of Visit 1 or 
who have previously participated in this study. 
3. Subjects who have an acute illness (e.g., upper respiratory tract infection, viral 
infection) requiring treatment in the 4 weeks prior to Visit 1. 
4. Subjects with significant abnormalities in their clinical laboratory evaluations or 
ECG.  
5. Subjects who have used any nicotine or tobacco product other than e-cigarettes or 

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factory-made combustible cigarettes in the 14 days prior to the Visit 1.  
6. Subjects who are self-reported or observed (during the trial session at Visit 1) 
non-inhalers during ENDS/cigarette use.   
7. Subjects who have used any prescription or over-the-counter (OTC) smoking 
cessation treatments, including, but not limited to any form of nicotine replacement 
therapy (NRT), varenicline, or bupropion within 30 days prior to Visit 1. 
8. Is planning to quit smoking during the study or postponing a quit attempt in order to 
participate in the study. 
9. Subjects who have used prescription or OTC bronchodilator medication (e.g., inhaled 
or oral β-adrenergic agonists) to treat a chronic condition within the 12 months prior 
to Visit 1 or have a history of lung disease. 
10. Subjects who have received any medications or substances that interfere with the 
cyclooxygenase pathway within 14 days prior to Visit 1 or are known to be strong 
inducers or inhibitors of cytochrome P450 (CYP) enzymes within 14 days or 
5 half-lives of the drug (whichever is longer) prior to Visit 1. 
11. Women who are pregnant or who have a positive urine pregnancy test. 
12. Women who are breast-feeding an infant. 
13. Subject has a history or diagnosis of adult asthma, COPD (including emphysema and 
chronic bronchitis), or use of an inhaler within the past 3 months.   
14. Subject has an active respiratory infection at time of Screening.  
15. Subject has been hospitalized in the 28 days prior to Visit 1.  
16. Subject has a history of schizophrenia, psychosis, or bipolar disorder.  
17. Subject provides a positive drugs of abuse urine test at Visit 1. Tested drugs will 
include cocaine, amphetamines, methamphetamines, opiates (morphine, heroin), 
barbiturates, and benzodiazepine.   
18. Subject has a self-reported use of more than 21 drinks per week.  A drink is defined as 
1.5 oz of spirits (e.g., whiskey, vodka), 12 oz of beer, or 5 oz of wine. 
19. Subjects who have lost or donated more than 450 mL of blood within the 2 months 
preceding the first product use.  
20. Subject is an employee of the sponsor or the study site, or members of their 
immediate family. 
21. In the opinion of the investigator, the subject should not participate in this study. 
 
4.2.2 Visits 2 to 7 
22. Subject continues to meet all Screening exclusion criteria.  Pregnancy test to be 
performed on all female subjects at each visit before product use.  
23. Any emergent medical condition (including, but not limited to COVID-19) or 
concomitant medication that may have an impact on the safety and objectives of the 
study (at the investigator’s discretion).  
 
4.3 
Study Restrictions 
4.3.1 Food and Beverages 
Before Visits 2 to 7, food and beverage restrictions include: 
• No alcohol should be consumed for 24 hours before the appointment time. 
• No caffeinated beverages for 1 hour before the appointment time or during each 

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product use session.  Water will be permitted during the hour before the appointment 
but not during each product use episode.  An exception to the water restriction can be 
made if a subject starts coughing uncontrollably while smoking/vaping the study 
products. 
• No food for 1 hour before the appointment time or during each product use session.   
4.3.2 Nicotine 
Subjects must abstain from the use of any nicotine-containing products (e.g., cigarettes, 
e-cigarettes, oral tobacco products) for a period of 12 hours prior to Visits 2 to 7.  
4.3.3 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 Screening through the end 
of study will be recorded.  Except for those medications noted in the exclusion criteria, 
prescription or OTC 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 OTC products such as analgesics (e.g., ibuprofen, acetaminophen), 
antihistamines, nasal decongestants, and dietary supplements are permitted.  
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. 
4.3.4 Tobacco Use/Considerations 
For a period of 1 day before Visits 3 to 7, subjects will undergo an at-home familiarization 
period with their assigned product (blu disposable e-cigarette) they are to use at the next 
study visit.  During each familiarization period, subjects will be allowed to smoke their usual 
brand of cigarettes but will be instructed to predominantly use the blu disposable e-cigarette 
as their primary source of nicotine.   
Subjects must abstain from use of any tobacco- or nicotine-containing products for a period 
of at least 12 hours prior to each product use visit. 
5. CRITERIA FOR PREMATURE DISCONTINUATION OF STUDY PRODUCT 
USE OR SUBJECT WITHDRAWAL FROM STUDY  
Subjects should be encouraged to complete all study assessments.  However, subjects may 
refuse additional study product use or withdraw consent to participate in this study at any 
time without penalty or loss of benefits to which they are otherwise entitled.  
5.1 
Premature Discontinuation (Drop Out) from Study Product Use  
All subjects who were randomized, used at least one of the study products, and are 
prematurely discontinued from the study should have End of Study assessments performed on 
the day of discontinuation. 

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Reasons for premature discontinuation from study product use will be recorded on the 
appropriate page(s) of the case report form (CRF) and may include, but are not limited to: 
• Withdrawal of consent 
• Significant subject noncompliance, defined as refusal or inability to adhere to the 
protocol requirements (e.g., subject restrictions and Schedule of Assessments and 
Procedures) 
• The occurrence of an AE or serious adverse event (SAE) that, in the opinion of the 
investigator, warrants the subject’s permanent discontinuation from study product use 
• The investigator determines that it is in the best interest of the subject to withdraw 
from study participation due to a reason other than an AE or SAE.  
In the event of study product discontinuation due to an AE, study site personnel should notify 
the medical monitor as soon as possible.  
5.2 
Replacement of Subjects 
The study aims to have 20 subjects complete all 6 study visits (Visits 2-7).  Twenty of the 
subjects who have qualified at Screening will be scheduled to attend Visit 2.  An additional 
2 qualified subjects will be designated as alternates.  They will also attend Visit 2 but will 
only be randomized if any of the original 20 subjects do not complete Visit 2.  After Visit 2, 
subjects who drop out or are withdrawn may be replaced at the discretion of sponsor.     
6. SUBJECT IDENTIFICATION AND BLINDING 
It is not possible to blind the study products.  
Each subject who signs the informed consent at Screening will be assigned a Screening 
Number beginning with 1001.  
Eligible subjects at Visit 2 will be assigned a randomization number beginning with 2001.  
The randomization will determine the order in which the subjects will test the study products 
at Visits 3 to 7.  The randomization code for the study products will be produced using a 
computer-generated Latin-square procedure. 
7. STUDY PRODUCTS/MATERIALS 
7.1 
Description of Study Products 
All blu disposable e-cigarettes (Table 1) will be provided by the sponsor.   
Table 1: Study Products 
Product 
Flavor 
Nicotine Strength  
A 
 
2.4% 
B 
 
2.4% 
C 
 
2.4% 
D 
 
2.4% 
E 
 
2.4% 
F 
Subject’s Usual Brand Combustible Cigarette 

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blu disposable e-cigarettes are intended for one-time use only and cannot be disassembled.  
Disposables contain an internal tank pre-filled with-e-liquid and include an internal battery 
that is not rechargeable.  Upon taking a draw on the disposable, a sensor activates the battery 
to generate heat.  Once heated, e-liquid is converted to vapor.  Instructions provided to 
subjects will include:  1. Remove the rubber cap from the mouthpiece at the end of the 
disposable.  2. As you inhale, the blue LED tip on the end of the disposable will illuminate. 
At Visit 2, subjects will smoke their own brand of combustible cigarette.  
7.2 
Study Product Accountability 
Records will be maintained showing the receipt and disposition of the study supplies.  The 
sponsor will be permitted, at intervals, and upon request during the study, to check the 
supplies storage and dispensing procedures and records.  
Subjects will be instructed to attend the clinic at Visit 2 with a sufficient supply of their usual 
brand of combustible cigarette to smoke during the 2 use sessions.  
All study products will be stored in a locked, limited-access area at the study site.  The site 
staff will document and reconcile the total number of products shipped to the site, the total 
number of products dispensed during the study, and the total number of products remaining at 
the end of clinical conduct. 
Following completion of the clinical phase of the study and sponsor review of accountability, 
all used and unused supplies (other than those required for retention purposes) will either be 
returned to the sponsor together with accountability records or will be destroyed and 
Certificates of Destruction provided to the sponsor.  
7.3 
Study Product Use and Mass Change 
During the PK testing at Visits 3 to 7, an unused blu disposable e-cigarette will be used for 
each subject.  A backup blu disposable e-cigarette will be available in the unlikely event that 
there is a malfunction.  Before both the standardized and ad lib puffing sessions, the staff will 
weigh the product and record the weight in the source document.  Immediately after each 
puffing session, the staff will again weigh the product and record the weight in the source 
document.   
The number of cigarettes smoked and e-cigarettes used in each respective ad lib session will 
also be recorded.   
Study products for dispensing 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 site staff for each subject.  
The study staff will document the start time and stop time of each product use episode.  
Subjects will smoke their usual brand combustible cigarette and use the study products only 
in designated areas of the clinical site. 

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8. VISIT DURATION AND WINDOWS 
8.1 
Visit 1 (Screening) 
Following a telephone screening interview conducted by the study staff, qualified subjects 
will be scheduled for Visit 1.  Visit 1 will last approximately 1.5 hours. 
8.2 
Visits 2 to 7 (Combustible Cigarette Smoking and ENDS Use) 
Visit 2 will occur between 2 and 14 days after Visit 1. 
Visits 2 to 7 will be scheduled before 1 pm, and each of these visits will last approximately 
3.5 hours.  Visits 2 to 7 will occur at least 2 days following the previous visit.  
8.3 
Post-study Assessments 
Between 5 and 7 days after the last study site visit (Visit 7), a post-study follow-up will be 
performed, which will be conducted via a telephone call with the subjects.  A full physical 
examination and safety assessments will be conducted only if indicated after review by the 
study physician.  
9. STUDY PROCEDURES 
Study procedures will be performed as delineated in the Study Events Flow Chart.  
9.1 
Informed Consent 
The investigator or designee will obtain written informed consent from each subject 
participating in the study after thoroughly explaining the aims, objectives, procedures, 
payment schedule, and potential hazards of the study.  Subjects will be made aware that they 
are free not to participate in the study and that they can withdraw at any time.  Subjects will 
receive a copy of the informed consent that they and the site staff and investigator signed.  
Subjects will be re-consented with an updated consent form if any new information becomes 
available that could affect the participant’s willingness to continue.  
9.2 
Demographic Data 
The site staff will record each subject’s date of birth, sex, and race/ethnicity.   
9.3 
Clinical Laboratory Assessments  
Two 10 mL and two 5 mL blood samples and a urine sample will be collected for 
biochemistry, hematology, and urinalysis testing.  All clinical laboratory tests will be 
conducted by a laboratory accredited by the Centers for Medicare and Medicaid Services 
(Clinical Laboratory Improvement Amendments of 1988 [CLIA-88]).  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: 
Clinical Chemistry 1 
Urinalysis 2  
• 
Albumin 
• 
Alkaline phosphatase 
• 
Alanine aminotransferase 
• 
Aspartate aminotransferase 
• 
Blood urea nitrogen 
• 
Bilirubin 
• 
Blood, occult 
• 
Glucose 
• 
Ketones 
• 
Nitrite 

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• 
Carbon dioxide (bicarbonate) 
• 
Creatinine 
• 
Estimated glomerular filtration rate 
• 
Glucose 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid  
 
Hematology 
• 
Eosinophils 
• 
Basophils 
• 
Hematocrit 
• 
Hemoglobin 
• 
Lymphocytes 
• 
Monocytes 
• 
Neutrophils 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count with differential 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
• 
WBC esterase 
1Clinical 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 clinical chemistry sample being taken. 
2A 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. 
 
9.4 
SARS-CoV-2 (Coronavirus)  
If the subject has a COVID-19 vaccination card, a copy of it will be obtained for the subject’s 
study record; however, being vaccinated is not a requirement to enter the study. 
At Visit 1, a nasal swab will be used to collect a sample of mucus that will be used to test for 
a COVID-19 antigen (CareStartTM, Access Bio, Inc).  It is a rapid test (results in 10 minutes).  
Subjects will not be allowed in the clinic for their visit unless the result is negative.  If the test 
is positive, subjects will be excluded from the study.    
The rapid test may be administered during the study if the subject reports or shows symptoms 
suggestive of COVID-19. 
9.5 
Urine Screen for Drugs of Abuse and Alcohol Breath Test 
The site staff will administer a commercially available urine dipstick screen for the following 
drugs of abuse: cocaine, amphetamines, methamphetamines, cannabis, opiates (morphine, 
heroin), phencyclidine, barbiturates, and benzodiazepines.  Subjects with a positive test will 
be excluded from the study.   
In addition, an alcohol breath test will be conducted.  Subjects with a reading >0.01% will be 
excluded from the study. 
9.6 
Inclusion/Exclusion Criteria 
The site staff will assess each potential subject’s eligibility to participate in the study based 
on the inclusion/exclusion criteria (Sections 4.1 and 4.2).   

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9.7 
Urine Pregnancy Test 
The site staff will administer a commercially available urine dipstick pregnancy test to all 
females. 
9.8 
COVID-19 Screening 
In addition to the lab test for COVID-19 (Section 9.4), subjects will be queried for symptoms 
of COVID-19 at each encounter (both in person and during telephone reminder calls for 
visits) during the study (Section 13.1).  In addition, at each study site visit, body temperature 
(SmartGlow EXERGEN Temporal Scanner) will be assessed before allowing the subject to 
enter the clinic.  Subjects with results ≥100.4°F will not be allowed to enter the clinic.  
The study physician will take into account the answers on the COVID-19 screen, temperature 
results, and laboratory test (Section 9.4) to determine if subjects should be excluded from the 
study (results at Screening), rescheduled, or discontinued.   
9.9 
Electrocardiogram 
A single 12-lead ECG will be taken following resting in the supine position for at least 
5 minutes.  ECGs will be interpreted, signed, and dated by appropriate site personnel.  
9.10 Medical History and Record of Concomitant Medication 
The site staff will obtain and record a medical history from each subject.  Any relevant 
medical history within the previous year, including surgeries, allergies, and drug sensitivities 
will be included.  Any concomitant medications taken within the previous 30 days will also 
be recorded.  Any changes to concomitant medications will be documented throughout the 
study.   
A physical examination may be conducted during Screening if deemed necessary by the 
study physician to assess the subject’s eligibility for the study.  A symptom-driven physical 
examination may be conducted at other times as deemed appropriate by the investigator or 
designee.  
9.11 Tobacco/Nicotine Product Use 
9.11.1 Nicotine Use History Questionnaire 
Subjects will be required to report previous tobacco and nicotine product use histories to 
satisfy the study inclusion and exclusion criteria.  The study staff will administer a 
questionnaire that collects data on previous and current use of combustible and 
non-combustible tobacco products, ENDS products, and NRTs (Section 13.2.1). 
9.11.2 Fagerström Test for Nicotine Dependence Questionnaire 
The FTND is a self-administered questionnaire widely used to measure nicotine dependence 
among cigarette smokers [19].  Subjects respond to a series of 6 questions, and responses will 
be summed to produce a total score (Section 13.2.2).  
9.11.3 Exhaled Carbon Monoxide 
The site staff will obtain an eCO level from each subject using a Bedfont Micro + carbon 
monoxide monitor.  The manufacturer’s instructions for obtaining the samples will be 

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followed, with subjects taking a deep breath and holding it for 15 seconds before exhaling 
into the mouthpiece of the device.   
9.11.4 Urinary Cotinine 
Urinary cotinine will be analyzed and must be >200 ng/mL for the subject to be eligible for 
the study.   
9.12 Vital Signs, Height, and Weight 
The subject’s height and weight will be recorded.  The BMI will be calculated using a 
standard formula of weight (kg)/[height (m)]2.   
Site personnel will measure blood pressure and heart rate (Omron Model Number: 
HEM-907XL) after the subject has spent at least 5 minutes in the seated position.  At product 
use visits, blood pressure and heart rate will be recorded at -10 (baseline), 8, 60, 120, and 
180 minutes.   
9.13 Trial of Study Products 
At Screening, potential subjects will participate in a brief, observed trial use of a 
blu disposable e-cigarette to demonstrate that they can successfully comply with the 
instructions for use of study products using the following protocol:  
• 
Study staff will instruct the subject on the proper use of the ENDS device. 
• Subject will take up to 5 ad lib puffs from Study Product C (Table 1) to become 
familiar with the product and demonstrate that they can inhale the aerosol without 
excessive coughing or discomfort. 
• Based on the testing, subject expresses confidence in his/her ability to use each of the 
study products during the at-home familiarization period as well as the puffing 
sessions during Visits 3 to 7. 
9.14 Product Use Sessions (Visits 2 to 7) 
9.14.1 Defined Product Use Session  
During Visits 2 to 7, subjects will undergo a product use session in which they take 10 puffs 
from their usual brand of combustible cigarette (Visit 2 only) or 10 puffs from their randomly 
allocated blu disposable e-cigarette.  The beginning of each puff will be separated by a period 
of 30 seconds.  For each puff, subjects will be instructed to achieve a puff duration of at least 
1 second.  Blood samples will be taken for nicotine PK analysis (Section 9.14.3).  
9.14.2 Ad libitum Product Use Session 
During Visits 2 to 7, subjects will undergo an additional product use session during which 
they use the cigarette (Visit 2 only) or blu disposable e-cigarettes ad libitum, i.e., by taking as 
many and as frequent puffs as they desire.  Subjects may use as many cigarettes and 
e-cigarettes as they would like.  During this session, puffing topography measurements will 
be made using the CReSS Pocket device (Section 9.14.4), and blood samples will be taken 
for PK analysis (Section 9.14.3). 

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9.14.3 Nicotine Pharmacokinetics 
At Visits 2 to 7, a 4 mL blood sample for plasma nicotine analysis will be drawn into a plastic 
K2-EDTA (lavender top) vacutainer tube at -5, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 135, 
150, 165, and 180 minutes relative to the first puff of the combustible cigarette/blu disposable 
e-cigarette at that visit; i.e., at the start of the defined use session.  
PK blood samples will be collected by through an intravenous catheter port, or if necessary, 
direct venipuncture as determined by the clinical staff.  
Procedures for processing and storing samples will be performed according to the laboratory 
manual.   
Plasma samples will be shipped in batches on dry ice for analysis to a commercial 
bioanalytical laboratory.  The level of nicotine will be measured in samples at each time point 
and following analysis, all samples will be stored for up to one year and then destroyed.  
Nicotine bioanalysis will be conducted in accordance with appropriate standards including 
Good Laboratory Practice.  
9.14.4 Puff Topography  
Puff topography will be evaluated in the second product use session at Visits 2 to 7.  Subjects 
will engage in a 1 hour ad libitum product use session with either their usual brand cigarette 
or the assigned blu disposable e-cigarette, both of which will be used with the CReSS Pocket 
topography device.    
9.14.5 Mass Change 
For both the defined and ad libitum use sessions, the e-cigarette will be weighed before and 
after use, and these weights will be recorded.  
9.14.6 Subjective Effects Questionnaires 
The Urge to Smoke, PES (7-point scale), Product Liking (VAS), and Intent to Use Product 
Again (VAS) questionnaires will be completed on paper.  The Urge to Smoke questionnaire 
will be completed up to 30 seconds prior to the scheduled blood draw; however, if necessary, 
the blood draw will take precedence over completing the questionnaire.  For any other 
questionnaires scheduled at the same time as a PK blood draw, they will be completed within 
approximately 2 minutes after the scheduled blood draw. 
9.14.6.1 Urge to Smoke Questionnaire 
The Urge to Smoke questionnaire (Appendix 13.2.4) will be administered at the same time 
points when there is a blood draw for nicotine PK; i.e., at -5, 3, 5, 7, 10, 15, 20, 30, 45, 60, 
90, 120, 135 (or 15 minutes into ad lib session), 150 (or 30 minutes into ad lib session), 
165 (or 45 minutes into ad lib session), and 180 (or 60 minutes into ad lib session) minutes 
relative to the first puff of the cigarette/ENDS at that visit during Visits 2 to 7. 

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9.14.6.2 Product Evaluation Scale (PES) 
The PES (Appendix 13.2.6) will be administered at 180 minutes (i.e., 60 minutes into ad lib 
session) relative to the first puff of the cigarette/ENDS at that visit at Visits 2 to 7.  
9.14.6.3 Product Liking Questionnaire 
The Product Liking questionnaire (Appendix 13.2.3) will be completed at approximately 
180 minutes (i.e., 60 minutes into ad lib session) relative to the first puff of the 
cigarette/ENDS at that visit at Visits 2 to 7. 
9.14.6.4 Intent to Use Product Again Questionnaire 
The Intent to Use Product Again questionnaire (Appendix 13.2.5) will be completed at 
approximately 180 minutes (i.e., 60 minutes into ad lib session) relative to the first puff of the 
cigarette/ENDS at that visit at Visits 2 to 7. 
9.15 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. 
9.15.1 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. 
9.15.1.1 Adverse Event 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. 
When appropriate, medical tests and examinations will be performed to document resolution 
of the event(s). 
9.15.1.2 Reporting 
All AEs occurring during this clinical trial after the subject has used the first study product 
will be recorded on the CRF, 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 use, and severity for each event. 

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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 use 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. 
9.15.1.3 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 
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 site’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. The investigator must also inform the IRB, in compliance with GCP 
reporting guidelines, and the site monitor of any SAE. 
9.15.2 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 site staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site staff will follow up 
with the subject until the end of pregnancy, if in compliance with the site’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. 
9.15.3 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 

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will be encouraged to contact a qualified medical professional for advice on smoking 
cessation. 
9.16 Blood Sample Collection 
Blood sampling will include 2x10 mL and 2x5 mL blood draws during Visit 1 for clinical 
laboratory assessments and 16x5 mL PK blood draws (4 mL to fill the vacutainer, 1 mL 
wasted to assure proper blood flow and to clear residual blood and saline from the extension 
tube connected between the catheter the vacutainer tube) at Visits 2 to 7.  Therefore, total 
blood draw volume is expected to be 510 mL for each subject during the study. 
10. DATA ANALYSIS 
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 LA Clinical Trials, LLC 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, additional statistical analyses other than those 
described in this section may be performed and included in the SAP.  
10.1 Sample Size Estimation 
Since this study is the first to examine the nicotine PK in subjects using all of these 
blu disposable e-cigarettes, no formal power calculations will be performed.  The sample size 
is typical of other studies reported in literature examining the PK and subjective effects of 
different tobacco/nicotine products.  A sample size of 20 subjects has been determined 
adequate to meet the study objectives.  
10.2 Analysis Populations 
10.2.1 Safety Population 
The Safety Population will include all subjects who have successfully completed eligibility 
requirements and using at least one study product. 
10.2.2 Outcomes Population 
The Outcomes Population is a subset of the Safety Population and will consist of subjects 
who use a study product and have evaluable PK, subjective effects, or topography data. This 
population will be used in the summary and analysis of PK, subjective effects, topography, 
and product use. 
10.2.3 Pharmacokinetic Subpopulation 
The PK Subpopulation is a subset of the Outcomes Population and will consist of subjects 
who appear to have met the pre-exposure smoking abstinence period.  Upon review of the 
bioanalytical data, subjects with baseline nicotine levels that are higher than their 120-minute 
values will be considered as not meeting the pre-exposure smoking abstinence criteria and 
will be considered for exclusion from the PK Subpopulation.  Subjects who have this 
evidence of not meeting the abstinence criteria in ≥50% of their visits will be excluded from 
the PK Subpopulation. 

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10.3 Data Analysis, Summarization, and Statistical Methods 
SAS software (version 9.3 or higher, Cary, NC) will be used for all data presentation and 
summarization including summary tables, graphs, and data listings, except as noted in 10.3.1.  
In general, all data will be listed by subject and time point and summarized by study product 
and time point 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.  
10.3.1 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 baseline nicotine concentration from each 
nicotine concentration obtained after test product use on that day for each subject.  
Pharmacokinetic parameters of plasma nicotine levels will be calculated using 
noncompartmental methods with the Phoenix WinNonlin version 8 software platform 
(Certara, Princeton, NJ).  Plasma concentrations and the computed plasma PK parameters 
will be listed for each study product and subject.   
Plasma nicotine levels will be plotted as mean concentration in relation to time, with 
95% confidence intervals of the mean for each product at each time point.   
The following PK parameters will be calculated; all parameters will be baseline-adjusted 
using the value at time -5 minutes:  
• Cmax0-120 = Maximum plasma concentration during defined use session 
• Tmax0-120 = Time of maximum plasma concentration during defined use session 
• AUC0-120 = Area under the plasma concentration-time curve from time 0 to 
120 minutes during defined use session 
• Cavg0-120 = Average concentration from 0 to 120 minutes defined as AUC0-120/120 
minutes. 
• Cmax120-180 = Maximum plasma concentration during the ad libitum puffing session 
• Tmax120-180 = Time of maximum plasma concentration during the ad libitum puffing 
session 
• AUC120-180 = Area under the plasma concentration-time curve from time 120 minutes 
to 180 minutes during the ad libitum puffing session 
• Cavg120-180 = Average concentration from 120 to 180 minutes defined as 
AUC120-180/60 minutes. 
• AUC0-180 = Area under the plasma concentration-time curve from time 0 minutes to 
180 minutes during both puffing sessions 
• Ratio of Cmax120-180/Cmax0-120 = ratio of these two parameters 
• Ratio of Cavg120-180/Cavg0-120 = ratio of these two parameters 
 

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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 using descriptive statistics. 
A one-way or repeated measures analysis of variance will be conducted on the Outcomes 
Population Cmax0-120 and AUC0-120 to assess for statistical differences between the Usual 
Brand combustible cigarette and the blu disposable e-cigarettes.  Significance based on a 
Dunnett’s multiple comparison assessment will be reported.   
10.3.2 Subjective Effects Measures 
Where applicable, responses to the questionnaires recorded as VAS scores or Likert scales 
will be treated as continuous variables and summarized descriptively by study product and 
time point for each questionnaire item using means, standard deviations (SD), medians, and 
ranges. 
The PES 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; 
d) Relief: average of Questions 11, 13, 14, 15, and reversed for Question 20 (i.e., not at 
all = 7, extremely = 1); 
e) Questions 17, 19, 21 will be summarized as individual item scores. 
The maximum response (Emax) and time to maximum response (TEmax) will be determined for 
the Urge to Smoke questionnaire. 
Responses and parameters will be listed by subject and summarized by study product using 
descriptive statistics. 
10.3.3 Puff Topography  
The following topography parameters will be assessed: 
• 
Puff duration 
• 
Puff volume 
• 
Peak puff flow rate 
• 
Average puff flow rate 
• 
Inter-puff interval 
 
Summary statistics of puff topography parameters will be presented, including means, SD, 
medians, and ranges. 

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10.3.4 Mass Loss 
The difference in weights before and after each product use session will be summarized by 
study product using descriptive statistics.   
10.3.5 Safety 
All clinical safety data will be 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. 
All concomitant medications recorded will be listed by subject. 
11. STUDY ADMINISTRATION 
11.1 Ethics 
11.1.1 Institutional Review Board 
This protocol will be reviewed by the Advarra 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 
Regulations (21 CFR Part 56).  The IRB is compliant to International Council for 
Harmonisation (ICH) guidelines, and may be reached at: 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
Phone: 410.884.2900 
11.1.2 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). 
11.1.3 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. 

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Subjects will be given a copy of their signed ICF. 
11.2 Termination of the Study 
The investigator reserves the right to terminate the study in the interest of subject welfare. 
The sponsor reserves the right to suspend or terminate the study at any time. 
11.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at LA Clinical Trials, 
LLC relevant to the quality of this study.  Designated personnel of LA Clinical Trials, LLC 
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 generated, 
documented and 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.  
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using SAS® 
or comparable statistical program to check for missing data, data inconsistencies, data ranges, 
etc.  Corrections will be made prior to database lock. 
11.4 Direct Access to Source Data/Documents 
LA Clinical Trials, LLC 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.  
11.4.1 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, CRFs, 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 CRF. 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 CRF. 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. 
In addition, the sponsor’s internal auditors (or designee) and government inspectors may 
evaluate the study and must be allowed access to CRFs, source documents, and other study 
files. 

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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).  
11.5 Reporting for the Study 
11.5.1 Case Report Forms 
LA Clinical Trials, LLC standard CRFs will be supplied.  CRFs are produced, stored 
electronically, and are available to the designated study team members.  Each CRF is 
reviewed and signed by the investigator.  The final signed CRFs are provided to the sponsor 
in the format as decided upon between LA Clinical Trials, LLC and the sponsor (e.g., 
compact disc, flash drive, secure file transfer protocol). This will be documented in the Data 
Management Plan (if applicable). 
AEs will be coded using MedDRA®.  Coding will be completed by qualified members of LA 
Clinical Trials, LLC staff. 
11.5.2 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). 
11.5.3 Record Keeping 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by LA Clinical Trials, LLC 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. 
11.6 Confidentiality 
All clinic sites and vendors will have signed confidentiality agreements with LA Clinical 
Trials, LLC. By signing this protocol, the investigator and LA Clinical Trials, LLC staff will 
regard all information provided by the sponsor and all information obtained during the course 
of the study as confidential. 
Neither the clinic site nor LA Clinical Trials, LLC will supply to the sponsor any subject 
names, initials, date of birth (except year), or other personal identifiers in compliance with 
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 

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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. 
11.7 Publication Policy 
All unpublished information given to LA Clinical Trials, LLC 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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12. REFERENCES 
1. 
National Academies of Sciences, E., and Medicine, in Public Health Consequences of 
E-Cigarettes, D.L. Eaton, L.Y. Kwan, and K. Stratton, Editors. 2018, The National 
Academies Press: Washington (DC). 
2. 
Vansickel, A.R., et al., A clinical laboratory model for evaluating the acute effects of 
electronic "cigarettes": nicotine delivery profile and cardiovascular and subjective 
effects. Cancer Epidemiol Biomarkers Prev, 2010. 19(8): p. 1945-53. 
3. 
Bullen, C., et al., Effect of an electronic nicotine delivery device (e cigarette) on 
desire to smoke and withdrawal, user preferences and nicotine delivery: randomised 
cross-over trial. Tob Control, 2010. 19(2): p. 98-103. 
4. 
D'Ruiz, C.D., D.W. Graff, and X.S. Yan, Nicotine delivery, tolerability and reduction 
of smoking urge in smokers following short-term use of one brand of electronic 
cigarettes. BMC Public Health, 2015. 15: p. 991. 
5. 
Fearon, I.M., et al., E-cigarette Nicotine Delivery: Data and Learnings from 
Pharmacokinetic Studies. Am J Health Behav, 2017. 41(1): p. 16-32. 
6. 
Hajek, P., et al., Nicotine intake from electronic cigarettes on initial use and after 4 
weeks of regular use. Nicotine Tob Res, 2015. 17(2): p. 175-9. 
7. 
Lopez, A.A., et al., Effects of Electronic Cigarette Liquid Nicotine Concentration on 
Plasma Nicotine and Puff Topography in Tobacco Cigarette Smokers: A Preliminary 
Report. Nicotine Tob Res, 2016. 18(5): p. 720-3. 
8. 
Ramoa, C.P., et al., Electronic cigarette nicotine delivery can exceed that of 
combustible cigarettes: a preliminary report. Tob Control, 2016. 25(e1): p. e6-9. 
9. 
St Helen, G., et al., Nicotine delivery, retention and pharmacokinetics from various 
electronic cigarettes. Addiction, 2016. 111(3): p. 535-44. 
10. 
Nides, M.A., et al., Nicotine blood levels and short-term smoking reduction with an 
electronic nicotine delivery system. Am J Health Behav, 2014. 38(2): p. 265-74. 
11. 
Vansickel, A.R., et al., Characterization of puff topography of a prototype electronic 
cigarette in adult exclusive cigarette smokers and adult exclusive electronic cigarette 
users. Regul Toxicol Pharmacol, 2018. 98: p. 250-256. 
12. 
St Helen, G., et al., Impact of e-liquid flavors on e-cigarette vaping behavior. Drug 
Alcohol Depend, 2018. 189: p. 42-48. 
13. 
Lee, Y.O., et al., Examining Daily Electronic Cigarette Puff Topography Among 
Established and Nonestablished Cigarette Smokers in their Natural Environment. 
Nicotine Tob Res, 2018. 20(10): p. 1283-1288. 
14. 
Farsalinos, K., K. Poulas, and V. Voudris, Changes in Puffing Topography and 
Nicotine Consumption Depending on the Power Setting of Electronic Cigarettes. 
Nicotine Tob Res, 2018. 20(8): p. 993-997. 
15. 
Hiler, M., et al., Electronic cigarette user plasma nicotine concentration, puff 
topography, heart rate, and subjective effects: Influence of liquid nicotine 
concentration and user experience. Exp Clin Psychopharmacol, 2017. 25(5): p. 380-
392. 
16. 
Talih, S., et al., Effects of user puff topography, device voltage, and liquid nicotine 
concentration on electronic cigarette nicotine yield: measurements and model 
predictions. Nicotine Tob Res, 2015. 17(2): p. 150-7. 
17. 
Robinson, R.J., et al., Electronic Cigarette Topography in the Natural Environment. 
PLoS One, 2015. 10(6): p. e0129296. 

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18. 
Lee, Y.H., M. Gawron, and M.L. Goniewicz, Changes in puffing behavior among 
smokers who switched from tobacco to electronic cigarettes. Addict Behav, 2015. 48: 
p. 1-4. 
19. 
Heatherton, T.F., et al., The Fagerstrom Test for Nicotine Dependence: a revision of 
the Fagerstrom Tolerance Questionnaire. Br J Addict, 1991. 86(9): p. 1119-27. 
 

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13. APPENDICES 
13.1 Appendix 1. 
COVID-19 Screening 
 
Questions for Screening: 
 
At any time during the past 14 days have you…(check yes or no for each) 
Yes 
No 
Felt like you had a fever? 
 
 
Had a new or worsening cough? 
 
 
Had difficulty breathing? 
 
 
Had chills? 
 
 
Had a sore throat? 
 
 
Experienced body aches or muscle aches? 
 
 
Experienced a change in your ability to smell things? 
 
 
Experienced a change in your ability to taste things? 
 
 
Close contact with someone who is sick with suspected or confirmed 
COVID-19? 
 
 
 
 

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Before every Visit: 
 
Temperature:____________ Note: Fever = a temperature of 100.4° F (38° C) or greater 
 
 
Questions at every reminder call and every Product Use Visit: 
 
At any time since your last clinic visit have you…(check yes or no for each) 
Yes 
No 
Felt like you had a fever? 
 
 
Had a new or worsening cough? 
 
 
Had difficulty breathing? 
 
 
Had chills? 
 
 
Had a sore throat? 
 
 
Experienced body aches or muscle aches? 
 
 
Experienced a change in your ability to smell things? 
 
 
Experienced a change in your ability to taste things? 
 
 
Close contact with someone who is sick with suspected or confirmed 
COVID-19? 
 
 
 
 
 

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13.2 Appendix 2. 
Nicotine Use and Subjective Effects Questionnaires 
13.2.1 Nicotine use history questionnaire 
1. Do you currently smoke cigarettes?  Yes____  No____ (If no, exclude) 
 
2. If yes: 
a.  Average number of cigarettes smoked per day during the past 3 months? _____ 
i. What brand do you smoke?______________________  menthol or tobacco 
flavor?________   
ii. Full flavor_____  Medium____ Light____  Ultralight_______  
iii. Filter____ Non filter____  
iv. Commercially rolled______ roll your own_____ (exclude if roll your own) 
v.  
3. Age started smoking?  ______  
 
4. Maximum CPD smoked on average during any one year since started smoking? _____ 
 
5. Have you used any nicotine containing products other than cigarettes or e-cigarettes in the 
past 14 days? 
a. No____   Yes____  (exclude if yes) 
 
6. Number of serious quit attempts? _____ 
 
7. If >0: 
a. Longest time quit smoking?  Years____ Months_____ Days_____ 
b. Methods used to quit smoking: 
i. Counseling 
 
Yes____ No____ 
ii. Nicotine gum   
Yes____ No____ 
iii. Nicotine lozenge  
Yes____ No____ 
iv. Nicotine patch   
Yes____ No____ 
v. Nicotine inhaler  
Yes____ No____ 
vi. Nicotine nasal spray  
Yes____ No____ 
vii. Chantix  
 
Yes____ No____ 
viii. Zyban   
 
Yes____ No____ 
ix. Electronic Cigarette  
Yes____ No____ 
c. Did you use an electronic cigarette in your most recent attempt to quit smoking? 
Yes____ No____ 
 
8. Length of time you have used the following types of electronic cigarettes? 
a. Cigalike:  
 
Years_____  Months_____   Days_____   Never used_____ 
b. Cartridge/Pod type:  
Years_____  Months_____   Days_____   Never used_____ 
c. Vape pen:  
 
Years_____  Months_____   Days_____   Never used_____ 
d. Large tank:  
 
Years_____  Months_____   Days_____   Never used_____ 
e. Mod unit:   
 
Years_____  Months_____   Days_____   Never used_____ 
 
 
9. Are you currently using (within the past 7 days) any of the following types of electronic 
cigarettes: 
a. Cigalike:   
 
Yes____ No____ 
b. Cartridge/Pod type::  
Yes____ No____ 
c. Vape pen:  
 
Yes____ No____ 
d. Large tank:  
 
Yes____ No____ 
e. Mod unit:  
 
Yes____ No____ 

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10. Use of other tobacco products.  Have you ever used: 
a. Chewing tobacco    
Yes_______  No_______ 
b. Pipe 
 
 
Yes_______  No_______ 
c. Hookah  
 
Yes_______  No_______ 
d. Small Cigar 
 
Yes_______  No_______ 
e. Large Cigar 
 
Yes_______  No_______ 
f. Snus 
 
 
Yes_______  No_______ 
 

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13.2.2 Fagerström Test for Nicotine Dependence 
1. How soon after you wake up do you smoke 
your first cigarette? (Check one) 
Within 5 minutes           
6-30 minutes                  
31-60 minutes                
After 60 minutes            
2. Do you find it difficult to refrain from smoking 
in places where it is forbidden, e.g., in church, 
at the library, in cinema, etc.? (Check one) 
Yes       
No        
3. Which cigarette would you hate most to give 
up? (Check one) 
The first one in the morning      
Any others      
4. How many cigarettes/day do you smoke? 
10 or less          
11-20                
21-30                
31 or more        
5. Do you smoke more frequently during the first 
hours after waking than during the rest of the 
day? 
Yes       
No        
6. Do you smoke if you are so ill that you are in 
bed most of the day?  
Yes       
No        
 
                                                                                            Subject Initials_____ Date ______ 
 
 

CONFIDENTIAL 
Fontem-PK-01 
 
Page 47 
13.2.3 Product liking questionnaire 
 
Please indicate on the line below how much you liked the combustible cigarette or e-cigarette 
you have just used.  
 
 
Not at all 
 
 
 
 
 
 
 
 
A great deal 
 
 

CONFIDENTIAL 
Fontem-PK-01 
 
Page 48 
13.2.4 Urge to smoke questionnaire 
 
 
 
How strong is your current urge to smoke your usual brand cigarette?  
 
 
 
 
 
 
 
 
 
 
 
 
      No Urge                                                                                      Very Strong Urge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Urge to Smoke questionnaire will be completed up to 30 seconds prior to the scheduled 
blood draw; however, if necessary, the blood draw will take precedence over completing the 
questionnaire. 

CONFIDENTIAL 
Fontem-PK-01 
 
Page 49 
13.2.5 Intent to use product again questionnaire 
 
How likely are you to use the cigarette or e-cigarette you have just used in the future? 
 
 
 
 
 
 
Definitely would not                                                                Definitely would 

CONFIDENTIAL 
Fontem-PK-01 
 
 
 
Page 50 
13.2.6 Product Evaluation Scale  
 
1 
Not at all 
2 
Very Little 
3 
A little 
4 
Moderately 
5 
A lot 
6 
Quite a lot 
7 
Extremely 
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?