A Randomised, Cross-Over, Nicotine Pharmacokinetic and Pharmacodynamic Study of Heated Tobacco Products Compared to Combustible Cigarettes
Phase: NA
Conditions: Healthy Volunteers
Sponsor: Imperial Brands PLC

A Randomised, Cross-Over, Nicotine Pharmacokinetic and 
Pharmacodynamic Study of Heated Tobacco Products Compared to 
Combustible Cigarettes  
 
 
 
NCT05459857 
 
 
 
 
Study Protocol - FINAL (v3.0): 29 Oct 2021  
 
 
 
 

 
Page 1 
 
 
 
 
 
 
 
 
 
A Randomised, Cross-Over, Nicotine Pharmacokinetic and Pharmacodynamic Study of 
Heated Tobacco Products Compared to Combustible Cigarettes 
 
 
 
Sponsor Project No.: NER01/0004 
 
Celerion Project No.: CA35183 
 
 
Final Protocol (v1.0): 09-Sep-2021 
Protocol Amendment 1 (v2.0): 19-Oct-2021 
Protocol Amendment 2 (v3.0): 29-Oct-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 Imperial Brands PLC. 
Any viewing or disclosure of such information that is not authorised in writing by Imperial 
Brands PLC. is strictly prohibited. Such information may be used solely for the purpose of 
reviewing or performing this study. 

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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
A Randomised, Cross-Over, Nicotine Pharmacokinetic and Pharmacodynamic Study of 
Heated Tobacco Products Compared to Combustible Cigarettes  
 
 
 
 
 
 
Clinical Site and Principal Investigator: 
 
 
 
Celerion 
 
22-24 Lisburn Road 
Belfast, Northern Ireland, BT9 6AD 
Tel.: +44 (0) 28 90 554040 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
___ 
_________ 
 
S
Date 
 
 
 
 
 
 
 ________
____ 
 
 
Printed Name 
 
 
 
 
 
 
 
 
 
 
 
29 Oct 2021

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STUDY CONTACTS 
 
Medical Monitor 
To be provided separately 
 
 
 
Clinical Laboratory 
Celerion 
22-24 Lisburn Road 
Belfast, Northern Ireland 
BT9 6AD 
Tel.: +44 (0) 28 90 554040 
Fax: +44 (0) 28 90 554141 
 
 
Bioanalytical Laboratory 
Celerion 
621 Rose Street  
Lincoln, Nebraska 68502, USA 
Contact: Kirk Newland 
Tel.: +1 402 437-4719 
 
 
 

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SYNOPSIS 
Study Objectives 
Primary: 
1. To evaluate and compare the maximum plasma concentration 
(Cmax) and the area under the concentration-time curve at the last 
time point measured (AUCt) of nicotine after the use of each Heated 
Tobacco product or cigarette comparator. 
Secondary: 
1. To evaluate other pharmacokinetic (PK) parameters of nicotine after 
the use of each Heated Tobacco product or cigarette comparator. 
2. To evaluate the reduction in smoking urges observed after the use 
of each Heated Tobacco product or cigarette comparator.  
3. To evaluate product perception and preference by use of subjective 
assessments. 
4. To evaluate the tolerability and safety of each of the products used. 
5. To investigate usage behaviour for each product using 
measurements of topography parameters (puff count, puff 
duration, puff volume, peak puff flow rate, average puff flow rate, 
inter puff interval) for each product. 
Study Design 
This will be a randomised, cross-over, open-label, confinement study 
conducted in 24 adult male or female smokers of combustible cigarettes 
(CCs). The study will investigate combustible and heated tobacco (HT) 
products in a cross-over design, incorporating PK evaluation, subjective 
questionnaire assessments, usage behaviour, puff topography, as well 
as safety evaluation. 
Subjects will perform a screening visit and 1 study visit, including a 
5-day confinement period and finally a follow-up telephone call 
approximately 7 days after the final product use. 
Visit 1 (Screening) 
Screening procedures will be performed within 27 days prior to study 
procedures on Day -1 and will include an eligibility check, review of 
health status and assessment of nicotine consumption habits. Medical 
and tobacco-use histories and demographic data will be collected. Other 
screening procedures include a physical examination (including oral 
cavity and oropharynx), vital signs, electrocardiogram (ECG), body 
mass index (BMI), clinical laboratory tests (hematology, serum 
chemistry, urinalysis), serology, urine/saliva drug, urine/breath alcohol, 
cotinine screen, exhaled carbon monoxide (CO), and pregnancy and 
follicle-stimulating hormone (FSH) tests (for females as appropriate). 
If required, subjects will be offered smoking cessation advice and 
contact information for a smoking cessation support service. 

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Visit 2 (In-clinic period, Day -1 to Day 4) 
At Visit 2, subjects who successfully complete the screening 
procedures and meet all the inclusion criteria and none of the 
exclusion criteria will be eligible to check in to the clinical research 
unit (CRU) on Day -1 and will remain at the clinic until Day 4 for 
daily study product use, PK sampling, subjective questionnaire 
assessments, puff topography (as applicable), and safety assessments. 
On Day -1, following eligibility confirmation, subjects will undertake a 
familiarisation session of the study products and questionnaires. The 
clinical team will explain how the HT products will be used. Subjects 
will have the opportunity to see the products/devices and packaging and 
will participate in a Product Trial where they will consume one HT stick 
(flavour chosen by subject). All products/devices used in the trial 
session will not be used in the clinical study but will be retained as 
demonstration samples for accountability purposes. An explanation of 
how the questionnaires will be administered to the subjects will be 
given. After the familiarisation session and completion of check-in 
procedures, subjects will be allowed to smoke their own cigarettes 
ad libitum but will abstain from use of any tobacco- or 
nicotine-containing products for at least 12 hours prior to the start of 
the morning controlled product use session on Day 1. 
In the morning of Day 1, after pre-use assessments and confirmation of 
eligibility, the subjects will be randomised to 1 of 4 product sequences 
and then provided a single product of the study product in the sequence 
to which they have been randomised. On Days 1 through 4, subjects 
will use the assigned study product under controlled conditions 
(i.e., completely use a single unit of the assigned study product, with 
puffs taken at 30-second intervals and puffs 3 seconds in duration). PK 
samples will be collected within 5 minutes pre-study product use and at 
2, 4, 6, 8, 10, 15, 30, 45, 60, 120, and 240 minutes following the start 
of study product use. Questionnaires will be administered to the subject 
at defined intervals throughout the day. Safety will be monitored 
throughout the day.  
On Days 1 through 4, following the 4-hour PK blood collection, 
subjects will start a 4-hour ad libitum product use session (no limits on 
cigarette or HT consumption) with the same study product used during 
the morning controlled use session. 
On Days 3 and 4, puff topography will be performed during the last 
2 hours of the 4-hour ad libitum product use session. The Sodim 
Smoking Puff Analyzer Mobile (SPA-M) topography device will 
collect data (puff count, puff duration, puff volume, peak puff flow rate, 
average puff flow rate, inter-puff interval) for 2 hours. The topography 
session will span a 2-hour period and the SPA-M topography device 

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will be stopped and restarted with each new stick or cigarette during 
that time. 
The ad libitum product use session on Days 1 through 4 will start at 
approximately the same time each day, with lunch served at the start of 
the ad libitum product use session, at approximately the same time each 
day. After completion of the ad libitum use session, subjects will be 
allowed to smoke their own cigarettes (ad libitum) but will abstain from 
use of any tobacco- or nicotine-containing products for at least 12 hours 
prior to the start of the morning controlled product use scheduled on the 
following day. 
A new/unused device will be provided to the subjects on each day of 
HT product use (i.e., the same device will be used for the morning 
controlled product use and ad libitum product use sessions on the same 
day). 
On Day 4, following completion of study assessments, subjects will be 
allowed to use their own cigarettes and will leave the CRU after 
completing all final check out requirements.   
Visit 3 (Follow-up phone call) 
A follow-up telephone call (Visit 3) will be made by the CRU in an 
attempt to contact all subjects who used at least one study product 
(including subjects who terminate the study early) using their standard 
procedures approximately 7 days after the final product use to 
determine if any adverse event (AE) has occurred since the last study 
visit. 
Study Population 
The study population will be comprised of healthy, adult male and 
female smokers, who are between 21 and 65 years of age (inclusive). 
Each subject must self-report smoking an average of 10 or more 
manufactured combustible cigarettes per day (CPD) for at least 
12 months prior to Screening. Twenty-four (24) subjects will be 
enrolled. 
Duration of Study 
Conduct 
Subjects will participate in the study for up to 35 days, including an up 
to 28-day screening period. 
Study Products and 
Administration 
Details of the study products are presented as follows: 
Product 
Designation 
Study Product Name 
A 
HT device with 
 
stick 
B 
 HT device with 
 
stick 
C 
 HT device with 
 stick 

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D 
Subject’s own brand combustible cigarette 
(OBCC) 
Endpoints, Key 
Assessments, and 
Summarisation 
Pharmacokinetics: 
For each morning product use session on Days 1 through 4, plasma 
nicotine PK parameters (AUCinf, AUC0-90, AUC0-240, AUCt, Cmax, Clast, 
Tmax, T1/2) will be computed from the individual plasma 
concentrations for each study product. Baseline adjustments will be 
performed. 
Nicotine concentrations and PK parameters will be listed by subject 
and summarised using descriptive statistics. 
Subjective Effects: 
Intent to Use (ITU) 
Descriptive statistics of the visual analog scale (VAS) will be 
provided by study product and product use session. Individual 
responses will be listed by subject. 
Urge to Smoke 
Responses and derived parameters (Emax, TEmax, AUEC0-240) will be 
listed by subject and summarised using descriptive statistics.  
Product Evaluation Scale 
Responses will be considered as a 7-point scale, and will be presented 
as factors outlined in Section 7.3.2.2. 
Descriptive statistics of the subscales will be provided by study 
product and product use session. Individual responses will be listed by 
subject. 
Puff Topography: 
Topography parameters (puff count, puff duration, puff volume, peak 
puff flow rate, average flow rate, inter-puff interval) will be listed by 
subject and summarised using descriptive statistics. 
Product Use Behaviour: 
All product use data, including the number of HT sticks used and the 
number of CCs smoked (Days -1 through Day 4) will be summarised 
using descriptive statistics.  
Incidence of device malfunction(s) will also be tabulated. 
Safety: 
Safety will be monitored in-study through physical examination 
(symptom-driven), vital signs measurements, ECGs, and clinical 
laboratory tests (serum chemistry, hematology, and urinalysis).  

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Adverse Events (AEs) spontaneously reported by the subjects or 
observed by the Investigator or other study personnel will be 
monitored from Screening until the follow-up.  
AEs will be tabulated and summary statistics for vital signs and 
clinical laboratory tests may be computed and provided, as deemed 
clinically appropriate. 
 

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l: 
The number of cigarettes smoked, as appropriate, will be documented from Check-in until beginning of smoking abstinence (Day -1, until at least 12 hours 
prior to the start of morning controlled product use on Day 1; Days 1 through 3, 8 hours post morning controlled use session IP start until at least 12 hours 
prior to the start of morning controlled product use scheduled on the following day). The number of cigarettes smoked and the number of HT sticks used will 
be documented during each 4-hour ad libitum product use session (Days 1 through 4). 
m: The number of inhalations and reasons for missed puffs will be documented. 
n: To be performed approximately 5 minutes prior to the start of the product use session. 
o: Subjects will be familiarised with the questionnaires. An explanation of how the questionnaires will be administered to the subjects will be given. Responses 
will not be recorded. 
p: To be performed approximately 10 minutes prior to the start of the product use session. 
q: To be performed approximately 30 seconds prior the scheduled PK blood draws. 
r: 
On Day -1, subjects will participate in a Product Trial period where subjects will consume one HT stick (flavour chosen by subject).   
s: 
On Days 3 and 4 only, puff topography measurements will be performed for 2 hours during the last 2 hours of the 4-hour ad libitum product use session. The 
topography session will span a 2-hour period and the SPA-M topography device will be stopped and restarted with each new stick or cigarette during that 
time. 
t: 
The CRU will attempt to contact all subjects who used at least one study product (including subjects who terminate the study early) using their standard 
procedures approximately 7 days after the final product use to determine if any AE has occurred since the last study visit. 
 
Abbreviations:  AE = Adverse event, BMI = Body mass index, BP = Blood pressure, Chem = Serum chemistry, CO = Carbon monoxide, CRU = Clinical 
research unit, ECG = Electrocardiogram, EOS = End-of-study, FSH = Follicle-stimulating hormone, FU = Follow-up, HBsAg = Hepatitis B surface antigen, 
HCV = Hepatitis C virus, HIV = Human immunodeficiency virus, HR = Heart rate, HT = Heated tobacco, I/E = Inclusion/exclusion, IP = Investigational 
product, PK = Pharmacokinetic(s), RR = Respiratory rate, Scr = Screening, SPA-M = Sodim Smoking Puff Analyzer Mobile, T = Temperature, OBCC = Own 
brand combustible cigarette.

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ABBREVIATIONS 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC 
Area under the concentration-time curve 
AUC0-90 
Area under the nicotine concentration-time curve from time 0 to 
90 minutes 
AUC0-240 
Area under the nicotine concentration-time curve from time 0 to 
240 minutes 
AUCinf 
Area under the nicotine concentration-time curve from time 0 to 
infinity 
AUCt 
The area under the concentration time curve, from time 0 to the last 
observed non-zero concentration, as calculated by the linear 
trapezoidal method. 
AUEC0-240 
Area under the change from baseline score versus time curve from 
time 0 to 240 minutes 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
qC 
Degree Celsius 
CC 
Combustible cigarette 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Clast 
Plasma concentration at last time point 
Cmax 
Maximum measured plasma concentration 
CO 
Carbon monoxide 
CPD 
Cigarette(s) per day 
CRF 
Case report form 
CRU 
Clinical research unit 
EC 
Ethics committee 
ECG 
Electrocardiogram 
Emax 
Maximum change from baseline score 
EOS 
End-of-Study 
qF 
Degree Fahrenheit 

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FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
g 
Gram 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HT 
Heated tobacco 
HTP 
Heated tobacco product 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ITU 
Intent to Use 
K2-EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
ln 
Natural logarithm 
m2 
Meters squared 
mAh 
Milliampere hour 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
ng 
Nanogram 
NGP 
Next generation product(s) 
OBCC 
Own brand combustible cigarette 
PK 
Pharmacokinetic(s) 
ppm 
Parts per million 
PPS 
Product Preference Scale 
QA 
Quality Assurance 
RCF 
Relative centrifugal force 
REC 
Research Ethics Committee 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOP 
Standard operating procedure 
SPA-M 
Sodim Smoking Puff Analyzer Mobile 

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SUSAR 
Suspected unexpected serious adverse reaction 
TEmax 
Time of the Emax 
Tmax 
Time to reach the maximum measured plasma concentration 
US or USA 
United States of America 
USB 
Universal serial bus 
V 
Volt 
VAS 
Visual analog scale 

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DEFINITION OF TERMS 
Check-in 
Check-in is defined as the time when the subject arrives at the 
CRU to start confinement 
Concomitant 
medication 
Concomitant medication refers to all medication taken during the 
study conduct period from 28 days prior to Screening through 
End-of-Study. Medications started prior to Screening but which 
the subject continues to take during the study, are considered to be 
concomitant medications 
Randomisation 
Assignment of subjects to a specific sequence 
Screening 
Screening is defined as the 27-day period prior to study 
procedures on Day -1, during which subjects will undergo 
screening assessments 
Screening failure 
Any subject who does not meet the entry criteria at Screening or 
Day -1 for study enrollment will be considered a Screening failure 
Sponsor 
‘Sponsor’ refers to Imperial Brands PLC 
Subject 
‘Subject’ refers to an individual who participates in the clinical 
study 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL REVISION HISTORY ........................................................................................2 
SPONSOR SIGNATURE PAGE ..............................................................................................6 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE .............................................................7 
STUDY CONTACTS ................................................................................................................8 
SYNOPSIS .................................................................................................................................9 
STUDY EVENTS FLOW CHART .........................................................................................14 
ABBREVIATIONS .................................................................................................................17 
DEFINITION OF TERMS ......................................................................................................20 
TABLE OF CONTENTS .........................................................................................................21 
1. 
INTRODUCTION AND BACKGROUND ................................................................25 
1.1 
Background ......................................................................................................25 
1.2 
Pulze HT Previous Clinical Experience ...........................................................25 
1.3 
Study Purpose ..................................................................................................25 
2. 
STUDY OBJECTIVES AND ENDPOINTS ...............................................................26 
2.1 
Study Objectives ..............................................................................................26 
2.2 
Study Endpoints ...............................................................................................26 
3. 
SUMMARY OF STUDY DESIGN .............................................................................28 
3.1 
Design and Procedures .....................................................................................28 
3.2 
Confinement and Follow-Up ...........................................................................31 
3.3 
End of Study Definition ...................................................................................31 
4. 
STUDY POPULATION ..............................................................................................31 
4.1 
Inclusion Criteria .............................................................................................31 
4.2 
Exclusion Criteria ............................................................................................32 
4.3 
Study Restrictions ............................................................................................35 
4.3.1 
Food and Beverages ..........................................................................35 
4.3.2 
Medications .......................................................................................35 
4.3.3 
Meals/Dietary Considerations ...........................................................35 
4.3.4 
Activity .............................................................................................36 
4.3.5 
Tobacco Use/Considerations ............................................................36 
4.4 
Subject Early Discontinuation or Withdrawal .................................................36 
4.5 
Subject Randomisation ....................................................................................37 
5. 
STUDY PRODUCTS/MATERIALS ..........................................................................37 
5.1 
Description of Study Products .........................................................................37 
5.1.1 
Usual Brand Combustible Cigarette .................................................37 

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5.1.2 
Pulze HT Device with Stick ..............................................................38 
5.2 
Study Product Accountability and Dispensing ................................................40 
6. 
STUDY PROCEDURES .............................................................................................41 
6.1 
Screening..........................................................................................................41 
6.1.1 
Informed Consent..............................................................................41 
6.1.2 
Medical History/Demographic Data/Record of Concomitant 
Medication ........................................................................................41 
6.1.3 
Tobacco/Nicotine Product Use History ............................................42 
6.1.4 
Exhaled Carbon Monoxide ...............................................................42 
6.2 
Check-in and Confinement ..............................................................................42 
6.2.1 
Baseline Assessments (Day -1) .........................................................42 
6.3 
Product Use (Days 1 Through 4) .....................................................................43 
6.4 
Study Assessments ...........................................................................................43 
6.4.1 
Nicotine Pharmacokinetics ...............................................................43 
6.4.1.1 
Future Research ...........................................................44 
6.4.2 
Subjective Effects Questionnaires ....................................................44 
6.4.3 
Puff Topography ...............................................................................44 
6.4.4 
Safety Assessments ...........................................................................45 
6.4.4.1 
Physical Examination...................................................45 
6.4.4.2 
Body Weight, Height, and BMI ...................................45 
6.4.4.3 
Electrocardiogram ........................................................45 
6.4.4.4 
Vital Signs ....................................................................45 
6.4.4.5 
Clinical Laboratory ......................................................46 
6.4.5 
Adverse Events .................................................................................47 
6.4.5.1 
Monitoring ...................................................................47 
6.4.5.2 
Reporting......................................................................47 
6.4.5.3 
Serious Adverse Events ...............................................47 
6.4.5.4 
Suspected Unexpected Serious Adverse 
Reactions ......................................................................48 
6.4.5.5 
Pregnancy .....................................................................48 
6.4.5.6 
Smoking Cessation Information ..................................48 
7. 
DATA ANALYSIS ......................................................................................................49 
7.1 
Sample Size Estimation ...................................................................................49 
7.2 
Analysis Populations ........................................................................................49 

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7.3 
Data Analysis, Summarisation, and Statistical Methods .................................49 
7.3.1 
Nicotine Pharmacokinetic Analysis ..................................................50 
7.3.2 
Subjective Effects .............................................................................51 
7.3.2.1 
Urge to Smoke Parameters...........................................51 
7.3.2.2 
Product Evaluation Scale .............................................52 
7.3.2.3 
Intent to Use .................................................................52 
7.3.3 
Puff Topography ...............................................................................52 
7.3.4 
Product Use Behaviour .....................................................................52 
7.3.5 
Safety ................................................................................................53 
8. 
STUDY ADMINISTRATION.....................................................................................53 
8.1 
Ethics................................................................................................................53 
8.1.1 
Institutional Review Board ...............................................................53 
8.1.2 
Ethical Conduct of the Study ............................................................53 
8.1.3 
Subject Information and Consent......................................................53 
8.2 
Confidentiality .................................................................................................54 
8.3 
Termination of the Study .................................................................................54 
8.4 
Data Quality Assurance ...................................................................................54 
8.5 
Direct Access to Source Data/Documents .......................................................55 
8.5.1 
Monitoring the Study ........................................................................55 
8.6 
Reporting for the Study ....................................................................................55 
8.6.1 
Case Report Forms ............................................................................55 
8.6.2 
Data Coding ......................................................................................56 
8.6.3 
Report Format ...................................................................................56 
8.6.4 
Record Keeping ................................................................................56 
8.7 
Publication Policy ............................................................................................56 
9. 
REFERENCES ............................................................................................................57 
10. 
APPENDICES .............................................................................................................58 
 
 

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List of Appendices 
Appendix 1: 
Demographics Questionnaires ........................................................................ 59 
Appendix 2: 
Urge to Smoke Questionnaire ......................................................................... 60 
Appendix 3: 
Product Evaluation Scale (PES)...................................................................... 61 
Appendix 4: 
Intent to Use Questionnaire ............................................................................ 62 
 
 
List of Tables 
Table 1. Study Events ............................................................................................................. 14 
 
 
List of Figures 
Figure 1. Overall Study Design .............................................................................................. 30 
Figure 2. Heated Tobacco Product Diagram........................................................................... 39 
Figure 3. iD Stick Assembly ................................................................................................... 40 
 

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1. INTRODUCTION AND BACKGROUND 
1.1 
Background 
Smoking is a cause of serious diseases in smokers, including lung cancer, heart disease and 
emphysema. Despite the well characterised health risks, smoking rates in adult populations 
worldwide remain at 15% to 25%. In addition to methods of helping people quit, 
investigations are ongoing into the health benefits of reducing exposure to toxicants in people 
who continue to use tobacco and nicotine, in the absence of combustion. This is being done 
through the development of new non-combustible tobacco and nicotine products, often 
referred to as next generation products (NGP). 
Tobacco-related health risks are assumed to be due to repeated and sustained exposure to a 
range of smoke toxicants at high levels. Smoke from conventional cigarettes (CC) is a 
complex and dynamic mixture of more than 7000 chemical constituents, in both its 
particulate and vapour phases. Some of these chemicals have been identified as potential 
contributors to the harmful effects of cigarette smoke and can be evaluated by measuring the 
levels of these chemicals themselves, or their metabolites, in urine. 
Nicotine is an addictive chemical present in combustible cigarette smoke. Nicotine is rapidly 
absorbed into the bloodstream during cigarette smoking, from where it is rapidly distributed 
causing both systemic and central effects. In the central nervous system, nicotine acts at 
neuronal nicotinic receptors and this interaction may underpin its effects on mood and 
relaxation. The pharmacokinetic (PK) profile of nicotine during cigarette smoking is a rapid 
rise and fall in plasma nicotine concentrations. Correspondingly, the delivery of nicotine to 
the brain, and the consequent pleasurable effects experienced by the smoker, are also rapid. 
Imperial Brands PLC aim to increasingly transition adult smokers, who would otherwise 
continue to smoke, to NGPs that are potentially less harmful than CC. Heated tobacco (HT) 
and electronic cigarettes (E- cigarettes) are two platforms that are being increasingly 
recognised by public health bodies and regulators as having the potential to reduce the risk of 
continued smoking. HT products also offer greater optionality in parts of the world where 
vaping is not permitted or where smokers prefer HT. Imperial Brands have therefore added 
the Pulze heated tobacco product (HTP) device and iD stick HT consumables to a growing 
repertoire of NGP. 
1.2 
Pulze HT Previous Clinical Experience 
No clinical studies have been conducted for the Pulze HT products. Pulze was commercially 
available following a city pilot launch in Fukuoka, Japan, in May 2019.  
1.3 
Study Purpose 
This study is being conducted to evaluate the overall performance of Imperial Brands’ Pulze 
HT device and three flavoured iD HT consumable (sticks) and compare to CC. It will provide 
data on nicotine PK, product perception and preference, product usage as measured by 
topography and tolerability and safety of each of the products compared to OBCC. Along 
with other pre-clinical in vitro studies, clinical and behavioural and population studies, the 

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results of this study are intended to contribute to a body of evidence to assess the harm 
reduction potential of Pulze HT and will support regulatory submissions as required. The 
endpoints to be assessed are based on Section 910 of the Federal Food, Drug, and Cosmetic 
Act - Application for Review of Certain Tobacco Products (FDA 2019), and the data may 
also be included in future premarket tobacco application submissions to the Center for 
Tobacco Products.  
The risk to subjects participating in this study is minimized by compliance with the eligibility 
criteria (Section 4.1 and Section 4.2) and study procedures, adherence to the protocol, as well 
as close clinical monitoring (i.e., AEs, ECG, vital sign measurements, clinical laboratory 
tests, and physical examination). The risk that subjects develop clinical symptoms is also low 
as they will be administered products similar to those that they already use. In addition, 
menthol-flavoured HTPs will only be given to subjects who are currently smoking menthol 
combustible cigarettes and/or have customarily smoked them in the past and will not be 
given to smokers who have had no previous experience of cigarettes or nicotine products 
containing menthol flavouring. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
Primary 
1. To evaluate and compare the Cmax and AUCt of nicotine after the use of each Heated 
Tobacco product or cigarette comparator. 
Secondary 
1. To evaluate other PK parameters of nicotine after the use of each Heated Tobacco 
product or cigarette comparator. 
2. To evaluate the reduction in smoking urges observed after the use of each Heated 
Tobacco product or cigarette comparator.  
3. To evaluate product perception and preference by use of subjective assessments. 
4. To evaluate the tolerability and safety of each of the products used. 
5. To investigate usage behaviour for each product using measurements of topography 
parameters (puff count, puff duration, puff volume, peak puff flow rate, average puff 
flow rate, inter puff interval) for each product. 
2.2 
Study Endpoints 
Pharmacokinetics: 
For each morning product use session on Days 1 through 4, plasma nicotine PK parameters 
(AUCinf, AUC0-90, AUC0-240, AUCt, Cmax, Clast, Tmax, T1/2) will be computed from the individual 

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plasma concentrations for each study product. Baseline adjustments will be performed. 
Nicotine concentrations and PK parameters will be listed by subject and summarised using 
descriptive statistics. 
Subjective Effects: 
Intent to Use (ITU) 
Descriptive statistics of the visual analog scale (VAS) will be provided by study product and 
product use session. Individual responses will be listed by subject. 
Urge to Smoke 
Responses and derived parameters (Emax, TEmax, AUEC0-240) will be listed by subject and 
summarised using descriptive statistics.  
Product Evaluation Scale 
Responses will be considered as a 7-point scale, and will be presented as factors outlined in 
Section 7.3.2.2. 
Descriptive statistics of the subscales will be provided by study product and product use 
session. Individual responses will be listed. 
Puff Topography: 
Puff topopgraphy will be assessed using a SPA-M topography device. The topography session 
will span a 2-hour period and the SPA-M topography device will be stopped and restarted with 
each new stick or cigarette during that time. Topography parameters (puff count, puff duration, 
puff volume, peak puff flow rate, average flow rate, inter-puff interval) will be listed by subject 
and summarised using descriptive statistics. 
Product Use Behaviour: 
All product use data, including the number HT sticks used and the number of CCs smoked 
(Days -1 through Day 4), will be summarised using descriptive statistics.  
Incidence of device malfunction(s) will also be tabulated. 
Safety: 
Safety will be monitored in-study through physical examination (symptom-driven), vital signs 
measurements, ECGs, and clinical laboratory tests (serum chemistry, hematology, and 
urinalysis).  
AEs spontaneously reported by the subjects or observed by the Investigator or other study 
personnel will be monitored from Screening until the follow-up.  

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AEs will be tabulated and summary statistics for vital signs and clinical laboratory tests may 
be computed and provided, as deemed clinically appropriate. 
3. SUMMARY OF STUDY DESIGN 
3.1 
Design and Procedures 
This will be a randomised, cross-over, open-label, confinement study conducted in 24 adult 
male or female smokers of CCs. The study will investigate combustible and HT products in a 
cross-over design, incorporating PK evaluation, subjective questionnaire assessments, usage 
behaviour, puff topography, as well as safety evaluation. 
During the study, subjects will perform a screening visit and 1 study visit, including a 5-day 
confinement period and finally a follow-up telephone call approximately 7 days after the 
final product use. 
Visit 1 (Screening) 
Screening procedures will be performed within 27 days prior to study procedures on Day -1 
and will include an eligibility check, review of health status and assessment of nicotine 
consumption habits. Medical and tobacco-use histories and demographic data will be 
collected. Other screening procedures include a physical examination (including oral cavity 
and oropharynx), vital signs, ECG, BMI, clinical laboratory tests (hematology, serum 
chemistry, and urinalysis), serology, urine/saliva drug, urine/breath alcohol, cotinine screen, 
exhaled CO, and pregnancy and FSH tests (for females as appropriate). If required, subjects 
will be offered smoking cessation advice and contact information for a smoking cessation 
support service. 
Visit 2 (In-clinic period, Day -1 to Day 4) 
At Visit 2, subjects who successfully complete the screening procedures and meet all the 
inclusion criteria and none of the exclusion criteria will be eligible to check in to the CRU on 
Day -1 and will remain at the clinic until Day 4 for daily study product use, PK sampling, 
subjective questionnaire assessments, puff topography (as applicable), and safety 
assessments. 
On Day -1, following eligibility confirmation, subjects will undertake a familiarisation 
session of the study products and questionnaires. The clinical team will explain how the HT 
products will be used. Subjects will have the opportunity to see the products/devices and 
packaging and will participate in a Product Trial where they will consume one HT stick 
(flavour chosen by subject). All products/devices used in the trial session will not be used in 
the clinical study but will be retained as demonstration samples for accountability purposes. 
An explanation of how the questionnaires will be administered to the subjects will be given. 
After the familiarisation session and completion of check-in procedures, subjects will be 
allowed to smoke their own cigarettes ad libitum but will abstain from use of any tobacco- or 
nicotine-containing products for at least 12 hours prior to the start of the morning controlled 
product use session on Day 1. 

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In the morning of Day 1, after pre-use assessments and confirmation of eligibility, the 
subjects will be randomised to 1 of 4 product sequences and then provided a single product 
of the study product in the sequence to which they have been randomised. On Days 1 through 
4, subjects will use the assigned study product under controlled conditions (i.e., completely 
use a single unit of the assigned study product, with puffs taken at 30-second intervals and 
puffs 3 seconds in duration). PK samples will be collected within 5 minutes pre-study 
product use and at 2, 4, 6, 8, 10, 15, 30, 45, 60, 120, and 240 minutes following the start of 
study product use. Questionnaires will be administered to the subject at defined intervals 
throughout the day. Safety will be monitored throughout the day.  
On Days 1 through 4, following the 4-hour PK blood collection, subjects will start a 4-hour 
ad libitum product use session (no limits on cigarette or HT consumption) with the same 
study product used during the morning controlled use session. 
On Days 3 and 4, puff topography will be performed during the last 2 hours of the 4-hour 
ad libitum product use session. The SPA-M topography device will collect data for 2 hours. 
The topography session will span a 2-hour period and the SPA-M topography device will be 
stopped and restarted with each new stick or cigarette during that time. 
The ad libitum product use session on Days 1 through 4 will start at approximately the same 
time each day, with lunch served at the start of the ad libitum product use session, at 
approximately the same time each day. After completion of the ad libitum use session, 
subjects will be allowed to smoke their own cigarettes (ad libitum) until at least 12 hours 
prior to the start of the morning controlled product use session scheduled on the following 
day. 
A new/unused device will be provided to the subjects on each day of HT product use (i.e., the 
same device will be used for the morning controlled product use and ad libitum product use 
sessions on the same day). A new HT stick will be provided at the start of the morning 
controlled product use session. During the ad libitum product use session, subjects will have 
access to the assigned HT sticks for ad libitum use, but a new HT stick will be provided at 
the start of puff topography. 
On Day 4, following completion of study assessments, subjects will be allowed to use their 
own cigarettes and will leave the CRU after completing all final check out requirements. 
Visit 3 (Follow-up phone call) 
A follow-up telephone call (Visit 3) will be made by the CRU in an attempt to contact all 
subjects who used at least one study product (including subjects who terminate the study 
early) using their standard procedures approximately 7 days after the final product use to 
determine if any AE has occurred since the last study visit. 
Subjects will not be forced to use any tobacco/nicotine products at any time during the study. 
The overall study design is depicted in Figure 1. 

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Safety will be monitored through physical examination (symptom-driven), vital signs 
measurements, ECGs, and clinical laboratory tests (serum chemistry, hematology, and 
urinalysis). 
Device malfunctions will also be recorded. 
The safety monitoring practices employed by this protocol (i.e., vital signs, 12-lead ECGs, 
clinical laboratory tests, AE questioning, and physical examinations) are adequate to protect 
the subjects’ safety and should detect all expected emergent AEs. 
Discontinued subjects may be replaced at the discretion of the Sponsor. 
 
Figure 1. Overall Study Design 
 
 
a: 
To be performed within 27 days prior to study procedures on Day -1. 
b: At Check-in, baseline study assessments, questionnaire training and Product Trial will be performed on 
Day -1. 
c: 
Subjects will be randomised on Day 1 and start study product use and study assessments. 
d: A follow-up telephone call will be made by the CRU in an attempt to contact all subjects who used at least 
one study product (including subjects who terminate the study early) using their standard procedures 
approximately 7 days after the final product use to determine if any AE has occurred since the last study 
visit. 
Study Days
-1
1
2
3
4
Check-In
X
Product Trial
X
Randomization
X
PK Blood Sampling
X
X
X
X
Subjective Questionnaires
X
X
X
X
X
Puff Topography
X
X
Screening a
Check-In Procedures b
PK based on 
Randomization 
Schedule c
Follow-up d

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5. A female subject of childbearing potential must have been using 1 of the following forms 
of contraception and agree to continue using it through completion of the study and for at 
least 28 days after the final product use: 
x hormonal (e.g., oral, vaginal ring, transdermal patch, implant, or injection) 
consistently for at least 3 months prior to Check-in; 
x double barrier method (e.g., condom with spermicide, diaphragm with spermicide) 
consistently for at least 14 days prior to Check-in; 
x intrauterine device for at least 3 months prior to Check-in; 
x a partner who has been vasectomised for at least 4 months prior to Check-in; 
x abstinence beginning at least 28 days prior to Check-in. 
6. A female subject of non-childbearing potential must have undergone one of the following 
sterilisation procedures at least 6 months prior to Check-in: 
x hysteroscopic sterilisation; 
x bilateral tubal ligation or bilateral salpingectomy; 
x hysterectomy; 
x bilateral oophorectomy;  
or be postmenopausal with amenorrhea for at least 1 year prior to Check-in and FSH 
levels consistent with postmenopausal status. 
7. A non-vasectomised, male subject must agree to use a condom with spermicide or abstain 
from heterosexual intercourse from Check-in until at least 90 days after the final product 
use. No restrictions are required for a vasectomised male provided his vasectomy has 
been performed 4 months or more prior to Check-in. A male who has been vasectomised 
less than 4 months prior to Check-in must follow the same restrictions as a 
non-vasectomised male. 
8. A male subject must agree not to donate sperm from Check-in until at least 90 days after 
the last final product use. 
9. Is willing to comply with the requirements of the study, including a willingness to use the 
HT products. 
10. Provides voluntary consent to participate in this study documented on the signed 
informed consent form (ICF). 
4.2 
Exclusion Criteria 
Subjects may be excluded from the study if there is evidence of any of the following criteria 
at Screening, Check-in, or during the study as noted, in the opinion of the Investigator: 
1. Has a history or presence of clinically significant gastrointestinal, renal, hepatic, 
neurologic, hematologic, endocrine, oncologic, urologic, pulmonary (especially 

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bronchospastic diseases and asthma), immunologic, psychiatric, or cardiovascular 
disease, or any other condition that, in the opinion of the Investigator, would jeopardise 
the safety of the subject or impact the validity of the study results. 
2. Has a clinically significant abnormal finding on the physical examination, medical 
history, vital signs, ECG, or clinical laboratory results, in the opinion of the Investigator. 
3. Has a positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C virus (HCV) at Screening. 
4. Has previously been diagnosed with any form of cancer, except for basal cell or 
squamous epithelial carcinomas of the skin that have been resected at least 1 year prior to 
Screening. 
5. Has diabetes mellitus that is not controlled by diet/exercise alone, in the opinion of the 
Investigator. 
6. Has had an acute illness (e.g., upper respiratory infection, viral infection) requiring 
treatment within 14 days prior to Check-in. 
7. Has a fever (> 100.5°F/38.05°C) at Screening or Check-in. 
8. Has a body mass index (BMI) > 30.0 kg/m2 or < 18.0 kg/m2 at Screening. 
9. Has a history or presence of drug or alcohol abuse within 24 months of Check-in, as 
determined by the Investigator. 
10. Has a systolic blood pressure < 90 mmHg or > 150 mmHg, diastolic blood pressure 
< 40 mmHg or > 95 mmHg, or heart rate < 40 bpm or > 99 bpm at Screening. 
11. Has an estimated creatinine clearance < 70 mL/minute (using the Cockcroft-Gault 
equation) at Screening. 
12. Has a positive urine/breath screen for alcohol or positive urine screen for drugs of abuse 
at Screening or Check-in. 
13. Drinks alcohol in excess of 21 glasses/units per week for males or 14 glasses/units per 
week for females, with one unit = 150 mL of wine or 360 mL of beer or 45 mL of 45% 
alcohol. 
14. If female, the subject is pregnant, lactating, or intends to become pregnant during the 
time period from Screening through the end of study. 
15. Has taken medication for depression or asthma within 12 months prior to Check-in and 
throughout the study. 
16. Has used prescription anti-diabetic medication and/or insulin therapy within 12 months 
prior to Check-in and throughout the study. 

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17. Has used medications known to interact with cytochrome P450 (CYP) 2A6 (including, 
but not limited to, amiodarone, desipramine, isoniazid, ketoconazole, miconazole, 
phenobarbital, rifampin, tranylcypromine, methoxsalen) within 3 months prior to 
Check-in and throughout the study. 
18. Has used prescription drugs within 7 days prior to Check-in and throughout the study. 
Medication listed as part of acceptable birth control methods, hormonal replacement 
therapy, and occasional or seasonal use of over-the-counter products such as analgesics, 
antihistamines, nasal decongestants, and dietary supplements are permitted at the 
discretion of the Investigator (refer to Section 4.3.2). 
19. Has used inhalers to treat any medical condition within 3 months prior to Check-in and 
throughout the study. 
20. Use of prescription or over-the-counter bronchodilator medication (e.g., inhaled or oral 
ȕ-agonists) for treatment of any illness within 12 months prior to Check-in and 
throughout the study. 
21. Is allergic to or cannot tolerate menthol flavouring agents. 
22. Has never smoked any menthol cigarettes or cannot tolerate smoking them. 
23. Has used other nicotine-containing products other than manufactured combustible 
cigarettes (e.g., e-cigarettes, roll-your-own cigarettes, bidis, snuff, nicotine inhaler, pipe, 
cigar, chewing tobacco, nicotine patch, nicotine spray, nicotine lozenge, or nicotine gum) 
within 14 days prior to Check-in. 
24. Has used any prescription smoking cessation treatments, including, but not limited to, 
varenicline (Chantix®) or bupropion (Zyban®) within 3 months prior to Check-in. 
25. Is a self-reported puffer (i.e., adult smoker who draws smoke from the cigarette into the 
mouth and throat but does not inhale). 
26. Is planning to quit smoking during the study or within the next 3 months or is postponing 
a quit attempt in order to participate in the study. 
27. Has donated blood or blood products (including plasma), had significant blood loss, or 
received whole blood or a blood product transfusion within 90 days prior to Check-in. 
28. Donation of bone marrow within the last 6 months prior to Check-in. 
29. Has participated in a previous clinical study for an investigational drug, device, biologic, 
or tobacco product within 90 days prior to Check-in. 
30. Is or has a first-degree relative (i.e., parent, spouse, sibling, child) who is a current or 
former employee of the tobacco or vaping industry or a named party or class 
representative in litigation with the tobacco or vaping industry. 

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31. Is or has a first-degree relative (i.e., parent, spouse, sibling, child) who is a current 
employee of the CRU. 
32. In the opinion of the Investigator, the subject should not participate in this study. 
4.3 
Study Restrictions 
4.3.1 Food and Beverages 
Foods and beverages containing the following substances should not be consumed as 
indicated below: 
x Alcohol should be avoided for 48 hours prior to Screening and Check-in to avoid 
exclusion for a positive alcohol test and throughout the study. 
x Foods containing poppy seeds should be avoided for 48 hours prior to Screening and 
Check-in to avoid exclusion for a positive urine drug test and throughout the study. 
x Food and beverages containing grapefruit for 14 days prior to Check-in and 
throughout the study. 
x Caffeinated beverages will be restricted throughout confinement. 
4.3.2 Medications 
Medication use will be assessed to satisfy the inclusion and exclusion criteria. All 
medications (and reasons for their use) taken from 30 days prior to Check-in through the 
end-of-study will be recorded. Except for those medications noted in the exclusion criteria 
(Section 4.2), prescription or over-the-counter medications required to treat a disease or 
condition are permitted at the discretion of the Investigator. Hormonal contraceptives 
(e.g., oral, vaginal ring, transdermal patch, implant, injection) and hormonal replacement 
therapy are permitted. Occasional or seasonal use of over-the-counter products such as 
analgesics (e.g., acetaminophen), antihistamines, nasal decongestants, and dietary 
supplements are permitted at the discretion of the Investigator. Other medications may be 
permitted at the discretion of the Investigator, providing the medication in question would 
have no impact on the study. Use of any medication will be documented. 
Decisions to use concomitant medications during the study will be made in the best interest 
of the health of the subject. If use of a prohibited medication is required during the study, a 
decision will be made by the Investigator to continue or discontinue the subject. Any 
required medications that might impact study endpoints should be considered during 
interpretation of the study results. 
4.3.3 Meals/Dietary Considerations 
For all subjects, meals and snacks will be provided at the appropriate times during 
confinement at the CRU. Each meal and/or snacks served at the CRU will be standardised 
and will be similar in caloric content and composition and will be taken at approximately the 
same time on each day. When confined in the CRU, subjects will be required to fast from all 
food and drink except water between meals and snacks. 

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Subjects will fast for at least 1 hour prior to and for at least 4 hours after the start of each 
controlled morning product use session on Days 1, 2, 3, and 4. Lunch will be served at 
approximately the same time on Days 1 through 4, at the start of the 4-hour ad libitum 
product use session (after collection of the 4-hour PK blood sample). After lunch, subjects 
will fast for the remainder of the 4-hour ad libitum product use session.  
During confinement, water will be allowed ad libitum, except that subjects may not consume 
beverages of any kind (including water) during the morning product use sessions on Days 1, 
2, 3 and 4. An exception to the water restriction can be made if a subject starts coughing 
uncontrollably while smoking or using the study products. 
4.3.4 Activity 
Subjects will be instructed to refrain from abnormal strenuous physical activity which could 
cause muscle aches or injury, including contact sports at any time from 48 hours prior to 
Screening and Check-in, and during confinement. 
4.3.5 Tobacco Use/Considerations 
Except as allowed by the study, consumption of tobacco- or nicotine-containing products will 
not be permitted from Check-in through discharge. On Days -1 through 4, subjects will be 
allowed to use their OBCCs, ad libitum, after completion of study assessments and after the 
4-hour ad libitum product use session, but will abstain from use of any tobacco- or 
nicotine-containing products for at least 12 hours prior to the start of morning controlled 
product use session scheduled on the following day. 
4.4 
Subject Early Discontinuation or Withdrawal 
Subjects will be advised that they are free to withdraw from the study at any time. In 
addition, subject participation in this study may be discontinued for any of the following 
reasons: 
x AE 
x Lost to follow-up 
x Non-compliance with study procedures 
x Protocol violation 
x Study terminated by Sponsor or other regulatory authorities 
x Withdrawal of consent 
x Investigator’s discretion, including a severe laboratory abnormality or other medical 
condition that indicates to the Investigator that continued participation is not in the 
best interest of the subject 
Protocol deviations/violations should not lead to subject withdrawal unless they indicate a 
significant risk to the subject’s safety or jeopardise the scientific integrity of the study. 

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If premature withdrawal from the study occurs for any reason, the Investigator must 
determine the primary reason and record this information in the case report form (CRF). 
Additionally, subjects withdrawing after study product administration will undergo all 
discharge safety procedures as feasible and as deemed necessary by the Investigator. 
A subject withdrawn from the study due to any AE or clinically significant abnormal 
laboratory test values will be evaluated by the Investigator or other qualified individual and 
will be treated and/or followed up until the symptoms or values return to normal or 
acceptable levels or until lost to follow-up, as appropriate in the opinion of the Investigator. 
Subjects withdrawing or removed from this study cannot re-enter. 
4.5 
Subject Randomisation 
Subjects who complete the study screening assessments and meet all the eligibility criteria 
and are randomised will be assigned a unique randomisation identification number on Day 1 
and will receive study products according to the randomisation scheme generated by 
Celerion. 
The sequences to be used in the randomisation will be ABCD, BDAC, CADB, and DCBA. 
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (e.g., Subject No. 101 will replace Subject No. 1). 
5. STUDY PRODUCTS/MATERIALS 
5.1 
Description of Study Products 
All subjects will use Products A through D.  
The following study products will be used in this study: 
Product 
Designation Study Product Name 
A 
 HT device with 
 stick 
B 
HT device with 
 stick 
C 
 HT device with 
 stick 
D 
Subject’s own brand combustible cigarette (OBCC) 
5.1.1 Usual Brand Combustible Cigarette 
Subjects will be required to bring with them to the CRU a sufficient supply (i.e., 5-day 
supply [unopened packs]) of their OBCCs for personal use throughout confinement. 

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documented on Day -1 prior to smoking abstinence (at least 12 hours prior to the start of 
morning controlled product use session on Day 1), and on Days 1 through 3 following the 
4-hour ad libitum product use session until at least 12 hours prior to the start of morning 
controlled product use session scheduled on the following day. 
Subjects will smoke their OBCC and use each assigned product only in designated areas of 
the CRU. 
Opened and unopened packages of 
 HT devices and sticks will be returned to the 
Sponsor or destroyed at the direction of the Sponsor. Opened and unopened packages of 
subject’s OBCC will be returned to the subjects at the end of the study. All returns or 
destruction of study products will be documented. 
HT device has two power settings: standard mode (345°C temperature) and Eco 
(315°C temperature). Subjects should use the device set on the standard mode. 
6. STUDY PROCEDURES 
6.1 
Screening 
Potential subjects will undergo Screening procedures to ensure that they meet the 
requirements for inclusion in the study within 27 days prior to study procedures on Day -1. 
Screening procedures will be performed as delineated in the Study Events Flow Chart 
(Table 1). 
6.1.1 Informed Consent 
All prospective subjects will have the study explained by the Investigator or his/her designee 
and will be required to read, sign, and date an ethics committee (EC)-approved ICF prior to 
completion of screening or other study procedures. This consent form will provide the 
subjects in non-technical terms with the purpose of the study, procedures to be carried out, 
and potential hazards. The subjects will be assured that they may withdraw from the study at 
any time without jeopardising medical care related to or required as a result of study 
participation. Subjects will be given a copy of their signed ICF. 
6.1.2 Medical History/Demographic Data/Record of Concomitant Medication 
Medical history and socio-demographic data, including name, sex, age (each subject must 
show proof of age with government-issued identification [e.g., driver’s license]), race, 
ethnicity, address, and phone number will be recorded at Screening for each subject. 
Additional data including National Insurance Number, as applicable, will be recorded at 
Check-in. 
Any concomitant medications taken from 30 days prior to Check-in through discharge will 
be recorded in the CRF and source document. 

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6.1.3 Tobacco/Nicotine Product Use History 
Subjects will be required to report previous tobacco-product and nicotine-product use 
histories to satisfy the study inclusion and exclusion criteria.  
Details of the subject’s OBCC, including the brand, brand style, flavour, cigarette length, and 
amount of daily use will be recorded at Screening and updated at Check-in as necessary. A 
color photocopy or photograph of the subject’s OBCC package (including the branding and 
the UPC code) will be taken by the CRU staff at Check-in. 
6.1.4 Exhaled Carbon Monoxide 
Exhaled CO levels will be measured using a Bedfont Micro+ Smokerlyzer or similar device, 
at Screening and at Check-in. 
6.2 
Check-in and Confinement 
Subjects will check in to the CRU on Day -1 at a time specified by the CRU. Check-in 
procedures will be performed as delineated in the Study Events Flow Chart (Table 1).  
After check-in, subjects will complete one set of questionnaires for the purpose of 
familiarisation with subjective effects questions, appropriate use of the VAS, and use of the 
computerised tablet system. Data collected from the training session will not be used for any 
analysis.  
The clinical team will explain how the HT products will be used. Subjects will have the 
opportunity to see the products/devices and packaging and will participate in a Product Trial 
where they will use the 
 device with the HT stick (flavour) of their choice. The HT stick 
flavour will be recorded; however, no assessments will be made. The purpose of the Product 
Trial is to familiarise subjects to the 
device and HT stick prior to PK assessments. All 
products/devices used in the trial session will not be used in the clinical study but will be 
retained as demonstration samples for accountability purposes. 
Subjects will have their personal belongings thoroughly checked during Check-in. All 
subjects will be required to shower and will receive clean articles of clothing prior to the start 
of each morning controlled product use (i.e., during the 12-hour abstinence) on Days 1, 2, 3 
and 4.  
Subjects will be confined from Check-in on Day -1 through completion of scheduled study 
events on Day 4. 
A subject may be required to remain at the CRU for longer at the discretion of the 
Investigator or designee. 
6.2.1 Baseline Assessments (Day -1) 
Subjects will continue to smoke their OBCC from Check-in (after completion of the Product 
Trial and check-in procedures) through Day -1, but will abstain from use of any tobacco- or 

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nicotine-containing products for at least 12 hours prior to the start of morning controlled 
product use session on Day 1.  
The number of OBCC smoked per day will be documented. 
Baseline assessments will be performed as delineated in the Study Events Flow Chart 
(Table 1).  
6.3 
Product Use (Days 1 Through 4) 
On Days 1, 2, 3, and 4, subjects will use the study product they are assigned to use according 
to the randomisation scheme.  
In the morning of each day, subjects will use the assigned study product under controlled 
conditions (i.e., completely use a single unit of the assigned study product, with puffs taken 
at 30-second intervals and puffs 3 seconds in duration). Following the 4-hour PK blood 
collection, subjects will start a 4-hour ad libitum product use session (no limits on cigarette 
or HT consumption) with the same study product used during the morning controlled use 
session. 
Each subject will be provided with a new/unused 
HT device for each day of HT 
product use (i.e., the same device will be used for the morning controlled product use session 
and the ad libitum product use session on the same day). Subjects will be provided the 
assigned HT stick (based on randomisation sequence) or OBCC on each day. The clinic staff 
will document the time each product is dispensed. The Pulze HT device should be used on 
the Standard Mode Setting. Products that stop functioning should be replaced as soon as 
possible, with the failure documented.  
6.4 
Study Assessments 
All study assessments will take place at the times delineated in the Study Events Flow Chart 
(Table 1) unless otherwise noted below. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
6.4.1 Nicotine Pharmacokinetics 
On each of Days 1, 2, 3 and 4, a 4 mL blood sample for plasma nicotine analysis will be 
drawn into a plastic K2-EDTA (lavender top) vacutainer tube at the time points delineated in 
the Study Events Flow Chart (Table 1). Allowable deviation windows for PK sampling are:  
± 30 seconds for samples collected from 3 - 15 minutes, ± 1 minute for samples collected 
from 30 - 60 minutes, and ± 3 minutes for all other samples. 
PK blood samples will be collected by direct venipuncture or through an intravenous catheter 
port as determined by the clinical staff.  

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Additional blood (typically up to approximately 1 mL) may be drawn between blood draws 
for the purpose of keeping the needle patent, if required. The blood from the 1 mL draws will 
be discarded. In total, approximately 250 mL of blood will be drawn from each subject 
during the entire study for nicotine PK analysis. 
The blood samples collected for plasma nicotine analysis may be kept at room temperature 
prior to centrifugation, and will be centrifuged at approximately 1000 to 1300 RCF at ~5°C 
for approximately 10 minutes, within 60 minutes from collection. After centrifugation, the 
plasma will be transferred to two methanol prewashed 3.5 mL polypropylene screw cap 
tubes, properly labeled, and then stored at -20°C (r 10°C) or below (within 120 minutes from 
collection) until analysis. 
Samples will be analyzed using a validated liquid chromatography coupled to tandem mass 
spectrometry detection analytical method with the appropriate quality controls in accordance 
with FDA Good Laboratory Practice regulations (Title 21 Code of Federal Regulations 
[CFR] Part 58). Additionally, processing of samples will completed by a non-tobacco user. 
6.4.1.1 Future Research 
No additional analysis is planned to be performed on the blood samples for possible future 
research.  
6.4.2 Subjective Effects Questionnaires 
The Intent to Use (VAS), Urge to Smoke (VAS), and Product Evaluation Scale (7-point 
scale) questionnaires will be completed using a computerised tablet device. All relevant 
software and staff training specific to the electronic questionnaires will be provided by 
IVRCC ePro. Any electronic device used must meet all regulatory requirements, including 
FDA 21 CFR Part 11. 
All questionnaires will be completed at the time points delineated in the Study Events Flow 
Chart (Table 1). 
When scheduled at the same time as a PK blood draw, the Urge to Smoke questionnaire will 
be completed approximately 30 seconds prior to the scheduled blood draw (except for the 
one scheduled at Time 0, which will be performed approximately 10 minutes prior to the start 
of the product use session), and all other questionnaires will be completed within 
approximately 2 minutes after the last scheduled blood draw. 
6.4.3 Puff Topography 
Puff topography will be evaluated over the last 2-hour period during the 4-hour ad libitum 
product use session on Days 3 and 4 as indicated in the Study Events Flow Chart (Table 1). 
Following the 4-hour PK blood collection and at the start of their meal, subjects will be 
allowed to use their assigned study product ad libitum for 4 hours. During the last 2 hours of 
the ad libitum session, topography measurements will be taken. The topography session will 
span a 2-hour period and the SPA-M topography device will be stopped and restarted with 
each new stick or cigarette during that time. Puff parameters will be recorded using SPA-M 

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devices (puff count, puff duration, puff volume, peak puff flow rate, average puff flow rate, 
inter puff interval) for each product.  
The ad libitum product use session on Days 1 through 4 will start at approximately the same 
time each day, with lunch served at the start of the ad libitum product use session, at 
approximately the same time each day. After completion of the ad libitum use session 
(i.e., approximately 8 hours after the start of the morning controlled product use), subjects 
will be allowed to smoke their own cigarettes (ad libitum) but will abstain from use of any 
tobacco- or nicotine-containing products for at least 12 hours prior to the start of morning 
controlled product use session scheduled on the following day. 
The topography device will be monitored to ensure the device is actively recording during 
each session. 
Additional details and instructions for puff topography procedures will be provided 
separately. 
Depending on the availability of topography equipment, puff topography may not be 
performed for some or all assigned subjects. 
6.4.4 Safety Assessments 
Safety assessments in addition to those below may be obtained as necessary at the discretion 
of the Investigator. In the case of an early subject withdrawal, discharge safety assessments 
should be collected to the extent possible. 
6.4.4.1 Physical Examination 
A standard physical examination assessing the general physical well-being will be performed 
at Screening. A symptom-driven physical examination will be conducted at other times as 
deemed appropriate by the Investigator (Table 1). 
6.4.4.2 Body Weight, Height, and BMI 
Body weight and body height will be measured as delineated in the Study Events Flow Chart 
(Table 1). BMI will be recorded as kg/m2. 
6.4.4.3 Electrocardiogram 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart (Table 1). 
ECGs will be taken following resting in the supine position for at least 5 minutes. All ECG 
tracings will be reviewed by the Investigator or a qualified designee. 
6.4.4.4 Vital Signs 
Single measurements of vital signs (respiratory rate, HR, BP, and oral temperature) will be 
performed as outlined in the Study Events Flow Chart (Table 1). Additional vital signs may 
be taken at any other times, if deemed necessary. 

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BP and HR measurements will be taken following a rest period of at least 5 minutes in a 
seated position. Vital signs are to be measured at least 15 minutes after the last tobacco- or 
nicotine-containing product used. 
On Days 1, 2, 3 and 4, vital signs measurements will be taken within 2 hours prior to the start 
of the morning product use session. 
6.4.4.5 Clinical Laboratory 
All clinical laboratory tests will be conducted by an accredited laboratory. Values for the 
clinical laboratory parameters are to be within the laboratory normal ranges or deemed not 
clinically significant in the opinion of the Investigator. All tests listed below will be 
performed as delineated in the Study Events Flow Chart (Table 1). Up to approximately 
38 mL of blood will be drawn from each subject during the entire study for clinical 
laboratory tests. 
Serum Chemistry 1 
Urinalysis 2  
Additional Tests 
x 
Albumin 
x 
Alkaline phosphatase 
x 
Alanine aminotransferase 
x 
Aspartate 
aminotransferase 
x 
Bicarbonate 
x 
Blood urea nitrogen 
x 
Creatinine 
x 
Glucose 
x 
Potassium 
x 
Sodium 
x 
Total protein 
x 
Uric acid  
 
Hematology 
x 
Hematocrit 
x 
Hemoglobin 
x 
Platelet count 
x 
Red blood cell count 
x 
White blood cell count 
with differential 
 
x 
Bilirubin 
x 
Blood 
x 
Glucose 
x 
Ketones 
x 
Leukocyte esterase 
x 
Nitrite 
x 
pH 
x 
Protein 
x 
Specific gravity 
x 
Urobilinogen 
x 
Serology 
o HIV 
o HBsAg 
o HCV 
x 
Serum pregnancy test 3  
x 
Serum FSH 4  
x 
Urine cotinine  
x 
Urine drug screen 
o Amphetamines 
o Cannabinoids 
o Cocaine 
o Opiates 
x 
Urine/breath alcohol 
1 Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, subjects may not have fasted for 8 hours prior to the serum chemistry sample being 
taken. For the samples collected at EOS, an 8-hour fast is not required. 
2  A microscopic examination for red blood cells, white blood cells, bacteria, and casts will be 
performed if an abnormality is noted in leukocyte esterase, protein, blood, or nitrite. 
3  Human chorionic gonadotropin (females only). 
4  For postmenopausal females only. 

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6.4.5 Adverse Events 
An AE is any untoward medical occurrence associated with the use of the study product, 
whether or not considered study product-related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a study product, whether or not related to the study 
product. 
6.4.5.1 Monitoring 
The subjects will be instructed to inform the Investigator or staff of any AEs and intercurrent 
illnesses experienced during the study (i.e., from Screening until follow-up). Additionally, a 
specific inquiry regarding AEs will be conducted prior to each product use and at discharge 
(or upon early withdrawal). The inquiry will be posed in a non-specific manner using open-
ended questions so as not to bias the response (e.g., How are you feeling today?). 
A subject who has any clinically significant AE or clinically significant abnormal laboratory 
test value will be evaluated by the Investigator or other qualified individual and will be 
treated and/or followed up until the symptoms or values return to normal or acceptable levels 
(as appropriate in the opinion of the Investigator), or until the subject is lost to follow-up. 
Where appropriate, medical tests and examinations will be performed to document resolution 
of the event(s). 
6.4.5.2 Reporting 
All AEs occurring during this clinical trial after the subject has received the first study 
product (i.e., at the Product Trial) must 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 administration, and severity for 
each event. AEs will be listed. 
Events captured between Screening and the first study product use will be documented as 
baseline signs and symptoms. 
The Investigator will review each event and assess its relationship to product administration 
as unrelated, unlikely, possibly, probably, or likely. 
In addition, each sign or symptom reported will be graded on a 3-point severity scale using 
mild, moderate, or severe. 
6.4.5.3 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that (WHO and ICH 
definitions): 
x results in death 
x is life-threatening 

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x results in permanently disabling or incapacitating 
x requires inpatient hospitalisation 
x prolongs inpatient hospitalisation 
x is a congenital anomaly / birth defect 
x may jeopardise the subject or may require intervention to prevent one or more of 
the other outcomes listed above. 
All SAEs, whether or not considered study-related, must be reported by telephone and by fax 
or e-mail to the Sponsor within 24 hours of the CRU’s learning of the SAE or, at the latest, 
on the following workday. The Sponsor’s representative to contact about this study is 
provided in the list of study contacts. The Investigator must also inform the EC, in 
compliance with GCP reporting guidelines, and the site monitor of any SAE. 
6.4.5.4 Suspected Unexpected Serious Adverse Reactions 
In accordance with the European Clinical Trial Directive (Directive 2001/20/EC), the 
Sponsor must ensure that the Ethics Committee, the appropriate Competent Authority, and 
the licensing authority are informed of all suspected “unexpected” serious adverse reactions 
(SUSARs) within 15 days of the event. All SUSARs leading to death, or which are 
life-threatening should be reported by the Sponsor to the ethics committee, the appropriate 
Competent Authority, and the licensing authority within 7 days of the event. The Sponsor 
should present all SUSARs to the appropriate Competent Authority once a year, or on 
request. Reporting of relevant events to ethics committee, the appropriate Competent 
Authority, and the licensing authority will be delegated by the Sponsor to the CRO 
(Celerion). 
6.4.5.5 Pregnancy 
A pregnancy occurring in a female study subject during the study will be documented in the 
clinical conduct study report to the EC. Pregnancy itself is not an AE. The Investigator or 
designee will discontinue the pregnant subject from the study and will advise her to seek 
prenatal care and counseling from her primary care provider. Advice given will be 
documented in the subject’s source document. 
The CRU staff will request the pregnant subject to notify the CRU of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the CRU staff will follow up 
with the subject until the end of pregnancy, if in compliance with the CRU’s standard 
operating procedures (SOPs) and with the subject’s consent. This request and the subject’s 
response will be documented in the subject’s source document. 
6.4.5.6 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. 
7. DATA ANALYSIS 
Data will be handled and processed according to Celerion SOPs, which are written based on 
the principles of GCP. A brief description of the statistical analysis is included below, 
detailed methodology for all summary and statistical analyses of the data collected in this 
trial will be documented in a statistical analysis plan (SAP) prepared by Celerion 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 plan. 
7.1 
Sample Size Estimation 
The sample size chosen for this study was selected without statistical considerations. It has 
been determined adequate to meet the study objectives. 
7.2 
Analysis Populations 
7.2.1 Safety Population 
The Safety Population will include all subjects who have successfully completed eligibility 
requirements after checking in to the CRU and used at least one study product. 
7.2.2 Outcomes Population 
The Outcomes Population is a subset of the safety population and will consist of subjects 
who used a study product and have evaluable PK, subjective effects, or topography data. This 
population will be used in the summary and analysis of PK, subjective effects, topography, 
and product use, and all available data will be included in the summary tables to the extent 
possible. 
7.3 
Data Analysis, Summarisation, and Statistical Methods 
SAS software (version 9.4 or higher, Cary, North Carolina) will be used for all data 
presentation and summarisation including summary tables, graphs, and data listings. In 
general, all data will be listed by subject and time point and summarised by study product, 
time point, product use session (as applicable), and sex using descriptive statistics 
appropriate for the endpoint. Figures will be used to display the data graphically. 
Missing data will not be imputed. Where individual data points are missing because of 
dropouts or other reasons, the data will be considered missing at random and summarised 
based on reduced denominators.  

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7.3.1 Nicotine Pharmacokinetic Analysis 
Individual nicotine concentrations will be adjusted for baseline nicotine (“baseline-adjusted”) 
and all PK parameters will be calculated based on the adjusted concentrations. Baseline 
adjustment will be performed by subtraction of the pre-existing nicotine concentration from 
each nicotine concentration obtained after test product administration in that period/day for 
each subject using the following equation: 
Ct  = Ct unadjusted – [C0 · e-Kel· t1] 
where Ct is the adjusted concentration at time t, Ct unadjusted is the observed concentration at 
time t, C0 is the pre-product use concentration (-5 minutes), Kel = 
୪୬ (ଶ)
୲Φ , t½ is 2 hours 
(average nicotine half-life), t is the actual sampling time since product administration, and t1 
is the actual sampling time since the time of the pre-product use sample. Any resulting 
negative concentration values following the baseline adjustment will be set to 0. 
Nicotine PK parameters will be determined from the adjusted individual subject plasma 
concentration-time profiles by applying a non-compartmental approach using appropriate 
validated PK software (e.g., Phoenix® WinNonlin® version 8.1 or higher).  
For each morning product use session on Days 1, 2, 3 and 4, the following PK parameters 
will be calculated from the baseline-adjusted nicotine concentration-time data: 
AUC0-90 
Area under the baseline-adjusted nicotine concentration-time curve from time 
0 (defined as the start of the product use session) to the 90-minute time point 
as calculated by the linear trapezoidal method 
AUC0-240 
Area under the baseline-adjusted nicotine concentration-time curve from time 
0 (defined as the start of the product use session) to the 240-minute time point 
as calculated by the linear trapezoidal method 
AUCt 
Area under the baseline-adjusted nicotine concentration-time curve from time 
0 (defined as the start of the product use session) to time t. 
AUCinf 
Area under the baseline-adjusted nicotine concentration-time curve from 
time 0 (defined as the start of the product use session) extrapolated to infinity 
(represents the total nicotine exposure across time). 
Cmax 
Maximum baseline-adjusted plasma concentration. 
Clast 
Plasma baseline-adjusted nicotine concentration at last time point measured 
Tmax 
Time to reach the maximum baseline-adjusted plasma concentration. If the 
maximum value occurs at more than one time point, Tmax is defined as the first 
time point with this value. 
T1/2 
Terminal elimination half-life. 

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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 summarised by 
study product, by sex and overall using descriptive statistics. 
7.3.1.1 Analysis of Variance 
A linear mixed model for analysis of variance will be performed on the log-transformed PK 
parameters Cmax and AUC following the morning product use session on each of Days 1, 2, 
3, and 4. The model will include sequence, study product, and study day as fixed effects and 
subject-nested-within-sequence as a random effect. Sequence will be tested using 
subject-nested-within-sequence as the error term. Geometric least-squares means (LSM) and 
95% confidence intervals (CIs) will be provided for the PK parameters of Cmax and AUC by 
study product. Geometric LSM ratio, 95% CIs of geometric LSM ratio, and p-values will be 
provided for the study product comparisons in Cmax and AUC. The comparisons of interest 
will include each of the study products compared to each other. 
The above statistical analyses will be performed using the appropriate SAS procedure.  
Non-parametric analysis (Wilcoxon Signed Rank test) will be performed for the comparisons 
of Tmax.  
Details of the statistical methods will be provided in the SAP. 
7.3.2 Subjective Effects 
7.3.2.1 Urge to Smoke Parameters 
The following parameters will be calculated for the urge to smoke assessments: 
Emax 
The maximum change from baseline VAS score 
(VASpre-use - VASpost-use). 
TEmax 
Time of the Emax. If the maximum value occurs at more than one time point, 
TEmax will be defined as the first time point with this value. 
AUEC0-240 
The area under the change from baseline VAS score versus time curve from 
time 0 to 240 minutes. 
Responses and derived parameters will be listed by subject and summarised by study 
product, by sex and overall using descriptive statistics. 
An appropriate statistical method, similar to the PK analysis detailed above, will be used to 
compare Urge to Smoke parameters (no data transformation). 

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7.3.2.2 Product Evaluation Scale 
Product Evaluation will be considered as a 7-point scale. Responses will be presented as the 
following factor scores:  
a) Satisfaction: average of the response scores from questions 1, 2, 3, and 12; 
b) Psychological reward: average of the response scores from questions 4 to 8; 
c) Aversion: average of the response scores from questions 9, 10, 16, and 18; 
d) Relief: average of items 11, 13, 14, 15, and reversed for item 20 (i.e., not at all = 7, 
extremely = 1); 
e) Items 17, 19, 21 will be summarised as individual item scores. 
Descriptive statistics of the subscales will be provided by study product, by sex and overall. 
Individual responses will be listed by subject. 
7.3.2.3 Intent to Use 
Descriptive statistics of the VAS will be provided by study product. Individual responses will 
be listed by subject. 
7.3.3 Puff Topography 
The following topography parameters will be assessed: 
x Puff count 
x Puff duration 
x Puff volume 
x Peak puff flow rate 
x Average puff flow rate 
x Inter-puff interval 
Topography parameters will be listed by subject and summarised by study product, study 
day, overall and by sex, usual brand cigarette flavour (non-menthol or menthol), age, number 
of years smoking, CPD, and time point using descriptive statistics. 
An appropriate statistical method, similar to the PK analysis detailed above, will be used to 
compare topography parameters. 
7.3.4 Product Use Behaviour 
The number of HT sticks used (ad libitum product use session), the number of CCs smoked 
(Days -1 through 4), and the number of puffs (morning controlled product use session) will 

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be listed by subject and summarised by study product, product use session, study day and 
overall using descriptive statistics. 
7.3.5 Safety 
Safety data including single vital signs assessments, ECGs, and clinical laboratory results 
will be listed and summarised 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 summarised. 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 summarised and sorted by system organ class. Frequencies of subjects 
with study product use-emergent serious AEs will be likewise summarised. Frequencies of 
study product use-emergent AEs will be summarised by severity and relationship to study 
product. 
Changes in physical examinations (if any) will be described in the text of the final report. 
All concomitant medications recorded will be listed by subject. 
Incidence of device malfunction(s) will be tabulated. 
8. STUDY ADMINISTRATION 
8.1 
Ethics 
8.1.1 Institutional Review Board 
This protocol, ICFs, and any amendments to the protocol will be reviewed by a Research 
Ethics Committee (REC) prior to initiation. The study will not be initiated without the 
approval from the REC. Notice that the protocol and informed consent that have been 
reviewed and approved by the REC will be in the final study report. 
8.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol and in accordance with the 
relevant articles of the Declaration of Helsinki as adopted by the 18th World Medical 
Assembly in 1964 and as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), South 
Africa (1996) and Edinburgh (2000); Notes of Clarification added Washington (2002) Tokyo 
(2004), South Korea (2008), and Brazil (2013). 
8.1.3 Subject Information and Consent 
The purpose of the study, the procedures to be carried out, and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign, and 

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date an ICF summarising the discussion prior to Screening, and will be assured that they may 
withdraw from the study at any time without jeopardising their medical care. 
Subjects will be given a copy of their signed ICF. 
8.2 
Confidentiality 
All clinical sites and vendors will have signed confidentiality agreements with Celerion. By 
signing this protocol, the Investigator and Celerion staff will regard all information provided 
by the Sponsor and all information obtained during the course of the study as confidential. 
Neither the clinical site nor Celerion will supply to the Sponsor any subject names, initials, 
date of birth (except year), or other personal identifiers (HIPAA 2015). All such information 
appearing on any study document must be redacted before a copy of the document is 
supplied to the Sponsor. The photocopied government-issued ID to verify subject age will be 
kept separate from other source documentation and not provided to the Sponsor. Study 
findings stored on a computer will be stored in accordance with local data protection laws. 
As required, in the case of an event where medical expenses are the responsibility of the 
Sponsor, personal information i.e., full name, National Insurance Number details etc. may be 
released to the Sponsor. The subjects will be informed during the consenting process that 
representatives of the Sponsor, EC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available 
for inspection will be handled in the strictest confidence and in accordance with local data 
protection laws. 
8.3 
Termination of the Study 
The Investigator reserves the right to terminate the study in the interest of subject welfare. 
The Sponsor reserves the right to suspend or terminate the study at any time. 
8.4 
Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion relevant 
to the quality of this study. Designated personnel of Celerion 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.  
The Clinical Study Report will be audited by the QA department and the QA audit certificate 
will be included in the study report. 
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 are made prior to database lock. 

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8.5 
Direct Access to Source Data/Documents 
All clinical sites and vendors will ensure that the Sponsor, EC and inspection by domestic 
and foreign regulatory authorities will have direct access to all study-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing 
(ICH[E6][R2] 5.1.2 & 6.10). In the event that other study-related monitoring should be done 
by other parties, they will be required to sign a confidentiality agreement prior to any 
monitoring and auditing.  
8.5.1 Monitoring the Study 
The responsible study monitor or Sponsor’s designee will contact and visit the Investigator as 
necessary, and he/she will be allowed, upon request, to inspect and verify all records of the 
study (e.g., source document, ICFs, 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. 
The Investigator must notify the Sponsor (or designee) promptly of any inspections of the 
study or activities related to the study scheduled by regulatory authorities, allow the Sponsor 
(or designee) to be present, and promptly forward copies of inspection reports to the Sponsor 
(or designee).  
8.6 
Reporting for the Study 
8.6.1 Case Report Forms 
Celerion 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 Celerion and the Sponsor (e.g., compact disc, flash drive, secure file transfer 
protocol). This will be documented in the Data Management Plan (if applicable). 

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8.6.2 Data Coding 
AEs will be coded using MedDRA®. Concomitant medications will be coded using the 
World Health Organization Drug Dictionary. Each dictionary version will remain the same 
throughout the trial. Coding will be completed by qualified members of the Celerion staff. 
8.6.3 Report Format 
According to the ICH Harmonised Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the 
ICH M2 Expert Working Group), the final report will be written according to the 
ICH E3 Guideline (Structure and Content of Clinical Study Reports). 
8.6.4 Record Keeping 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by Celerion 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. 
8.7 
Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
information. 

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9. REFERENCES 
Food and Drug Administration:  Section 910 of the Federal Food, Drug, and Cosmetic Act - 
Application for Review of Certain Tobacco Products (May 2019). Available at:  
https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/section-910-federal-
food-drug-and-cosmetic-act-application-review-certain-tobacco-products. 
Hatsukami DK, Zhang Y, O’Connor RJ, Severson HH. Subjective responses to oral tobacco 
products: scale validation. Nicotine Tob Res. 2013;15(7):1259-64. 
U.S. Department of Health and Human Services. National Institutes of Health. HIPAA 
Privacy Rule. Information for Researchers. Guidance Regarding Methods for 
De-identification of Protected Health Information in Accordance with the Health Insurance 
Portability and Accountability Act (HIPAA) Privacy Rule (06Nov2015). Available at:  
https://www.hhs.gov/hipaa/for-professionals/privacy/special-topics/de-
identification/index.html.  
 

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10. APPENDICES 
Appendix 1. 
Demographics Questionnaire 
Appendix 2. 
Urge to Smoke Questionnaire 
Appendix 3. 
Product Evaluation Scale (PES) 
Appendix 4. 
Intent to Use Questionnaire 
 
 

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Appendix 1: Demographics Questionnaires 
Screening Demographics Questionnaire  
 
1. What is your date of birth? 
 
 _____________________ 
 
2. What is your sex? 
 
 Male 
 Female 
 
3. Which one of these groups would you say best describes your race? 
 
 White/Caucasian 
 Black/African American 
 Asian 
 Native Hawaiian or other Pacific Islander 
 American Indian or Alaska Native 
 Other (SPECIFY): _________________________________   
 
4. Are you Hispanic or Latino? 
 
 Yes 
 No 
 
 
 
 

CONFIDENTIAL 
CA35183 (NER01/0004) Version 3.0 Amendment 2 Protocol, 29 Oct 2021 
Page 61 
Appendix 3: Product Evaluation Scale (PES)  
(Hatsukami 2013) 
Please mark the number that best represents how using the product made you feel. 
 
1. Was it satisfying? 
2. Did it taste good? 
3. Did you enjoy the sensations in your mouth? 
4. Did it calm you down? 
5. Did it make you feel more awake? 
6. Did it make you feel less irritable? 
7. Did it help you concentrate? 
8. Did it reduce your hunger for food? 
9. Did it make you dizzy? 
10. Did it make you nauseous? 
11. Did it immediately relieve your craving for a cigarette? 
12. Did you enjoy it? 
13. Did it relieve withdrawal symptoms? 
14. Did it relieve the urge to smoke? 
15. Was it enough nicotine? 
16. Was it too much nicotine? 
17. Was it easy to use? 
18. Were there bothersome side effects? 
19. Were you comfortable using the product in public? 
20. Did you still have a craving for a cigarette after using the product? 
21. Are you concerned that you would become dependent on this product? 
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Scale: 1 = not at all, 2 = very little, 3 = a little, 4 = moderately, 5 = a lot, 6 = quite a lot, 
7 = extremely 
 
Four multi-item subscales will be derived from "Satisfaction" (items 1, 2, 3, and 12); 
"Psychological Reward" (items 4 through 8); "Aversion" (items 9, 10, 16, and 18); and 
"Relief" (items 11, 13, 14, 15, and reversed for item 20) and single items 17, 19, and 21 will 
be summarised.