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

A Randomised, Cross-Over, Nicotine Pharmacokinetic and 
Pharmacodynamic Study of Heated Tobacco and Heated Herbal Products 
Compared with Combustible Cigarettes 
 
 
NCT# NCT06093659 
 
 
 
 
Study Protocol - FINAL (v1.0): 07 Jul 2023  
 
 
 
 

 
Page 1 
A Randomised, Cross-Over, Nicotine Pharmacokinetic and Pharmacodynamic Study of 
Heated Tobacco and Heated Herbal Products Compared with Combustible Cigarettes 
 
 
 
Sponsor Project No.: NER 01/005 
 
Celerion Project No.: CA41162 
 
 
Protocol (v1.0): 07 Jul 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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CA41162 (NER 01/005) Protocol Version 1.0, 07 Jul 2023 
Page 2 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
07 Jul 2023 
Ian Fearon 
 
Final Protocol v1.0 
 

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CA41162 (NER 01/005) Protocol Version 1.0, 07 Jul 2023 
Page 3 
SPONSOR SIGNATURE PAGE 
 
A Randomised, Cross-Over, Nicotine Pharmacokinetic and Pharmacodynamic Study of 
Heated Tobacco and Heated Herbal Products Compared with Combustible Cigarettes  
 
 
 
 
Sponsor 
Representatives: 
Thomas Nahde 
Global Head of Harm Reduction and Engagement 
Imperial Brands PLC 
121 Winterstoke Road 
Bristol 
BS3 2LL 
United Kingdom 
Tel: +44 (0) 117 3322447 
 
Email: thomas.nahde@reemtsma.de 
 
 
 
 
 
 
 
 
 
__________________________________ 
_________ 
Signature 
Date 
 
 
 
 
 
 
 
Alvaro-Flavio Marinas Lacasta 
Scientific Officer 
Imperial Brands PLC 
121 Winterstoke Road 
Bristol 
BS3 2LL 
United Kingdom 
Tel: +44 (0) 117 3322447 
 
 
Email: alvaro-
flavio.marinaslacasta@uk.imptob.com 
 
 
 
 
 
 
 
 
 
__________________________________ 
_________ 
Signature 
Date 
 
 
 
 
Álvaro-Flavio 
Marinas Lacasta
Digitally signed by Álvaro-
Flavio Marinas Lacasta 
Date: 2023.07.07 12:41:35 
+01'00'

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CA41162 (NER 01/005) Protocol Version 1.0, 07 Jul 2023 
Page 4 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
A Randomised, Cross-Over, Nicotine Pharmacokinetic and Pharmacodynamic Study of 
Heated Tobacco and Heated Herbal Products Compared with Combustible Cigarettes  
 
 
 
 
 
 
Clinical Site and Principal Investigator: 
 
 
 
Celerion 
 
22-24 Lisburn Road 
Belfast, Northern Ireland, BT9 6AD 
Tel.: +44 (0) 28 90 554040 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
__________________________________ 
_________ 
 
Signature 
Date 
 
 
 
 
 
 
 __________________________________ 
 
 
Printed Name 
 
 
 
 
 
 
 
 
 
 
 

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CA41162 (NER 01/005) Protocol Version 1.0, 07 Jul 2023 
Page 5 
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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CA41162 (NER 01/005) Protocol Version 1.0, 07 Jul 2023 
Page 6 
SYNOPSIS 
Study Objectives 
Primary: 
1. To  evaluate  and  compare  the  maximum  plasma  nicotine  concentration 
(Cmax) and the area under the plasma nicotine concentration-time curve at 
the last time point measured (AUCt) following controlled use of each Heated 
Tobacco Product, Heated Herbal Product, or cigarette comparator. 
Secondary: 
1. To  evaluate  other  pharmacokinetic  (PK)  parameters  of  nicotine  after  the 
controlled use of each Heated Tobacco Product, Heated Herbal Product, or 
cigarette comparator. 
2. To evaluate the change in smoking urges observed after the controlled use 
of  each  Heated  Tobacco  Product,  Heated  Herbal  Product,  or  cigarette 
comparator.  
3. To evaluate product perception and preference using 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 
during ad libitum use sessions. 
Study Design 
This will be a randomised, cross-over, open-label, confinement study conducted 
in 25 adult male or female smokers of combustible cigarettes (CCs). The study 
will  investigate  combustible  cigarettes,  heated tobacco  products  (HTPs),  and 
Heated  Herbal  Products  (HHPs),  in  a  cross-over  design,  incorporating  PK 
evaluation, subjective effects assessments, usage behaviour, and puff 
topography.  The study will also incorporate a product use safety evaluation. 
Subjects will perform a Screening Visit and 1 Study Visit, including a 6-day 
confinement period and finally a follow-up telephone call approximately 
7 days after the final study product use. 
Visit 1 (Screening) 
Screening procedures will be performed within 28 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  (haematology,  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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CA41162 (NER 01/005) Protocol Version 1.0, 07 Jul 2023 
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Visit 2 (In-clinic period, Day -1 to Day 6) 
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 6 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 HTPs and HHPs will be used. Subjects will have the 
opportunity to see the products/devices and packaging and will participate in a 
Product  Trial  in  which  they  will  take  5  puffs  on  a  single  HT  stick  (flavour 
chosen  by  subject)  and  5  puffs  on  a  single  HHP  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 Days 1 through 5, after pre-use assessments and confirmation 
of  eligibility,  subjects  will  use  their  randomly-assigned  study  product  under 
controlled conditions by completely using a single unit (one stick, 
approximately  10  puffs)  of  the  assigned  study  product,  with  puffs  taken  at 
30-second  intervals  and  of  3-second  duration.  PK  samples  will  be  collected 
within 5 minutes pre-study product use (timepoint ‘0’) 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 5, following the 4-hour PK blood collection, subjects will 
start a 4-hour ad libitum product use session (no  limits on cigarette, HTP or 
HHP  consumption)  with  the  same  study  product  used  during  the  morning 
controlled use session. 
On Days 1 through 5, puff topography will be performed over the last 2-hour 
period during 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 SPA-M topography device will  be reset at 60 
minutes in order to collect 2 hours of data.  
The ad libitum product use session on Days 1 through 5 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 on Days 1 to 4, subjects will be allowed 

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CA41162 (NER 01/005) Protocol Version 1.0, 07 Jul 2023 
Page 8 
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 HTP/HHP 
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 5, following completion of study assessments, subjects will be allowed 
to smoke their own cigarettes and will leave the CRU after completing all final 
check out requirements.   
Visit 3 (Follow-up telephone 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-five 
(25) subjects will be enrolled. 
Duration of Study 
Conduct 
Subjects will participate in the study for up to 34 days, including an up to 
28-day screening period. 
Study Products and 
Administration 
Details of the study products are as follows: 
Product 
Designation 
Product 
Type 
Product Name 
A 
HTP 
Pulze 2.0 device with iD Balanced Blue sticks 
B 
HTP 
Pulze 2.0 device with iD Rich Bronze sticks 
C 
HHP 
Pulze 2.0 device with iSenzia Forest Berry sticks* 
D 
HHP 
Pulze 2.0 device with iSenzia Summer Watermelon 
sticks** 
E 
Cigarette Subject’s own brand combustible cigarettes 
(OBCC) 
HTP, heated tobacco product (Pulze 2.0 device with iD tobacco stick).  HHP, heated herbal 
product (Pulze 2.0 device with iSenzia herbal stick).  
*The product will be supplied with plain packaging under the flavour name: Blueberry, as the 
iSenzia Forest Berry packaging is not available. 
**The product will be supplied with plain packaging under the flavour name: Hami Melon, as 
the iSenzia Summer Watermelon packaging is not available. 
 

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CA41162 (NER 01/005) Protocol Version 1.0, 07 Jul 2023 
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Endpoints, Key 
Assessments, and 
Summarisation 
Pharmacokinetics: 
For each morning product use session on Days 1 through 5, plasma nicotine PK 
parameters (AUCinf,  AUC0-90, AUC0-240, AUCt, C max, C last, T max, T 1/2) 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 analogue 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 (E max, TE max, 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 HTP/HHP sticks used and the 
number of OBCCs smoked (Days -1 through Day 5) 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, haematology, and urinalysis).  
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.  

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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. 
 

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CA41162 (NER 01/005) Protocol 
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STUDY EVENTS FLOW CHART 
Table 1. Study Events 
EVENTS/ASSESSMENTS 
Days → 
Scr a 
-1  
1 through 5 
Minutes → 
 
 
0 
2 
4 
6 
8 
10 
15 
30 
45 
60 
120 
240 
3
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-In b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review of I/E Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics 
X 
X c 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco/Nicotine Product Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Usual Brand Documentation 
X 
X c 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
Full Physical Examination d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight, Height, and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chem e, Haematology, Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBsAg, and HCV Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (Females) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (Postmenopausal Females 
Only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug and Urine/Breath Alcohol 
Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (RR and T) 
X 
X 
X g 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP and HR) 
X 
X 
X g 
 
 
 
 
 
 
 
 
 
 
 
Exhaled CO 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Cotinine Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Concomitant Medications 
X 
X 
Review of AEs 
X 
X 
Product Use/Study Assessments 
Randomisation 
 
X h 
 
 
 
 
 
 
 
 
 
 
 
 
Product Trial 
 
X i 
 
 
 
 
 
 
 
 
IP Use 
 
  
X j 
 
 
 
 
 
 
 
X

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CA41162 (NER 01/005) Protocol 
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EVENTS/ASSESSMENTS 
Days → 
Scr a 
-1  
1 through 5 
Minutes → 
 
 
0 
2 
4 
6 
8 
10 
15 
30 
45 
60 
120 
240 
3
Product Use Behaviour  
 
X l 
X m 
 
 
 
 
 
 
 
X
Blood Collection for Nicotine PK  
 
 
X n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intent to Use Questionnaire 
 
X o 
 
 
 
 
 
 
 
 
 
 
 
X 
Urge to Smoke Questionnaire  
 
X o 
X p 
 
X q 
 
X q 
 
X q 
 
X q 
X q 
X q 
X q 
Product Evaluation Scale Questionnaire 
 
X o 
 
 
 
 
 
 
 
 
 
 
 
X 
Puff Topography 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Procedures 
Tobacco Cessation Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaire Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the CRU b 
 
X 
Phone Call s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: 
Screening; within 28 days prior to study procedures on Day -1. 
b: Subjects will be admitted to the CRU on Day -1, at the time indicated by the CRU, and will remain confined until completion of s
Subjects may be admitted earlier than Day -1 for COVID-19 testing not related to study protocol as per CRU requirements. Check
identification, luggage check, questionnaire on study prohibitions, and subject orientation. 
c: 
To be updated at Check-in as necessary. 
d: Symptom-driven physical examinations may be performed at other times, at the Investigator or designee’s discretion. 
e: 
Samples for serum chemistry will be obtained following a fast of at least 8 hours, however, in case of dropouts or rechecks, subjec
8 hours prior to the serum chemistry sample being taken.  For the samples collected at EOS, an 8-hour fast is not required. 
f: 
To be performed prior to discharge or prior to early termination from the study. 
g: To be performed prior to the start of each morning product use session. 
h: On Day 1, subjects will be randomised to 1 of 5 sequences. 
i: 
Subjects will participate in a Product Trial in which they will take 5 puffs from a single HTP stick and 5 puffs from a single HHP 
subject for each type of stick). 
j: 
Subjects will use the assigned study product under controlled conditions by completely use a single unit of the assigned study pro
30-second intervals and of 3-second duration, with Hour 0 as the start time of product use. 
k: On Days 1 through 5, subjects will use their randomised product (same product as the morning session) ad libitum for 4 hours star
blood draw. 

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CA41162 (NER 01/005) Protocol 
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l: 
The number of cigarettes smoked, as appropriate, will be documented from Check-in until beginning of smoking abstinence (Day
prior to the start of morning controlled product use on Day 1; Days 1 through 5, 8 hours post morning controlled use session IP st
prior to the start of morning controlled product use scheduled on the following day). The number of cigarettes smoked and the num
be documented during each 4-hour ad libitum product use session (Days 1 through 5). 
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. Subjects will receive an explanation of how the questionnaires will be admin
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 to the scheduled PK blood draws. 
r: 
On Days 1 through 5, puff topography measurements will be performed for a 2 hour period during last 2 hours of the 4-hour ad lib
The SPA-M device will need to be reset at 60 minutes as the device can only collect data for approximately 1 hour.). 
s: 
The CRU will attempt to contact all subjects who used at least one study product (including subjects who terminate the study early
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 monoxi
research unit, ECG = Electrocardiogram, EOS = End-of-study, FSH = Follicle-stimulating hormone, FU = Follow-up, HBsAg = Hepa
HCV = Hepatitis C virus, HIV = Human immunodeficiency virus, HR = Heart rate, HT = Heated tobacco, I/E = Inclusion/exclusion, I
product, PK = Pharmacokinetic(s), RR = Respiratory rate, Scr = Screening, T = Temperature, OBCC = Own brand combustible cigare

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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 
°C 
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 
°F 
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 
HHP 
Heated herbal product 
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 
Millilitre 
mmHg 
Millimetre 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 analogue 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 28-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 enrolment 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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Page 18 
TABLE OF CONTENTS 
PROTOCOL REVISION HISTORY ..................................................................................... 2  
SPONSOR SIGNATURE PAGE ........................................................................................... 3  
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ........................................................... 4  
STUDY CONTACTS ............................................................................................................ 5  
SYNOPSIS............................................................................................................................ 6
 
STUDY EVENTS FLOW CHART ..................................................................................... 11  
ABBREVIATIONS ............................................................................................................. 14  
DEFINITION OF TERMS .................................................................................................. 17
 
TABLE OF CONTENTS .................................................................................................... 18
 
1. 
INTRODUCTION AND BACKGROUND .............................................................. 22  
1.1 
Background .................................................................................................. 22  
1.2 
Pulze 2.0 Device and iD tobacco/iSenzia Herbal Sticks Previous 
Clinical Experience ...................................................................................... 22  
1.3 
Study Purpose .............................................................................................. 23  
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................ 23  
2.1 
Study Objectives .......................................................................................... 23  
2.2 
Study Endpoints ........................................................................................... 24  
3. 
SUMMARY OF STUDY DESIGN.......................................................................... 25  
3.1 
Design and Procedures ................................................................................. 25  
3.2 
Confinement and Follow-Up ........................................................................ 30  
3.3 
End of Study Definition................................................................................ 30  
4. 
STUDY POPULATION .......................................................................................... 30  
4.1 
Inclusion Criteria .......................................................................................... 30  
4.2 
Exclusion Criteria......................................................................................... 31  
4.3 
Study Restrictions ........................................................................................ 33  
4.3.1 
Food and Beverages ....................................................................... 33  
4.3.2 
Medications ................................................................................... 34  
4.3.3 
Meals/Dietary Considerations ........................................................ 34  
4.3.4 
Activity.......................................................................................... 35  
4.3.5 
Tobacco Use/Considerations .......................................................... 35  
4.4 
Subject Early Discontinuation or Withdrawal ............................................... 35  
4.5 
Subject Randomisation ................................................................................. 36  
5. 
STUDY PRODUCTS/MATERIALS ....................................................................... 36  
5.1 
Description of Study Products ...................................................................... 36  

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5.1.1 
Own Brand Combustible Cigarettes ............................................... 36  
5.1.2 
Pulze 2.0 Device ............................................................................ 36  
5.2 
Study Product Accountability and Dispensing .............................................. 38  
6. 
STUDY PROCEDURES ......................................................................................... 40  
6.1 
Screening ..................................................................................................... 40
 
6.1.1 
Informed Consent .......................................................................... 40  
6.1.2 
Medical History/Demographic Data/Record of Concomitant 
Medication..................................................................................... 40  
6.1.3 
Tobacco/Nicotine Product Use History .......................................... 40  
6.1.4 
Exhaled Carbon Monoxide............................................................. 40  
6.2 
Check-in and Confinement ........................................................................... 41  
6.2.1 
Baseline Assessments (Day -1) ...................................................... 41  
6.3 
Product Use (Days 1 Through 5) .................................................................. 41  
6.4 
Study Assessments ....................................................................................... 42  
6.4.1 
Nicotine Pharmacokinetics ............................................................. 42  
6.4.1.1 
Future Research ......................................................... 43  
6.4.2 
Subjective Effects Questionnaires .................................................. 43  
6.4.3 
Puff Topography ............................................................................ 43  
6.4.4 
Safety Assessments ........................................................................ 44  
6.4.4.1 
Physical Examination ................................................ 44  
6.4.4.2 
Body Weight, Height, and BMI ................................. 44 
6.4.4.3 
Electrocardiogram ..................................................... 44  
6.4.4.4 
Vital Signs ................................................................. 44  
6.4.4.5 
Clinical Laboratory .................................................... 44  
6.4.5 
Adverse Events .............................................................................. 45  
6.4.5.1 
Monitoring ................................................................ 45  
6.4.5.2 
Reporting ................................................................... 46  
6.4.5.3 
Serious Adverse Events ............................................. 46  
6.4.5.4 
Suspected Unexpected Serious Adverse 
Reactions ................................................................... 46  
6.4.5.5 
Pregnancy .................................................................. 47  
6.4.5.6 
Smoking Cessation Information ................................. 47 
7. 
DATA ANALYSIS ................................................................................................. 47
 
7.1 
Sample Size Estimation ................................................................................ 47  

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7.2 
Analysis Populations .................................................................................... 47  
7.3 
Data Analysis, Summarisation, and Statistical Methods ................................ 48 
7.3.1 
Nicotine Pharmacokinetic Analysis ................................................ 48 
7.3.2 
Subjective Effects .......................................................................... 50  
7.3.2.1 
Urge to Smoke Parameters ......................................... 50 
7.3.2.2 
Product Evaluation Scale ........................................... 50  
7.3.2.3 
Intent to Use .............................................................. 50  
7.3.3 
Puff Topography ............................................................................ 50  
7.3.4 
Product Use Behaviour .................................................................. 51  
7.3.5 
Safety ............................................................................................ 51  
8. 
STUDY ADMINISTRATION ................................................................................. 52  
8.1 
Ethics ........................................................................................................... 52
 
8.1.1 
Institutional Review Board............................................................. 52  
8.1.2 
Ethical Conduct of the Study.......................................................... 52  
8.1.3 
Subject Information and Consent ................................................... 52  
8.2 
Confidentiality ............................................................................................. 52  
8.3 
Termination of the Study .............................................................................. 53  
8.4 
Data Quality Assurance ................................................................................ 53  
8.5 
Direct Access to Source Data/Documents ..................................................... 53  
8.5.1 
Monitoring the Study ..................................................................... 53  
8.6 
Reporting for the Study ................................................................................ 54  
8.6.1 
Case Report Forms ........................................................................ 54  
8.6.2 
Data Coding ................................................................................... 54  
8.6.3 
Report Format ................................................................................ 54  
8.6.4 
Record Keeping ............................................................................. 54  
8.7 
Publication Policy ........................................................................................ 54  
9. 
REFERENCES ........................................................................................................ 56  
10. 
APPENDICES ......................................................................................................... 57  
 
 
List of Appendices 
Appendix 1: Demographics Questionnaires ...................................................................... 58  
Appendix 2: Urge to Smoke Questionnaire ....................................................................... 59  
Appendix 3: Product Evaluation Scale (PES) .................................................................... 60  

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Appendix 4: Intent to Use Questionnaire .......................................................................... 61  
 
 
List of Tables 
Table 1. Study Events .......................................................................................................... 11  
 
 
List of Figures 
Figure 1. Overall Study Design............................................................................................ 29  
Figure 2. Pulze 2.0 Device Diagram .................................................................................... 37  
Figure 3. (A) iD HTP Stick and (B) iSenzia HHP Stick Assembly ....................................... 38 
 

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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 (NGPs). 
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 combustible 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 smoking 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  aims  to  increasingly  transition  adult  smokers,  who  would  otherwise 
continue to smoke, to NGPs that are potentially less harmful than CC. Heated tobacco products 
(HTPs) 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. HTPs also offer greater optionality in parts of the world where vaping is 
not permitted or where smokers prefer HTPs. In addition, heated herbal products (HHPs) are 
being developed which, similar to HTPs, are electrically heated to produce a 
nicotine-containing aerosol.  HHP consumables are similar in construction to heated tobacco 
products, but instead of containing tobacco leaf they are composed of a herbal, tobacco-free 
substrate. Imperial Brands PLC have therefore added the Pulze heating  device and iD  and 
iSenzia  consumables (sticks) to a growing repertoire of NGPs. 
1.2 
Pulze 2.0 Device and iD tobacco/iSenzia Herbal Sticks Previous Clinical 
Experience 
No clinical studies have been conducted for the Pulze HTPs (Pulze 2.0 device and iD tobacco 
sticks).  In addition, no clinical studies have been conducted for the iSenzia HHPs (Pulze 2.0 
device and iSenzia herbal sticks) to be used in this study.  A previous study, similar in design 
to the study in this protocol, has been conducted with the Pulze 1.0 device with iD tobacco 
sticks.  However, that study used an earlier version (1.0) of the Pulze device compared with 

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the Pulze 2.0 device to be used in this study.  In that study, nicotine delivery from the Pulze 
1.0 device and iD tobacco sticks was lower than that from combustible cigarettes. 
1.3 
Study Purpose 
This study is being conducted to evaluate the overall performance of Imperial Brands’ Pulze 
2.0  heating  device  when  used  with  iD  stick  HTP  consumables  or  with  iSenzia  stick  HHP 
consumables  compared  with  CC.    The  study  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  with  subjects’  own  brand  combustible  cigarettes 
(OBCC).  The  results  of  this  study  are  intended  to  contribute  to  an  awareness  of  the  harm 
reduction potential of the Pulze device when used with iD (HTP) and iSenzia (HHP) sticks, 
and the data may be included in future premarket tobacco application submissions to the Food 
and Drug Administration Center for Tobacco Products in the United States based on Section 
910 of the Federal Food, Drug, and Cosmetic Act - Application for Review of Certain Tobacco 
Products (FDA 2019).   
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
Primary 
1. To evaluate and compare the maximum plasma nicotine concentration (C max) and the area 
under the plasma nicotine concentration-time curve at the last time point measured (AUCt) 
following  controlled  use  of  each  Heated  Tobacco  Product,  Heated  Herbal  Product,  or 
cigarette comparator. 
 
Secondary 
1. To evaluate other pharmacokinetic (PK) parameters of nicotine after the controlled use of 
each Heated Tobacco Product, Heated Herbal Product, or cigarette comparator. 
2. To evaluate the change in smoking urges observed after the controlled use of each Heated 
Tobacco Product, Heated Herbal Product, or cigarette comparator.  
3. To evaluate product perception and preference using 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 following ad libitum product use sessions. 

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2.2 
Study Endpoints 
Pharmacokinetics: 
For each morning product use session on Days 1 through 5, 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 analogue 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. Since the device collects 
topography data for approximately 60 minutes, it will need to reset at 60 minutes in order to 
collect 2 hours of topography data. 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 HTP/HHP sticks used and the number of OBCCs 
smoked (Days -1 through Day 5), will be summarised using descriptive statistics.  
Incidence of device malfunction(s) will also be tabulated. 

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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.  
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 25 adult 
male or female smokers of combustible cigarettes (CCs). The study will investigate 
combustible cigarettes, heated tobacco products (HTPs), and Heated Herbal Products (HHPs), 
in  a  cross-over  design,  incorporating  PK  evaluation,  subjective  effects  assessments,  usage 
behaviour,  and  puff  topography.    The  study  will  also  incorporate  a  product  use  safety 
evaluation. 
Subjects  will  perform  a  Screening  Visit  and  1  Study  Visit,  including  a  6-day  confinement 
period and finally a follow-up telephone call approximately 7 days after the final study product 
use. 
Visit 1 (Screening) 
Screening procedures will be performed within 28 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  (haematology,  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. 
Visit 2 (In-clinic period, Day -1 to Day 5) 
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 5 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 HTPs and 

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HHPs  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 take 5 puffs on a single one 
HTP stick (flavour chosen by subject) and 5 puffs on a single HHP 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 Days 1 through 5, after pre-use assessments and confirmation of eligibility, 
subjects  will  use  their  randomly-assigned  study  product  under  controlled  conditions  by 
completely  using  a  single  unit  (one  stick,  approximately  10  puffs)  of  the  assigned  study 
product, with puffs taken at 30-second intervals and of 3-second duration. PK samples will be 
collected within 5 minutes pre-study product use (timepoint ‘0’) 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 5, following the 4-hour PK blood collection, subjects will start a 4-hour ad 
libitum product use session (no limits on cigarette, HTP or HHP consumption) with the same 
study product used during the morning controlled use session. 
On Days 1 through 5, puff topography will be performed over the last 2-hour period during 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 SPA-M topography device 
will be reset at 60 minutes in order to collect 2 hours of data.  
The ad libitum product use session on Days 1 through 5 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 HTP/HHP 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 5, following completion of study assessments, subjects will be allowed to smoke their 
own cigarettes and will leave the CRU after completing all final check out requirements.   
Visit 3 (Follow-up telephone 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.  

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Subjects will not be forced to use any tobacco/nicotine products at any time during the study. 
The overall study design is depicted in  
 

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Figure 1. 
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. 
 
 
 

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Figure 1. Overall Study Design 
 
Screening a 
Check-in procedures b 
PK based on Randomiza9on Schedule C 
Follow-up d 
Study Days 
-1 
1 
2 
3 
4 
  
Check-In 
X 
  
  
  
  
Product Trial 
X 
  
  
  
  
Randomiza9on 
X 
 
  
  
  
PK Blood Sampling 
 
X 
X 
X 
X 
Subjec9ve Ques9onnaires 
X 
X 
X 
X 
X 
Pu' Topography 
  
  
  
X 
X 
a: 
To be performed within 28 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 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 Products: 
Product 
Designation Product Type 
Study Product Name 
A 
HTP 
Pulze 2.0 device with iD Balanced Blue stick 
B 
HTP 
Pulze 2.0 device with iD Rich Bronze stick 
C 
HHP 
Pulze 2.0 device with iSenzia Forest Berry stick* 
D 
HHP 
Pulze 2.0 device with iSenzia Summer Watermelon 
stick** 
E 
Cigarette 
Subject’s own brand combustible cigarette (OBCC) 
HTP, heated tobacco product (Pulze 2.0 device with iD tobacco stick).  HHP, heated herbal product (Pulze 2.0 
device with iSenzia herbal stick).  
*The product will be supplied with plain packaging under the flavour name: Blueberry, as the iSenzia Forest 
Berry packaging is not available. 
**The product will be supplied with plain packaging under the flavour name: Hami Melon, as the iSenzia 
Summer Watermelon packaging is not available. 
 
 

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3.2 
Confinement and Follow-Up 
Subjects will be housed at the CRU on Day -1, at the time indicated by the CRU, until after 
completion of all study procedures on Day 5. Subjects may be admitted earlier than Day -1 for 
COVID-19  testing  not  related  to  study  protocol  as  per  CRU  requirements.  At  all  times,  a 
subject may be required to remain at the CRU for longer at the discretion of the Investigator 
or designee (i.e., for ongoing AE management). 
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. 
3.3 
End of Study Definition 
The end of study is defined as the date of the last scheduled study procedure as outlined in the 
Study Events Flow Chart (Table 1). 
4. STUDY POPULATION 
Subjects selected for this study will be identified via standard recruitment methods. 
4.1 
Inclusion Criteria 
Subjects must fulfil all of the following inclusion criteria to be eligible for participation in the 
study: 
1. Healthy, adult, male or female, 21 to 65 years of age, inclusive, at Screening. 
2. Reports smoking an average of at least 10 manufactured combustible (menthol or 
non-menthol) CPD for at least 12 months prior to Screening. Brief periods of non-smoking 
(e.g., up to ~7 consecutive days due to illness, participation in a study where smoking was 
prohibited)  within  60 days  prior  to  Check-in  will  be  permitted  at  the  discretion  of  the 
Investigator. 
3. Has a positive urine cotinine (≥ 500 ng/mL) at Screening. 
4. Has an exhaled CO > 10 ppm at Screening. 
5. A female subject of childbearing potential must have been using 1 of the following forms 
of contraception and agree to continue using it through completion of the study and for at 
least 28 days after the final product use: 
• hormonal (e.g., oral, vaginal ring, transdermal patch, implant, or injection) consistently 
for at least 3 months prior to Check-in; 
• double  barrier  method  (e.g.,  condom  with  spermicide,  diaphragm  with  spermicide) 
consistently for at least 14 days prior to Check-in; 
• intrauterine device for at least 3 months prior to Check-in; 

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• a partner who has been vasectomised for at least 4 months prior to Check-in; 
• 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: 
• hysteroscopic sterilisation; 
• bilateral tubal ligation or bilateral salpingectomy; 
• hysterectomy; 
• 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 
study HTPs/HHPs. 
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 
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. 

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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. 
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. 

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20. Use  of  prescription  or over-the-counter  bronchodilator  medication  (e.g.,  inhaled  or oral 
β-agonists) for treatment of any illness within 12 months prior to Check-in and throughout 
the study. 
21. Is  allergic  to or  cannot tolerate  any  of the  flavouring  agents  (tobacco,  berry  and  melon 
flavours) contained in the study iD or iSenzia sticks. 
22. 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. 
23. Has  used  any  prescription  smoking  cessation  treatments,  including,  but  not  limited  to, 
varenicline (Chantix®) or bupropion (Zyban®) within 3 months prior to Check-in. 
24. Is a self-reported puffer (i.e., adult smoker who draws smoke from the cigarette into the 
mouth and throat but does not inhale). 
25. 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. 
26. 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. 
27. Donation of bone marrow within the last 6 months prior to Check-in. 
28. Has participated in a previous clinical study for an investigational drug, device, biologic, 
or tobacco product within 90 days prior to Check-in. 
29. 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. 
30. Is  or  has  a  first-degree  relative  (i.e.,  parent,  spouse,  sibling,  child)  who  is  a  current 
employee of the CRU. 
31. In the opinion of the Investigator, the subject should not participate in this study. 
4.3 
Study Restrictions 
4.3.1 Food and Beverages 
Foods and beverages containing the following substances should not be consumed as indicated 
below: 
• Alcohol  should  be  avoided  for  48  hours  prior  to  Screening  and  Check-in  to  avoid 
exclusion for a positive alcohol test and throughout the study. 
• Foods containing poppy seeds should be avoided for 48 hours prior to Screening and 

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Check-in to avoid exclusion for a positive urine drug test and throughout the study. 
• Food and beverages containing grapefruit for 14 days prior to Check-in and throughout 
the study. 
• 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. 
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  through  5.  Lunch  will  be  served  at 
approximately the same time on Days 1 through 5, 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 
through  5.  An  exception  to  the  water  restriction  can  be  made  if  a  subject  starts  coughing 
uncontrollably while smoking or using the study products. 

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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  5,  subjects  will  be 
allowed to smoke 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: 
• AE 
• Lost to follow-up 
• Non-compliance with study procedures 
• Protocol violation 
• Study terminated by Sponsor or other regulatory authorities 
• Withdrawal of consent 
• Investigator’s discretion, including a severe laboratory abnormality or other medical 
condition that indicates to the Investigator that continued participation is not in the best 
interest of the subject 
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. 
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. 

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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 ABECD, BCADE, CDBEA, DECAB, 
and EADBC. 5 subjects will be randomly assigned to each sequence.  
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 E.  
The following study products will be used in this study: 
Product 
Designation Product Type 
Study Product Name 
A 
HTP 
Pulze 2.0 device with iD Balanced Blue stick 
B 
HTP 
Pulze 2.0 device with iD Rich Bronze stick 
C 
HHP 
Pulze 2.0 device with iSenzia Forest Berry stick* 
D 
HHP 
Pulze 2.0 device with iSenzia Summer Watermelon 
stick** 
E 
Cigarette 
Subject’s own brand combustible cigarette (OBCC) 
HTP, heated tobacco product (Pulze 2.0 device with iD tobacco stick).  HHP, heated herbal product (Pulze 
2.0 device with iSenzia herbal stick).  
*The product will be supplied with plain packaging under the flavour name: Blueberry, as the iSenzia Forest 
Berry packaging is not available. 
**The product will be supplied with plain packaging under the flavour name: Hami Melon, as the iSenzia 
Summer Watermelon packaging is not available. 
 
5.1.1 Own Brand Combustible Cigarettes 
Subjects will be required to bring with them to the CRU a sufficient supply (i.e., 6-day supply 
in unopened packs) of their OBCCs for personal use throughout confinement. 
5.1.2 Pulze 2.0 Device 
The Pulze device 2.0 works by the user inserting a specially designed consumable (iD tobacco 

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stick  or  iSenzia  herbal  stick)  into  the  handheld  device  which  contains  an  electronically 
controlled  heater (Figure 2). The handheld device heats the tobacco using an electronically 
controlled heating rod. The rod can be set to 2 temperatures: ‘mild’ mode (315°C) or ‘Intense’ 
mode (345°C). The handheld device supplies heat to the tobacco/herbal substrate portion of 
the respective stick (iD/ iSenzia) using the heating rod for 5 minutes. The heating device must 
be recharged after 25 consecutive uses. 
Both iD and iSenzia are designed in a manner that prevents them from being lit and combusted 
like a CC (Figure 3). 
Figure 2. Pulze 2.0 Device Diagram 
 
 
 

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Figure 3. (A) iD HTP Stick and (B) iSenzia HHP Stick Assembly 
 
(A) 
(B) 
 
5.2 
Study Product Accountability and Dispensing 
All Pulze 2.0 devices,  iD tobacco sticks, and  iSenzia  herbal sticks, will  be provided  by the 
Sponsor. The CRU staff will coordinate shipping of products and devices from the Sponsor. 
The staff will document the date each shipment was received and recorded in the inventory 
records. The CRU staff will document and reconcile the total number of products shipped to 
the CRU, the total  number of products dispensed during the study, and the total number of 
products remaining at the end of clinical conduct. Subjects will bring a 6-day supply (unopened 
packs) of their OBCCs  for personal use  at designated times throughout confinement  in the 

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CRU. 
For each day of HTP/HHP product use, subjects will be provided with a new/unused device to 
be used for the morning controlled product use and ad libitum product use sessions. A fresh 
stick will be provided at the start of the morning controlled product use session and at the start 
of puff topography. 
All products will be stored in a locked, limited-access area at the CRU and kept at controlled 
room  temperature  (defined  as  20-25°C  [68-77°F],  with  excursions  permitted  to  15-30°C 
[59-86°F]). Humidity is recorded but not controlled. 
Study products for dispensing (including OBCC) to subjects will be prepared by the study staff 
according to instructions provided by the Sponsor. Individual study product dispensing records 
will be maintained by the CRU staff for each subject. Care should be taken when repackaging 
the  study  products  for  use  at the  CRU  to  avoid  exposure  to  air  and  moisture to the  extent 
possible. The pharmacy will maintain records of the number of cigarettes dispensed for each 
subject. 
The study staff will document the start time and stop time of each product use session. The 
number  of  HTP/HHP  sticks  used  and  cigarettes  smoked  will  be  documented  during  each 
ad libitum product use session on Days 1 through 5. The number of cigarettes smoked will be 
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  4  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 Pulze 2.0 devices and iD/iSenzia 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. 
The Pulze 2.0 device has two power settings: ‘intense’ mode (345°C heating rod temperature) 
and  ‘mild’  (315°C  heating  rod  temperature).  Subjects  should  use  the  device  set  on  the 
‘intense’ mode during both the defined use and ad libitum use sessions.  
Immediately prior to use of the HHPs (Pulze 2.0 device with iSenzia herbal sticks), the 
filter section of the iSenzia sticks must be pressed firmly between the fingers in order to 
crush the capsule in the filter which contains the Forest Berry and Summer Watermelon 
flavours, according to the product use instructions.  This applies to both the defined use 
and ad libitum use sessions, and also to the product trial session on Day -1.   

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6. STUDY PROCEDURES 
6.1 
Screening 
Potential subjects will undergo Screening procedures to ensure that they meet the requirements 
for inclusion in the study within 28 days prior to study procedures on Day -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]),  National 
Insurance number, race, ethnicity, address, and phone number will be recorded at Screening 
for each subject. 
Any concomitant medications taken from 30 days prior to Check-in through discharge will be 
recorded in the CRF and source document. 
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 
colour 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. 

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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 Pulze 2.0 devices will be used. Subjects will have the 
opportunity to see the products/devices and packaging and will participate in a Product Trial 
in which they will use the Pulze 2.0 device by taking 5 puffs from an iD tobacco stick and 5 
puffs from an iSenzia herbal stick with the flavour of their choice. The iD/iSenzia stick flavours 
will be recorded; however, no assessments will be made. The purpose of the Product Trial is 
to familiarise subjects to the Pulze device and iD/iSenzia sticks prior to study 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, 4 and 5.  
Subjects will  be confined  from Check-in on Day -1 through completion of scheduled study 
events on Day 5. 
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 
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 5) 
On Days 1 through 5, 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 by completely using a single unit (one stick, approximately 10 puffs) of the assigned 

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study product, with puffs taken at 30-second intervals and of 3-seconds duration. Following 
the 4-hour PK blood collection, subjects will start a 4-hour ad libitum product use session (no 
limits on cigarette or HTP/HHP consumption) with the same study product used during the 
morning controlled use session. 
Each subject will be provided with a new/unused Pulze 2.0 device for each day of HTP/HHP 
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 
HTP/HHP stick (based on randomisation sequence) or OBCC on each day. The clinic staff will 
document the time each product is dispensed. The Pulze 2.0 device should be used on the 
‘Intense’ 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 non-scheduled 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 through 5, 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:  ± 1 minute 
for samples collected from 3-60 minutes, and ± 3 minutes for all other samples including the 
baseline (pre-study product use) sample.   
PK blood samples will be collected by direct venepuncture or through an intravenous catheter 
port as determined by the clinical staff.  
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 300 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 
labelled, and then stored at -20°C (± 10°C) or below (within 120 minutes from collection) until 
analysis. 
Samples will be analysed 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 be completed by a non-tobacco user. 

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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 and using Veeva ePro.  
All  relevant  software  and  staff  training  specific  to  the  electronic  questionnaires  will  be 
provided  by  Celerion.  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, subjective effects questionnaires will 
be completed within a timeframe of ±2 minutes relative to the blood draw.  The baseline Urge 
to Smoke questionnaire will be administered approximately 10 minutes prior to the start of the 
product use session.   
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 1 through 5 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 SPA-M device will need to reset 
at 60 minutes in order to record 2 hours of topography data. Puff parameters will be recorded 
using SPA-M 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 5 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) on Days 1 to 
4, 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. 

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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. 
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 through 5, 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. 

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Serum Chemistry 1 
Urinalysis 2  
Additional Tests 
• 
Albumin 
• 
Alkaline phosphatase 
• 
Alanine aminotransferase 
• 
Aspartate 
aminotransferase 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Glucose 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid  
 
Hematology 
• 
Hematocrit 
• 
Hemoglobin 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count 
with differential 
 
• 
Bilirubin 
• 
Blood 
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Nitrite 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
• 
Serology 
o HIV 
o HBsAg 
o HCV 
• 
Serum pregnancy test 3  
• 
Serum FSH 4  
• 
Urine cotinine  
• 
Urine drug screen 
o Amphetamines 
o Cannabinoids 
o Cocaine 
o Opiates 
• 
Urine/breath alcohol 
1  Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts or 
rechecks, subjects may not have fasted for 8 hours prior to the serum chemistry sample being taken.  
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. 
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 unfavourable 
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 

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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  AE  that  in  the  view  of  either  the  Investigator  (or 
designee) or Sponsor, results in any of the following outcomes: death, a life threatening AE, 
inpatient hospitalisation or prolongation of existing hospitalisation, a persistent or significant 
incapacity  or  substantial  disruption  of  the  ability  to  conduct  normal  life  functions,  or  a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life 
threatening, or require hospitalisation may be considered serious when, based upon appropriate 
medical  judgment,  they  may  jeopardise  the  subject  and  may  require  medical  or  surgical 
intervention to prevent one of the outcomes listed in the above definition. 
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 

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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 counselling 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 
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.  This sample size chosen is comparable 
to other similar studies in the literature (e.g., Hardie et al., 2022; Phillips-Waller et al., 2021).  
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 

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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.  
7.3.1 Nicotine Pharmacokinetic Analysis 
Individual nicotine concentrations will be adjusted for baseline nicotine (“baseline-adjusted”) 
and  all  PK  parameters  will  be  calculated  based  on  the  adjusted  concentrations.  Baseline 
adjustment will be performed by subtraction of the pre-existing nicotine concentration from 
each nicotine concentration obtained after test product administration  in that period/day  for 
each subject using the following equation: 
Ct  = Ct unadjusted – [C0 · e-Kel· t1] 
where Ct is the adjusted concentration at time t, Ct unadjusted is the observed concentration at time 
t,  C0  is  the  pre-product  use  concentration  (-5  minutes),  Kel  = 
ln (2)
t½ , t½  is  2  hours  (average 
nicotine half-life), t is the actual sampling time since product administration, and t1 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, through 5, 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 

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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, T max is defined as the first 
time point with this value. 
T1/2 
Terminal elimination half-life. 
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 
through 5.  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 C
max and AUC by 
study product. Geometric LSM ratio, 95% CIs of geometric LSM ratio, and p-values will be 
provided for the study product comparisons in Cmax and AUC. The comparisons of interest will 
include each of the study products compared to each other. 
The above statistical analyses will be performed using the appropriate SAS procedure.  
Non-parametric analysis (Wilcoxon Signed Rank test) will be performed for the comparisons 
of Tmax.  
Details of the statistical methods will be provided in the SAP. 

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7.3.2 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 (VASpreuse - VASpostuse). 
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). 
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: 
• Puff count 

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• Puff duration 
• Puff volume 
• Peak puff flow rate 
• Average puff flow rate 
• 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 HTP/HHP sticks used (ad libitum product use session), the number of CCs 
smoked (Days -1 through 5), and the number of puffs (morning controlled product use session) 
will 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. 

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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 
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. 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. 

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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. 
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. 

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In  addition,  the  Sponsor’s  internal  auditors  (or  designee)  and  government  inspectors  may 
evaluate the study and must be allowed access to 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). 
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. 

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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. 
Hardie G, Gale N, McEwan M, Oscar SM, Ziviani L, Proctor CJ, Murphy J.  An abuse liability 
assessment of the glo tobacco heating product in comparison to combustible cigarettes 
and nicotine replacement therapy.  Sci Rep. 2022;12(1):14701.  
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. 
Phillips-Waller  A,  Przulj  D,  Pesola  F,  Smith  KM,  Hajek  P.    Nicotine Delivery  and  User 
Ratings of IQOS Heated Tobacco System Compared With Cigarettes, Juul, and Refillable E-
Cigarettes.  Nicotine Tob Res. 2021;23(11):1889-1894.   
 
 
 

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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 
 
 
 
 

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Appendix 2: Urge to Smoke Questionnaire 
Note:  The following question will be paired with a VAS. The VAS will be anchored with “Not 
at All” on the left and “A great deal” on the right. 
 
Please respond to the question by making a vertical mark anywhere along the horizontal line. 
 
Right now, how much would you like to smoke a cigarette? 
 
 
Not at All                                                                              A great deal 
 
 
 
 
 
 
 
 
 
 
 
 

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

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Appendix 4: Intent to Use Questionnaire 
Note:  The following question will be paired with a VAS. The VAS will be anchored with “Not 
at All” on the left and “Extremely” on the right. 
 
Please respond to each phrase by making a vertical mark anywhere along the horizontal line. 
1. If  available,  how  likely  are  you  to  buy  and  use  your  assigned  study  product  in  the 
future? 
 
 
 
 
Not at All                                                                              Extremely 
 
 
 
 
 
 
100 %